Benzimidazoles and Imidazo[1,2-a]pyridines : Biological Activities, Method of Synthesis and

Perspectives on Combination of Deuce Pharmacophore

Souleymane Coulibaly1*, Ablo Evrard1, Amit Kumar2, Drissa Sissouma1
1Laboratoire de Constitution et Réaction de la Matière, UFR Sciences des Structures de la
Matière et Technologie, Université Félix Houphouët Boigny de Cocody, 22 BP 582 Abidjan
22, Côte d’Ivoire.
2UniversitéParis Cité, CNRS, Laboratoire de Chimie et de Biochimie Pharmacologiques et
Toxicologiques, F-75006 Paris, France
*Corresponding author : [email protected]

Abstract
The N heterocyclic scaffold has generated a lot of interest among medicinal chemists. Of those
potential heterocyclic drugs, benzimidazole and imidazopyridine scaffolds are considerably
prevalent. They have gained tremendous importance over the past few decades. Both are an
important class of molecules due to their wide spectrum of biological activities and clinical
applications. Both are used in fashion design and the development of novel synthetic analogs for
various therapeutic disorders. A wide variety of their derivatives have been developed as potential
anti-cancer, anti-microbial, anti-viral, and anti-inflammatory besides other chemotherapeutic
agents. Benzimidazole core was found in the natural system displaying a wide range of
pharmaceutical properties and it gained significant attention in medicinal chemistry reported in
several full articles and communications. While imidazopyridines exhibit a vast distribution in
many pharmacologically important compounds shown by its frequent occurrence in a large number
of marketed drug formulations and drug candidates as well as in other fields such as material and
organometallic chemistry. These scaffolds are characterized as structurally potential ligands which
can bind to different receptor sites for the discovery of various immerging drugs. They act as key
pharmacophore motifs for the identification and optimization of lead structures to increase the
medicinal chemistry toolbox. The present review outlines the synthesis and the medicinal
significance of benzimidazoles and imidazopyridines for their development as lead molecules with
improved therapeutic efficiencies. Here, we cover the various design used to obtain both
heterocycles to establish a relationship between their combination to features the biological
activities.
Keywords: Benzimidazole, Imidazopyridine, Heterocyclic scaffold, Biological activity,
Pharmacophore synthesis

Introduction
Antimicrobial resistance (AMR) and worldwide increase in infections are recognized by the World
Health Organization (WHO) as urgent risk for public health. The COVID-19 crisis, the monkeypox
virus and their variants increase these risks into all domains, even worse on the world economy.
AMR infections cause approximately 700 000 deaths annually, and they are expected to become
the leading cause of death by the year 2050, especially in low- and middle-income countries.[1] To
challenge this inauspicious outcome, the WHO launched strategic objectives and one of them set
out incentivization of investments in the research of new pharmaceutical tools and medicines.[2]
This latter strategic objective concerns chemists also. For this purpose, some intensification of
research around nitrogen-fused azoles known as lead compound in the literature, pushed our
curiosity and sum up it in this review. They have a wide range of applications in medicinal
chemistry. Although benzimidazole and imidazopyridine are structurally different, their
pharmacological properties are quite similar. Both heterocycles and their derivatives as well as
preparative methods for basic derivatives are here presented.
This review article will focus on presenting the biological activities of benzimidazoles and their
synthetic methods. Also imidazopyridine compounds are presented in the same way before their
combination prospects are presented.
Indeed benzimidazole derivatives are heterobicyclic aromatic compounds resulting from the
adhesion between benzene and imidazole. Due to their isostructural pharmacophore, molecules
possessing in their basic structures the benzimidazole scaffold, have revealed a panoply of
biological activities and among them we can mention the anticancer [3], acetylcholinesterase [4],
antimicrobial [5], anti-inflammatory [6] analgesic [7], antiviral [8] anti-protozoan [9], antimalarial
[10] and anti-leishmanial [11] activities. Benzimidazole scaffold are present in the structure of
some commercial drugs such as Thiabendazole, Mebendazole, Luxabendazole, Triclabendazole,
Albendazole and Oxibendazole (Figure 1).
Naturally, the wide applications and uses in a variety of fields have led to several synthetic routes
developed for the production of imidazo[1,2-a]pyridines. In recent years, this has remained
progress and innovation in the synthesis of imidazos[1,2-a]pyridines using several interesting
pathways, such as multi-component reactions, tandem sequences and C-H functionalization
catalyzed by transition metals. These methods provide ease of obtaining imidazos[1,2-a]pyridines
from simple and readily available precursors.
This has led to many discoveries concerning their biological properties including antimicrobial,
anti-inflammatory, anticancer and antiparasitic properties, [12] thus dedicating this scaffold for
molecular and biological explorations. The imidazo[1,2-a]pyridine core is also present in the
structure of many drugs, which have good properties on the central nervous system. [13] Such is
the case with Zolpidem, [14] a drug used to treat insomnia. Alpidem, Nécopidem and Saripidem,
are three active ingredients used as an anxiolytic agent. [13] However, Alpidem was withdrawn
from the market because of its toxicity. Olprinone, [15] is used in the treatment of acute heart
failure. Zolimidine is active on Escherichia Coli (E.Coli) so used in the treatment of peptic ulcers.
[16] An optically active drug with the imidazopyridine motif in its skeleton, GSK812397 is
intended for the treatment of HIV infection. [16]

Figure 1: some drugs based on the benzimidazole scaffold

I. Benzimidazoles and Derivatives : Biological Activities and Synthesis Methods
1. Biological Activities of benzimidazole derivatives
a. Antimicrobial properties
Several benzimidazole derivatives are described in the literature and, have shown excellent
antimicrobial activity.[17-18] The work of Ramya V. Shingalapur et al. [19] provided access to
benzimidazole molecules with interesting antimicrobial activities. In this work, the derivatives of
2-styryl-1H-benzimidazole (Figure 2-A) showed good antimicrobial activity in vitro on two Gram-
positive strains (Staphylococcus aureus ATCC25923 and Enterococcus faecalis ATCC29212) and
four Gram-negative strains (Klebsiella pneumoniae ATCC13883, Escherichia coli ATCC-25922,
Albicans candida ATCC10145 and Asperigillus fumigatus). All of the evaluated compounds
showed good antibacterial properties with Minimum Inhibitory Concentrations (MICs) between 16
and 1 µg/mL. Of these compounds, 3-[2-(5-bromo-1H-benzimidazol-2-yl)-vinyl]- phenol showed
the best activity on all strains with MIC values between 1 µg/mL and 4 µg/mL (Figure 2-A).
Muayed Redayan et al.[20] have shown that 5-(((1H-benzimidazol-2-yl)methyl)thio)-1,3,4-
thiadiazol-2-amine derivatives (Figure 2-B) present interesting antibacterial activities comparable
to existing standard antibiotics such as Ampicillin and Ciprofloxacin. During this work, the
synthesized compounds were screened for their antibacterial activities against Gram-negative (E.
coli, P. aeruginosa) and Gram-positive (B. subtilis, S. aureus) bacteria. Most of these derivatives
showed good antibacterial activity against all strains.
Amino-(2-(4-(((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)amino)phenyl)-1H-benzimidazol-5yl)
methaiminium (Figure 2-C) was evaluated for antibacterial activity in vitro on two Gram-positive
strains (S. Aureus ATCC 25923 and Enterococcus Fasalis (ATCC 29212) and five Gram-negative
strains (E. coli ATCC 25925, K. pneumoniae ATCC 700803, P. Aeruginosa ATCC 27853 and
Acinetobacter Baumannii ATCC 19606). The results of the antibacterial activity of this
benzimidazole-derived compound showed very good properties on Gram-positive strains
compared to antibiotics such as Ceftazidime, ciprofloxacin, ampicillin and gentamicin.[21]
Figure 2: Compound with good antimicrobial activities-A. 2-styryl-1H-benzimidazole derivatives, B. 5-
(((1H-benzimidazol-2-yl)methyl)thio)-1,3,4-thiadiazol-2-amine derivatives, C. Amino-(2-(4-(((1-benzyl-
1H-1,2,3-triazol-4-yl)methyl)amino)phenyl)-1H-benzimidazol-5yl) methaiminium.
b. Antifungal properties of benzimidazole derivatives
The antifungal activity of the benzimidazole scaffold was first reported in 1944 by Woolley[22],
[23] through chlormidazole or 1-(4-chlorobenzyl)-2-methyl-1H-benzimidazole. It became a fairly
well-known activity of benzimidazole that has generated behind a lot of research.
Mishra et al. [24] showed that the 2-chloromethyl-5H-methylbenzimidazole derivatives
substituted in the -2 position by 5-mercapto-l,3,4-oxadiazole or 4-amino-5-mercapto-1,2,4-triazole
showed good antifungal activity on Rhizoctonia solani and Helminthosporium oryzae fungi.
In the same vein, antifungal activities of the benzimidazole core were also highlighted by Gulgun
Ayhan et al.[25]. For example, in vitro testing of Candida albicans (C.albicans), Candida glabrata
(C.glabrata) and Candida krusei (C. krusei) strains showed that 5-amino-2-(p-fluorophenyl)-1-
propylbenzimidazole and 2-(p-fluorophenyl)-5-nitro-1-propylbenzimidazole (Figure 3) are potent
on these strains with a large antifungal activity spectrum. These benzimidazole compounds were
more active on C. albicans with a MIC of 12.5 g/mL compared to the reference antibiotic
Fluconazole. For the C. Krusei strain, compounds such as 5-amino-2-(p-fluorophenyl)-1-
propylbenzimidazole, 2-(p-fluorophenyl)-5-nitro-1-propylbenzimidazole and N-[2-(p-
fluorophenyl)-1-propyl-benzimidazol-5yl]-N-(p-chlorophenyl)-thiourea were more effective with
MICs of 5 to 6.25 g/mL.
Finally, Göker et al.[26] also evaluated the in vitro antifungal activity of 5-carbonitrile
benzimidazole. This compound was very active on strains such as C. albicans, C. grabrata, C.
krusei and C. parapsilosis with an activity similar to that of Fluconazole.
N N
F F
O2N N H2N N

Figure 3: 2-(4-fluorophényl)-1-propyl-1H-benzimidazole derivatives with antifungal activities.

c. Anticancer properties of benzimidazole derivatives
The anticancer activity of benzimidazole derivatives has been described in several research studies
[27], [28]. Among these works, we will mention those carried out by Hanan Refaat[29] on the
determination of the anticancer activity of 2-substitued benzimidazole derivatives. The cytotoxicity
of these benzimidazole compounds was evaluated on three cell lines representing three common
forms of human cancer, namely a human hepatocellular carcinoma cell line (HePG2), a human
breast adenocarcinoma cell line (MCF7) and a colon carcinoma cell line (HCT 116). In this work,
they were able to show that the position-2 substituted benzimidazole derivatives have anticancer
activity against all tumor cell lines with an IC50 of less than 10 mg/mL. Generally, all compounds
tested tended to be more active against HePG2 and other tumor cell lines. 5-chloro-2-[(4-
fluorobenzylidene)cyanomethyl]benzimidazole and 2-(4-amino-3-benzyl-2-thioxo-2,3-
dihydrothiazol-5-yl)benzimidazole-5-carboxylic acid showed the most increased activity against
HePG2 while 2-[(cyclohexylidene)cyanomethyl]benzimidazole-5-carboxylic, 5-chloro-2-[(3-
phenyl-4-oxothiazolidin-2-ylidene)cyano-methyl]benzimidazole and 2-[3-(4-bromophenyl)-4-(2-
methoxyphenylthiazol-2-ylidene)cyanomethyl]benzimidazole-5-carboxylic acid were most active
against MCF7 (Figure 4-A).
Salahuddin et al.[30] also synthesized derivatives of 2-(naphthalen-1-ylmethyl/naphthalen-2-
yloxymethyl)-1-[5-(substituephenyl)-[1,3,4]oxadiazol-2-ylmethyl]-1H-benzimidazole. In this
work, they showed that 2-naphthalen-1-ylmethyl-1-[5-(4-nitro-phenyl)-[1,3,4]oxadiazol-2-
ylmethyl]-1H-benzimidazole (Figure 4-B) had good anticancer activity on certain lines such as
leukemia, melanoma, lung cancers, colon, central nervous system, ovary, kidney, prostate and
breast at a single high dose around 10-5 M.
The2-(benzimidazol-2-yl)methylthio)-4-(substituted)-6-phenylpyrimidine-5-carbonitrile
derivatives synthesized by Abdel-Mohsen et al.[31] were evaluated for their anticancer activities
against twelve cancer cell lines KB, SKOV-3, SF-268, NCI-H460, RKOP27, HL60, U937, K562,
G361, SK-MEL-28, GOTO and NB-1. All of these benzimidazole derivatives evaluated in vitro
showed good anticancer activity on the various cancer lines.

Figure 4 : Anticancer properties possessed by A. Benzimidazole derivatives against HEPG2 and

MCF-7, B. 2-naphthalen-1-ylmethyl-1-[5-(4-nitro-phenyl)-[1,3,4]oxadiazol-2-ylmethyl]-1H-
benzimidazole.
d. Anthelminthic properties of benzimidazole derivatives
The anthelminthic activity is one of the main properties recognized for benzimidazole derivatives.
[32]–[34] Some of these compounds are used to fight parasitic diseases such as helminthiases. This
is the case for Flubendazole, Mebendazole, Albendazole and Thiabendazole. Also, new derivatives
of 2-((1H-benzimidazol-2-yl)thio)-1-(piperazin-1-yl)ethyan-1-one were synthesized (Figure 5-
compound 3) by Mavrova et al.[35] showed strong anthelminthic activity in vitro against
Trichinella spiralis. This activity was higher than that observed on the same germ when using a
drug such as Albendazole.
Ramesh Sawant et al.[36] also showed that the new 2-phenyl benzimidazole-1-acetamide
derivatives possess anthelmintic activities. Thus, anthelminthic tests have been carried out using
the derivatives of 2-(((1H-benzimidazol-2-yl)methyl)thio)-5-phenyl-1,3,4-thiadiazole (Figure 5-
compound 5) on Pheretima Posthuma which is an authenticated worm at the University of SSGM
(Shri Sadguru Gangageer Maharaj Sciences) in India.
This work revealed that these derivatives at the -2 position have an excellent anthelmintic activity.
 Figure 5: Benzimidazole derivatives with anthelminthic derivatives
e. Antiviral properties of benzimidazole derivatives
Several research studies have shown that benzimidazole derivatives substituted in position-1 or -2
have good antiviral properties too.[37-38] Erik De Clercq and Laura Garuti[39] synthesized
benzimidazole derivatives substituted in position-1 by sulfonyl. Subsequently, the antiviral activity
of these derivatives was evaluated against Human cytomegalovirus and Varicella-zoster virus.
Among evaluated compounds, the 5,6-dichloro-1-(isopropylsulfonyl)-2-(2-(pyridin-2-yl)ethyl)-
2,3-dihydro-1H-benzimidazole (Figure 6.compound 1) showed the best antiviral activity against
the different strains with an IC50 of 1.6 to 1.1 mg/mL. In the same study, some benzimidazole-
coumarin derivatives have shown excellent activities against the hepatitis C virus with IC50
between 3.4 μM and 4.1 μM.
Antiviral activity was also shown through the work of Deepika Sharma et al.[40] on the 4-
nitrophenyl-2-phenyl-1H-benzoimidazol-1-ylmethanone derivatives. The demonstration of the
antiviral properties of these derivatives was done. In addition, these authors showed that 4-
nitrophenyl-2-(4-chlorophenyl)-1H-benzimidazol-1-ylmethanone and 2-bromophenyl-2-phenyl-
1H-benzimidazol-1-ylmethanone (Figure 6-compounds 2 and 3) were likely good candidates for
the manufacture of an antiviral vaccine.

Figure 6 : Benzimidazoles derivatives with antiviral activities

 f. Anti-inflammatory properties of benzimidazole derivatives
The anti-inflammatory activity of benzimidazole derivatives has been reported through several
research studies.[41-42] However, the benzimidazole molecules (Figure 7-A) discussed in this
section are those that have shown good anti-inflammatory properties in the work of Monika Gaba
et al.[43]. Indeed, in this work, the anti-inflammatory activity of the molecules was compared with
those of reference drugs such as Indomethacin, Nimesulide, Ibuprofen and Diclofenac. These
benzimidazole derivatives showed activities above certain reference drugs.
Kavitha Achar et al.[44] also highlighted the anti-inflammatory activity of benzimidazole
derivatives. These authors showed that some derivatives of N-((1H-benzimidazol-2-
yl)methyl)aniline (Figure 7-B) had very good anti-inflammatory activities. This study was
conducted using Nimesulide as a reference drug.

Figure 7 : A. Benzimidazole derivatives ref.43 B. N-((1H-benzimidazol-2-yl)methyl)aniline derivatives

with good anti-inflammatory activites ref.44
g. Anti-leukemia properties of benzimidazole derivatives
This biological property of benzimidazole derivatives was revealed through the work of Thimme
Gowda et al.[45] on the synthesis and evaluation of the anti-leukemia activity of new 1-(4-
methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives. The screening of twenty-two
(22) new synthesized compounds showed that methyl 2-(4-fluoro-3-nitrophenyl)-1-(4-
methoxyphenyl)-1H-benzimidazole-5-carboxylate (Figure I-14) was a good anti-leukemic
properties. This molecule inhibits human leukemia cells with an IC50 of 3 µM.
 Figure 8: Structure of methyl 2-(4-fluoro-3-nitrophenyl)-1-(4-methoxyphenethyl)-1H-benzimidazole-5-
carboxylate
h. Anti-plasmodial properties of benzimidazole derivatives
In our group, Ouattara Mahama et al.[46] demonstrated the antiplasmodial behavior of
benzimidazole through the synthesis and evaluation of benzimidazolyl-chalcone derivatives
(Figure 9-compounds 1, 2). In their work, anti-plasmodial screening of Plasmodium Falciparum
(P. falciparum) chloroquino-sensitive and chloroquinoresistant isolates has shown that
benzimidazolyl-chalcones are excellent antiplasmodial pharmacophores. Indeed, 1-(fluoro-1H-
benzimidazol-2-yl)-3-phenylprop-2-en-1-one (compound 1) with an IC50 value of 5.63 μM showed
the best profile on the chloroquino-sensitive P. falciparum isolate.
Bandyopadhyay et al.[47] synthesized and evaluated the antimalarial activity of benzimidazole
phosphorylated derivatives against Albopictus and Culex Quinquefasciatus mosquitoes. They
showed that dimethyl-(4-(1H-benzimidazol-2-yl)phenyl)phosphoramidate (Figure 9-compound 3)
was more potent on Albopictus and C. Quinquefasciatus.
Camacho et al.[48] synthesized benzimidazole derivatives to test in vitro antimalarial activities to
inhibit the formation of β-hematic (IβHS) responsible for hemoglobin hydrolysis. But also, in vivo
study was done on a rodent like the Plasmodium Berghei. Among these tested molecules, 2-(5-
nitrofuran-2-yl)-3H-benzimidazole-5-carboxylic acid (Figure 9-compound 4) showed the most
inhibition of β-hematic formation, meaning the best antimalarial activity.
Divatia et al.[49] synthesized thiosemicarbazones supported by the benzimidazole scaffold and
evaluated their antimalarial activity in vitro against P. falciparum in comparison to chloroquine
and quinine as reference molecules. Some of the compounds synthesized include (E)-2-[1-(5-
chloro-1H-benzimidazol-2-yl)ethylidene]-N-(benzoyl)hydrazine carbothioamine, (E)-2-[1-(5-
chloro-1H-benzimidazol-2-yl)ethylidene]-N-(4-fluorophenyl)hydrazine carbothioamine and (E)-
2-2-[1-(5-chloro-1H-benzimidazol-2-yl)ethylidene]-N-(4-iodophenyl)hydrazine carbothioamine
have shown excellent antimalarial activities. Indeed, the structure-activity relationship study
conducted suggests that compounds with mesomeric electron donor groups (EDG) such as halogen
had excellent antimalarial activity (Figure 9-compound 5).
The work conducted by Toro et al.[50] on the synthesis and evaluation of the anti-plasmodial
activity of benzimidazole derivatives. The anti-plasmodial tests were carried out in vitro against P.
falciparum on compounds such as 2-ferrocenyl-benzimidazole and N-ferrocenylmethyl-2-
ferrocenyl-benzimidazole (Figure 9-compound 6). These molecules showed good anti-plasmodial
properties with IC50 between 10.4 to26.5 μM.

Figure 9 : Benzimidazole derivatives with antiplasmodial activity

i. Antioxidant properties of benzimidazole derivatives
Sarika Saini et al.[51] showed that the 2-methyl-1H-benzimidazole has an interesting
antioxidant activity. Using 2,2-diphenyl 1-picrylhydrazyl (DDPH), they were able to show that 2-
methyl-1H-benzimidazole (Figure 10.A) had a higher antioxidant activity than ascorbic acid at
higher concentrations.
The antioxidant activity of benzimidazole was demonstrated in the work of Dvornikova et al. [52].
They evaluated this activity with 2-hydroxylphenyl benzimidazole derivatives (Figure 10.B) using
the in vitro method and compared it to a few refence molecules. It was shown that the compounds
possessing the phenol group with substituents such as isobornyl and tert-butyl showed a much
higher antioxidant activity than the references.
R. A. Sabrina et al. [53] evaluated the antioxidant activity of some 5-nitrobenzimidazole
derivatives (Figure 10.C) in their work. Indeed, they proved that all the 5-nitro-2-substituted
benzimidazole derivatives that they synthesized had an antioxidant activity far superior to the
reference molecule with minimum inhibitory concentrations between 3.17 to 7.59 μg/mL.

Figure 10: A. 2-methyl-1H-benzimidazole B. 2-hydroxylphenyl benzimidazole derivatives C. 5-

nitrobenzimidazole derivatives
2. Methods for Benzimidazole and derivatives synthesis.
Benzimidazole is one of the oldest nitrogen heterocycles. It was first synthesized by Codebreaker
in 1872 and then later repeated in 1878 by Ladenburg and Wundt [54]. Since then, several synthetic
methods have been developed to obtain functionalized benzimidazole mainly at positions -1, -2, -
3 and -5.
a. The Phillips methods
In 1928, Phillipssynthesized 2-substituted benzimidazole derivatives by reacting
orthophenylenediamine (OPDA) with various organic acids in 4N hydrochloric acid under reflux
for 30 to 40 minutes [55]. These 2-substituted benzimidazole derivatives were obtained with yields
ranging from 50 to 70 % (Figure 11.A). This method is the most used to obtain benzimidazole
derivatives. Carboxylic acid derivatives can be replaced by mercaptoacetic acid. El-Gohary et
al.[56] were able to synthesize 2-mercaptomethyl-1H-benzimidazole by condensation of
mercaptoacetic acid with OPDA under the same conditions as in the Phillips reaction (Figure
11.B).By condensing OPDA with benzoic acid derivatives, Odame et al.[57] synthesized
substituted benzimidazole derivatives at the 2-position. This reaction occurred in toluene at reflux
for 6 hours in the presence of polyphosphoric acid (PPA) (Figure 11.C). Saini et al.[51] did the
same kind of work, condensing OPDA with 90 % acetic acid at a temperature of 100°C for 2 hours.
After treatment of the reaction medium, they obtained 2-methyl-1H-benzimidazole with a yield of
72 % (Figure 11.D).

Figure 11: A. Benzimidazole synthesis by Phillips method. B. Synthesis of 2-

mercaptomethylbenzimidazole. C. Synthesis of 2-m-tolyl-1H-benzimidazole according to Odame et al. D.
Synthesis of 2-methyl-1H-benzimidazole according to Saini et al.
b. Synthesis method from orthophenylenediamine and aldehydes
The synthesis of benzimidazole from the condensation between OPDA and aldehydes are
commonly the most described in the literature. The reactions of obtaining benzimidazole
derivatives from OPDA and aldehydes using hydrogen peroxide (H2O2) and hydrochloric acid
(HCl) solution at 100°C (Figure 12.A) have been described by Kiumars Bahrami et al.[58]. This
method made possible to obtain benzimidazole derivatives substituted in position -2 by aryl
groupswith yields ranging from 85 to 96 %. Shortly thereafter, same authors repeated the process
at room temperature this time, replacing the water by acetonitrile[59]. This method has been used
in other works. Hydrochloric acid (HCl) was replaced by cerium ammonium nitrate (CAN) and
resulted in the production of 2-aryl-1H-benzimidazole with yields between 92 and 97 % (Figure
12.B) [60].
In another study, Li-Hua Du et al.[61] also synthesized 2-substituted benzimidazole derivatives.
They condensed OPDA derivatives with benzaldehyde derivatives in various organic solvents in
the presence of iodobenzenediacetate (IBD) as an oxidizing agent. This reaction took place at room
temperature for 3 to 5 min to obtain substituted benzimidazole at the -2 position with yields ranging
from 68 to 98 %. The best yields were obtained by using dioxane as a reaction solvent (Figure
12.C).Karthikeyan et al.[62] synthesized derivatives of 2-aryl-1H-benzimidazole substituted in
position-5 by the carboxylic acid function (Figure 12.D). They put in reaction 3,4-diamimo benzoic
acid or 3,4-diamino ethyl benzoate with benzaldehyde derivatives in N,N-dimethyl acetamide
(DMAc) at 100°C for 6 to 12 h in the presence of sodium metabisulfite (Na2S2O5).
The condensation of OPDA with furan carbaldehyde derivatives in ethanol at room temperature
resulted in a series of benzimidazole substituted in the -2 position by furan[63] with a yield of 90
% for two hours. This reaction was catalyzed by copper II associated with a Schiff base (Figure
12.E).The synthesis of 2-alkyl-1H-benzimidazoles from OPDA and aldehydes was also performed
by Alloum et al.[64]. This synthesis method involved the reaction of various aldehyde derivatives
with OPDA on a solid base (silica SiO2 treated with thionyl chloride SOCl2) in DCM at room
temperature (Figure 12.F). This reaction occurs through the formation of imine intermediate,
followed by aromatization by sulfur dioxide formed in situ to lead to the substituted benzimidazole
derivatives in position-2.
Figure 12: A.Synthesis of 2-aryl-1H-benzimidazole according to Kiumars Bahrami et al. B. synthesis of
2-aryl-1H-benzimidazole. C. Synthesis of the derivatives of 2-phenyl-1H-benzimidazole according to Li-
Hua Du et al. D. Synthesis of derivatives of 2-aryl-1H-benzimidazole according to Karthikeyan et al. E.
Synthesis of 2-substituted benzimidazole catalyzed by a Schiff base. F. 2-substituted benzimidazole
synthesis according to Alloum et al.

c. Synthesis method of benzimidazole derivatives from aniline derivatives

The synthesis of benzimidazole from aniline and aldehyde derivatives is most often catalyzed by
transition metals. Some of these reactions are carried out in the presence of catalysts which possess
oxidation or reduction properties. The work of Devuapally Mehsesh et al.[65] present the
synthesis of benzimidazole derivatives by reacting aniline with primary amines (benzylamine) in
the presence of sodium azidure (NaN3) and copper II used as catalyst in dimethylsulfoxide (DMSO)
at a moderate temperature. To improve the efficiency of this method, ter-butyl hydroperoxide
(THBP) and acetic acid derivatives were added to the reaction medium. This reaction worked in
10 h in the range of 52 to 79 % yield (Figure 13.A). In the same work, benzylamine derivatives
were replaced by benzylic alcohol derivatives. They obtain benzimidazoles with yields ranging
from 35 to 62 %, but with a longer reaction time than that of benzylamines (Figure 13.B).
Yong Kim et al. [66] obtained benzimidazole derivatives by reacting the 2-halogeno anilines with
the aromatic aldehydes for 12 h under reflux of dimethyl sulfoxide (DMSO).They were synthesized
with yields ranging from 44 % to 98 %. The best yields were obtained with 2-iodoaniline in the
presence of ligands such as 1,2-Dimethylethylenediamine (DMEDA) and
Tetramethylethylenediamine (TMEDA) (Figure 13.C).Thanh N'guyen et al. [67] synthesized a 2-
substituted benzimidazole variety without using an organic solvent. They condensed 2-nitroaniline
with benzylamines in the presence of iron chloride for 24 h at 120°C. The 2-substituted
benzimidazole derivatives were obtained with yields between 58 and 92 % (Figure 13.D).The
production of benzimidazole derivatives was first described in 1872 by Hobrecker [68]. This
method is one of the oldest methods to access to the benzimidazole scaffold. After a reduction of
2-nitro-5-methylacetanilide, an intramolecular cyclization followed and yielded to 2,5-dimethyl-
1H-benzimidazole (Figure 13.E).
Figure 13: synthesis of the derivatives of 2-phenyl-1H-benzimidazole using benzylamine according to
Devuapally Mehsesh et al. B. synthesis of the derivatives of 2-phenyl-1H-benzimidazole using
phenylmethanol according to Devuapally Mehsesh et al. C. synthesis of the derivatives of 2-phenyl
benzimidazole according to Yong Kim et al. D. synthesis of benzimidazole-2-substituted derivatives
according to Thanh N'guyen . E. Hobrecker synthesis of 2-methyl-1H-benzimidazole

d. Method of synthesis from orthophenylenediamine (OPDA) derivatives and N-

substituted formamide and amidinium salts
Deepak Nale et al. [69] synthesized derivatives of N-alkylbenzimidazole by reacting a variety of
OPDA with formamide N-substituted with zinc diacetate (Zn(OAc)2) as a catalyst in the presence
of poly(methylhydrosiloxane) (PMHS) for 18 h at 120°C (Figure 14.A).In our group, we worked
also on the synthesis of benzimidazole scaffold. We developed a method by Sissouma Drissa et al.
[70], [71] in which, a thioalkyl or thioaryl group of amidinium salts was introduced to the -3
position. The condensation of these amidinium salts with OPDA in dichloromethane provided
access to the 2-thioalkylbenzimidazole and 1H-benzimidazole derivatives (Figure 14.B).

Figure 14: A. Synthesis of N-substituted benzimidazole derivatives according to Deepak Nale. B.

Synthesis of benzimidazole and 2-thiobenzimidazole according to Sissouma et al

e. Synthesis method from benzodiazepines

We also developed another method in a work done by Timotou et al. [71]. We were able to
synthesize benzimidazole derivatives by cyclic regression of benzodiazepines. This method
consisted of treating chalcones in an alkaline medium to access benzodiazepine derivatives. Then,
these benzodiazepines were treated under DMF reflux in the presence of potassium carbonate
(K2CO3) for 24 h to obtain the benzimidazole derivatives. Camara et al. [72] repeated this method
by treating benzodiazepine formed either in acid or basic medium under DMF reflux for 2 h. The
yields have been improved in acid medium, between 60 and 80%, while in basic medium, the yields
varied between 40 and 60% (Figure 15).

Figure 15: synthesis of derivatives of 2-aryl benzimidazole according to Camara et al.

f. Method of synthesis from OPDA derivatives and other reagents
By reacting OPDA with ethyl acetoacetate under reflux of xylene for 6 h, Denise Mondieig et al.
[73] were able to synthesize benzimidazole by introducing the isopropenyl group into position-1.
Thus, they obtained N-isopropenylbenzimidazolone with a yield of 70 % (Figure 16.A).

Figure 16: A.Synthesis of N-alkylbenzimidazolone derivatives according to Denise Mondieig et al. B.

synthesis of N-alkylbenzimidazolone derivatives according to Vakhid Mamedovet et al. C. synthesis of
derivatives of 2-aminobenzimidazole Leonard et al. D. Albendazole synthesis method. E. Synthesis of 1,3-
bis(1H-benzimidazol-2-yl)benzene according to Yang et al.
The same method was used by Vakhid Mamedov et al. [74] to describe the synthesis of
benzimidazolone derivatives through the formation of a reactive intermediate, benzodiazopinone.
Once isolated, it was treated under reflux of methoxyethanol, allowing a rearrangement to lead to
benzimidazolone derivatives with a yield of 60% (Figure 16.B). The 2-amino-5-
chlorobenzimidazole was synthesized by Leonard et al. [75] by a reaction between p-chloro-OPDA
and cyanogen bromide (BrCN). This reaction was carried out in the presence of hydrochloric acid
in an EtOH/H2O mixture at 70 °C. Thus, after cooling, the reaction medium was neutralized with
a sodium hydroxide solution to give 2-amino-5 chlorobenzimidazole with a yield of 73 % (Figure
16.C). By applying the Phillips method to iminoester [76] and thiocarbamate [77] acid derivatives,
benzimidazole derivatives were synthesized by reacting thiocarbamates with OPDA derivatives in
an aqueous solution of sodium hydroxyde. This reaction resulted in Albendazole analogues after
the removal of the thiol group and ammonia (Figure 16.D). Yang et al.[78] synthesized
bisbenzimidazole through a condensation reaction of an excess of OPDA with 1,3-
bis(dibromomethyl)benzene to produce 1,3-bis(1H-benzimidazol-2-yl)benzene with a yield of
87% (Figure 16.E).
g.Method of synthesis from derivatives of orthophenylenediamine and carbon
disulfide
The synthesis of the derivatives of 2-mercapto-1H-benzimidazole was carried out according to the
method described by Van Allan et al.[79].
Thus, the action of carbon disulfide on OPDA derivatives in dimethylformamide (DMF) under
magnetic agitation for 24 h leads, after addition of water into the reaction mixture to the formation
of 2-mercapto-1H-benzimidazoles (Figure 17.A). By replacing carbon disulfide with urea,
Bhanage et al. [78] synthesized 1,3-dihydrobenzimidazol-2-one. For this purpose, they condensed
OPDA with urea in DMF at 150°C. They obtain 1,3-dihydrobenzimidazol-2-one with a 98% yield
(Figure 17.B).
Figure 17: A. Synthesis of mercapto-1H-benzimidazole according to Van Allan et al. B.Synthesis of 1,3-
dihydrobenzimidazol-2-one according to Bhanage et al.

II. Imidazo[1,2-a]pyridines : Biological Activities and Synthesis Methods

Imidazo[1,2-a]pyridines are aromatic bis-heterocyclic compounds resulting from the addition of
an a-type fusion of pyridine and imidazole rings with angular nitrogen connecting the two cyles.
Depending on the position of the pyrrolic nitrogen and also the angular one, three isomers are
obatined (Figure 18.A) Imidazopyridine is an important pharmacophore because it is widely used
in many biologically active compounds. A multitude of research works has been donearound this
bis-heterocyclic, and even some drugs came from those researchs.
 Figure 18 : A.Three imidazopyridine isomers B. Few drugs based on Imidazopyridine scaffold
II-1. Biological activities of the imidazopyridine scaffold
According to the pharmacomodulations undertaken on the different positions of the imidazo[1,2-
a]pyridine moiety, in particular on the pyrrolic core, interesting biological activities are obtained.
These have been described in the literature. Furthermore, the most common biological activities
will be mentioned.
a. Imidazo[1,2-a]pyridine as antimicrobial agent
The antibacterial activity of imidazo[1,2-a]pyridine derivatives has been proven by Pushpalatha
Budumuru et al.[80] on various strains, including in vitro antimicrobial activities against E. coli
(ATCC-25922), S.aureus (ATCC-9144), K. pneumoniae (ATCC-13883) and B. subtilis (ATCC-
6051). The study was performed against the reference drug Streptomycin and the inhibition zones
were calculated. Thus all their synthesized compounds, at a concentration of 1000 μg/mL, showed
a promising inhibition against the various microbial pathogens tested. Of the compounds
synthesized (Figure 19), compounds 1a, 1c, 1e and 1g containing benzyl, 4-fluorobenzyl, 4-
methylbenzyl and 4-methoxybenzyl substituents demonstrated inhibition against all pathogens.
The 9c and 9e compounds with 4-fluorobenzyl and 4-methylbenzyl as their respective substituents
showed moderate activity against E. coli. In addition, compounds 9e, 9g and 9j containing 4-
methylbenzyl, 4-methoxybenzyl and 3,4,5-triflouromethybenzyl substitutes showed inhibition
against K. pneumonia. All synthesized compounds showed less activity against S. aureus.
Similarly, no activity was recorded by the compounds 1a, 1b, 1d, 1g, 1h, 1i and 1l at their lowest
concentrations (500 μg/mL) tested against K.pneumoniae.
In addition, the work of Kai et al.[81] has led to the antimycobacterium (Tuberculosis bacteria)
activity of new imidazo[1,2-a]pyridine-3-carboxamide derivatives.Thus, they proved that
compounds with donor groups on the phenyl nucleus, had excellent antimycobacterial activity
against two MTB H37RV drugs and drug-resistant clinical isolates with inhibition concentrations
between 0.0041 to 2.64 µM.

Figure 19 : Imidazo[1,2-a]pyridine derivatives by Pushpalatha Budumuru et al. against E. coli (ATCC-

25922), S.aureus (ATCC-9144), K. pneumoniae (ATCC-13883) and B. subtilis (ATCC-6051)
b. Imidazo[1,2-a]pyridine as an anticancer agent
Various in vitro studies have shown that several imidazopyridine-based compounds have potential
therapeutic effects against different cancer cell lines. These include breast, liver, colon, brain, lung
and kidney cancers. [82] The anticancer effects of these compounds are primarily the result of their
inhibitory effects on different molecular mechanisms. Namely, PI3K/ AKT, CENP-E, IGF-1R,
CDK, inhibition of tubulin polymerization and C-encounter inhibition.
Similarly, Gui-Ting Song et al. [83] initiated modulations around the imidazopyridine core
conferring anticancer activities. Thus the modulations at the -2 position by phenyl derivatives and
at the -3 position by quinoxaline and quinoxalone derivatives led to imidazo[1,2-a]pyridine
derivatives that inhibited tumour cell proliferation. This is the case with compounds 2 and 3 at the
20 μM concentration, which over 48 hours showed a very high inhibition rate on HCT-116, HeLa
and MCF-7 cells.
The anticancer activity of the imidazopyridine nucleus was also demonstrated by Nurit Dahan-
Farkas et al.[84] on colon cancer. For this purpose, the 6-substituted imidazo[1,2-a]pyridines
compounds they synthesized were evaluated for their anticancer activities on the HT-29 and Caco-
2 cell lines. Thus, all compounds bearing a 6-position nitro-substituent (NO2) in the
imidazopyridine nucleus and all those bearing a 2,5-dihydroxyphenyl substituent attached to
imidazopyridine, showed little reduction in cell growth of colon cancer cell line. In contrast,
imidazopyridine derivatives containing the protected hydroxyl group (such as OMe, compound 4)
and the nitrogen-substituted phenyl group (compound 5) generally performed well by reducing the
cell viability tested by more than 50% with concentration values inhibitions well above 50 µM.

Figure 20 : Modulations around the imidazopyridine core conferring anticancer activities. Compound 2, 3
(ref 83) and 3,4 (ref 84)
c. Imidazo[1,2-a]pyridine as an antiplasmodial
The antiplasmodial activity of the imidazo[1,2-a]pyridine motif was demonstrated in our group and
published by Mahama Ouattara et al.[85] We designed by juxtaposition of anti-infectious moieties,
a series of hybrid imidazopyridinyl-arylpropenone compounds and performed the anti-plasmodial
screening of five imidazopyridinyl-arylpropenone derivatives using the Rieckmann method,
followed by the determination of HRP2 antigen production by ELISA on chloroquino-sensitive
and chloroquino-resistant P. falciparum isolates. The analysis of antiplasmodial activities was
translated into an inhibitory concentration of 50 (IC50) and expressed in micromoles (mM). Their
results on the chloroquino-sensitive Plasmodium falciparum isolates reveal that the 6k and 6y
compounds (IC50 =35.92 and 24.08 mM respectively) have moderate antiplasmodial activity, while
the other three (5a, 5n and 5q) possess have very good antiplasmodial activities, between 8.65 and
6.23 mM. Five imidazopyridinyl-arylpropenone compounds (6a, 6k, 6n,6q and 6w) were found to
be very active on P. falciparum chloroquino-resistant isolates.

Figure 21: 3-(phenyl)-1-(2-methylH-imidazo[1,2-a]pyridin-3-yl)prop-2-en-1-one derivatives against

Plasmodium Falciparum

d. Imidazo[1,2-a]pyridine as an antiviral agent

The antiviral activity of the imidazopyridine scaffold has been demonstrated by researchers since
the 1990s. Thus, Chafiq Hamdouchi et al.[86] was able to show that some derivatives of 2-amino-
3-substituted-6-[-1-phenyl-2- (N-methylcarbamoyl) vinyl] imidazo [1,2-a]pyridines (compounds
7, Figure 22) had strong anti-rhinovirus activity and no obvious cell toxicity.
Alain Gueiffier[87] et al. performed chemical modifications at the position-3 of the imidazo [1,2-
a]pyridine ring. This improved the therapeutic index of this new class of antiviral agents. Thus,
antiviral as says on the series of their molecule have shown that some of their compounds
(compounds 8 and 9) appear to be as the most potent and selective inhibitors of CMV and VZV
compared with three reference drugs such as ganciclovir, acyclovir and brivudin.
Several sugar-substituted imidazopyridine derivatives showed significant activity against human
cytomegalovirus. Indeed, the evaluation of their activities against two selected herpes and
cytotoxicity studies demonstrated that racemic 2,6-dichloro-3- (β-D / L-
Erythrofuranofuranosyl)imidazo[1,2-a] Pyridine and 2,6-dichloro-3-(α-D / L-Erythrofuranosyl)
imidazo[1,2-a]pyridine (compound 11) were both inactive against HCMV and HSV-1 and nontoxic
on uninfected cells.[88] [89] In contrast, the enantiomer mixture of 2,6,7-trichloro-3- (α-D/L-
Erythrofuranosyl)imidazo[1,2-a]pyridine (10) was active against HCMV and HSV-1. They noted
that the α (10) anomer is more active than the β anomer.

Figure 22 : Imidazopyridine derivatives with antiviral activities

e. Imidazo[1,2-a]pyridine as an anthelminthic
Jean-Paul Déto et al. [90] described a new series of imidazo[1,2-a] pyridine-based anthelminthic,
showing an action on the parasitic nematode Strongyle Haemonchus contortus. One (compound
12) of its compounds (Figure 23) , the most powerful inhibited the motility of worms at 31.25 μM.
In addition, an original mode of action was unveiled for this compound, since the observed
paralysis was correlated with an antagonistic effect on the two Levaamisole – nAChR1 and two
other subtypes.

Figure 23: Structure of 4-(4-chlorophenyl)-3-((6-(4-methylpiperazin-1-yl)H-imidazo[1,2-a]pyridin-2-

yl)methyl)but-3-enenitrile with anthelminthic activity

f. Imidazo[1,2-a]pyridine as an antileishmanial agent

Cyril Fersing et al. [91] showed that the 3-nitroimidazo[1,2-a]pyridine derivatives substituted in
the 2-position by thiobenzyl have good antileishmanial activities. Indeed, the in vitro evaluation of
these compounds showed that one of them (compound 13) was a successful pest control.
This single molecule exhibited low cytotoxicity to human cell-line HepG2 (CC50 > 100 μM)
showed good antileishmanial activity (IC50 = 12.1 μM) against L. donovani, L. infantum, and L.
major and good antitrypanosomian activities (IC50 = 1.3-2.2 μM) against T.brucei and T.cruzi, in
comparison with several reference drugs such as miltefosin, fexinidazole, eflornithine and
benznidazole (IC50 = 0.6 -13.3 μM).

Figure 24: Structure of 6-chloro-8-((4-chlorophenyl)thio)-3-nitro-2-((phenylsulfonyl)methyl)

imidazo[1,2-a]pyridine

g. Imidazo[1,2-a]pyridine as anti-tuberculosis drug

Mycobacterium tuberculosis is a major human pathogen and the cause of lung disease.[92] Through
the use of high-throughput whole cell screening from a library of extended compounds, a number
of imidazo[1,2-a]pyridine were obtained as highly active molecules against M. tuberculosis and
Mycobacterium Bovis BCG. Some of the imidazopyridine derivatives (compounds 14,15 and 16)
showed inhibitory diameters (MICs) in the 0.03 to 5 mm range against Mycobacterium Bovis strain.
Also, work by Garrett C. Moraski et al. on imidazopyridines, has led to antituberculosis
compounds.[93] The 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide derivatives (17, 18)
synthesized, were evaluated for their in vitro antituberculosis activities in comparison to the
replication of resistant MTB strains. The synthesized imidazopyridine derivatives showed better
anti-tuberculosis activities comparable to Nitroimidazole clinical candidate PA-82419 (CMIs
versus MDR-TB of 0.03 to 0.25 μg/mL or 0.08 to 0.7 μM, respectively) at concentrations below 1
μM.
 Figure25: 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamides derivatives found as antituberculosis
drugs

h. Imidazo[1,2-a]pyridine as a pest control

The pest control potency of imidazopyridine was assessed using Trichomonas Vaginalis. GT3 was
a highly pathogenic strain isolated in the city of Guanajuato, Mexico in 2012 [94]. Margarita
Lopez-Martinez et al. showed that most of the synthezisedcompounds got antiparasitic activity
after 24 h of treatment. As a result, the results, the ethyl 3-nitroimidazo[1,2-a]pyridine-2-
carboxylate (19) and the 3-nitroimidazo[1,2-a]pyridine (20) had good anti-parasitic activity,
requiring 2.45–3.96 uM to reach the desired effect. They also correlate partition coefficient (log P)
determination and antiparasitic activity for all the tested. A mathematical descriptor correlating the
exhibited pharmacological activity and log P was found (0.9 ± 0.3 log P), which suggests that an
optimum balance between hydrophilic and lipophilic properties is most convenient. Calculations
based on this equation show that 84% of the total activity variation found may be described by
these two variables.
 Figure26: 3-nitro-imidazopyridine derivatives possesing antiparasitic activity

i. Imidazo[1,2-a]pyridine as an antifungal agent

Several synthetic imidazopyridine derivatives were evaluated for their in vitro antifungal activities
against Aspergillus fumigates 3007 and Candida albicans 3018 [95]. The test on these strains of
showed that all the prepared compounds inhibited the growth of fungi to different degrees. Among
the prepared compounds, compound 23 had the highest inhibitory index of 52.12% after 96 h
incubation, followed by compounds 21 and 22, which showed with inhibitory index of 49.87 and
43.51%, respectively. The authors also investigated the effect of the synthetic compounds on the
unicellular fungus C.Albicans 3018 after 24h incubation. These compounds were tested at
concentrations ranging from 0.0976 to 100 μg/mL. Compound 23 was observed to have the lowest
inhibitory concentration of 0.390 μg/mL. Compounds 22 and 23 completely inhibited fungal
growth at a concentration of 0.781 μg/mL.

Figure 27: N-substitued- 2-aryl-imidazopyridine derivatives with antifungal acitivity

j. Imidazo[1,2-a]pyridine as an anti-inflammatory agent

Renata B. [96] analyzed in vivo assays of Nociception, hyperalgesia, inflammation and in vitro of
human PGHS-2 inhibitory compounds. The study suggests that some of the compounds can inhibit
significant edema formation. Three (24,25,26) of the prepared imidazopyridine derivatives
exhibited excellent anti-inflammatory activity with an inhibition concentration of 8.7 Lmol/kg (3.4
mg/kg) compared to celecoxib, a selective PGHS-2 inhibitor (IC50 = 2.8 lumens), representing the
standard anti-inflammatory drug (30% inhibition at 100 Lmol/kg).

Figure 28: Imidazo[1,2-a]pyridin-3-amine derivatives with anti-inflammatory activities

II-2. Methods of synthesis of the imidazopyridine scaffold

The imidazo[1,2-a]pyridine ring was first described by Chichibabin[97] in 1925 and for a long
time, this framework was not fully studied, partly because of the lack of effective functional
methods, structural variants, especially in the pyridine core. However, much work has been done
on the synthesis, physical and reactivity properties of this ring for decades. In particular, advances
in catalytic chemistry and metal coordination chemistry in particular have facilitate access to new
functions. It should be noted that to carry out the synthesis of imidazo[1,2-a]pyridines, several
methods are described in the literature. Of all the methods, two are the most famous. These include
the condensation of 2-aminopyridine with α-halogenocarbonyls and the multi-component reaction
between the same amino substrate itself and, a carbonyl compound and isonitrile compounds.

a. Synthesis from 2-aminopyridine with α-halognocarbonyl compounds

In 1961, W. L. Mosby was able to synthesize the imidazo[1,2-a]pyridine scaffold while modifying
the Chichibabin method, [98] using 2-aminopyridine and bromoacetadehyde in refluxing hydrated
ethanol in the presence of sodium bicarbonate (Figure 29a).
Also, Andrés A. Trabanco[99] et al. cycling between 2-bromo-4,4,4-trifluorobutanal and 2-amino-
4-chloro-3-iodopyridine in ethanol in the absence of a base but in a microwave oven at 150°C.
Substituted pyridine in position-3 with a good yield in 50 min which considerably reduces the
reaction time. In 2013, Castera-Ducros et al. synthesized 2-chloromethylimidazopyridine
derivatives in one-step with yields ranging from 40 to 70%.[100] For their part, they performed a
cyclic condensation rection between the 2-aminopyridine and 1,3-dichloroacetone derivatives by
refluxing in ethanol for 4 h.
Maxwellet al. [101] synthesized the imidazo[1,2-a]pyridine core substituted at the position-2 by a
two-stage reactive halogen. First, 2-aminopyridine reacts with 2-chloroacetic acid in water in the
presence of triethylamine at 90°C for 5 hours to obtain a reactive intermediate. The latter is treated
again in the presence of POCl3 in toluene at 115°C for 16 h to obtain the imidazo[1,2-a]pyridine
core substituted with chlorine at the -2 position .
Replacement of the imidazo[1,2-a]pyridine scaffold at the 2-position with an ester group was
achieved after condensation between 2-aminopyridine and refluxing ethyl bromopyruvate in
ethanol. [102] This compound was obtained with a 70% return.
Chezal et al. [103] were able to synthesize imidazo[1,2-a]pyridine substituted in position 2 by aryl
(benzyl and p-methoxybenzyl) and alkyl groups (terbutyl, isopropyl, methyl, trifluoromethyl) by
condensing various α-halogenocarbonyls with derivatives of 2-aminopyridine.
6-bromo-2-(3,4-dichlorophenyl)-imidazo[1,2-a]pyridine was reported by Shankarrapa et al. [104]
by microwave irradiation with a yield of 60%. This was achieved by addition of 5-bromo-2-
aminopyridine and 2-bromo-1-(3,4-dichlorophenyl)ethanone in DMF, while microwave irradiation
achieved 150°C for 10 minutes at a power of 200 Watts.
The solvent of this reaction can be replaced by cyclohexanone, but the reaction time increases at
18 hours and at a temperature of 130°C.[105]
This reaction was echoed by Dongjian Zhu et al. The work here consists of reacting derivatives of
2-aminopyridine with those of bromophenacyl at room temperature and without solvent. The
method is the crushing of the two compounds in a mortar. They obtained derivatives of the
imidazo[1,2-a]pyridine nucleus substituted in position -2 by aryl derivatives and in position -6 by
methyl in a very short time with yields ranging from 90 to 95%. [106], [107]
Figure 29: a.Chichibabin method of imidazopyridine synthesis b. synthesis of 3-(2,2,2-trifluoroethyl) H-
imidazo[1,2-a]pyridine according to Andrés A. Trabanco et al. c. Synthesis method of 2-chloromethyl
imidazopyridine derivatives according to Caroline Castera-Ducros et al. d. Synthesis methof of 2-
chloroimidazopyridine according to Brad D. Maxwell et al e. Synthesis method of ethyl H-imidazo[1,2-
a]pyridine-2-carboxylate derivatives f. Synthesis method of 2-substitued imidazopyridine according to
Chezal et al. g.Synthesis method of 2-(3,4-dichloro)-6-bromo imidazopyridine according to Shankarrapa et
al. h.Synthesis method of 2-substituted imidazopyridine according to Dongjian Zhu.
 b. Multicomponent synthesis
Multicomponent reactions are reactions that occur in one reaction step with at least three reagents.
This procedure made it possible the synthesis of several rings with very interesting
pharmacological properties.
Katrin Groebke et al. [108] obtained the substituted imidazopyridine core at the 2- and 3-positions,
while reacting the 2-aminopyridine with aldehydes derivatives and isonitrile . This reaction was
carried out in methanol at room temperature overnight. Adding a few drops of acetic acid speeds
up the condensation reaction. Derivatives of Imidazo[1,2-a] pyridine are obtained with yields
ranging from 38% to 90% In this same dynamic, Martina Hieke et al. adopted the same reaction
for their work, but made sure to replace morpholine for benzaldehyde [109] (Figure 30.a)..
Recently, in 2020, the team of Carlos et al..[110] this time synthesized imidazo[1,2-a]pyridine from
the condensation of 2-aminopyridine, tert-butylisonitrile and 3-formyl-chromone in ethanol in the
presence of a few drops of ammonium chloride (Figure 30.b). This reaction takes place in a
microwave at 80°C for 15 min. The yields obtained (23% to 36%) are lower than previously. Long
before them, the work of Taleb et al. followed the same path to the synthesis of imidazopyridines.
For their work, they reacted a derivative of 2-aminopyridine with aldehyde derivatives and
isonitrile in a methanol-dichloromethane mixture in volume ratio (2:3). [111] This reaction
occurred at room temperature for 12 hours in the presence of scandium triflate (Sc(OTf) 3) as a
catalyst (Figure 30.c).
Mehdi Adib et al. synthesized imidazo[1,2-a]pyridine derivatives substituted in position-2 by aryl
compounds and in position-3 by amine function, while condensing a mixture of isocyanide, various
aldehydes and derivatives of 2- aminopyridine [112] (Figure 30.d). The reaction is carried out in
water at 70°C for 7 hours to obtain various imidazo[1,2-a]pyridine with yields ranging from 85%
to 96%.
In 2012, Anneli Nordqvist et al. [113] used this method while changing reaction conditions (Figure
30.e). They react aldehyde derivatives, isocyanide and 2-amino-5-bromopyridine in the presence
of magnesium chloride (MgCl2) in ethanol for 20 to 30 min in a microwave oven at 160°C. They
obtained imidazo[1,2-a]pyridine derivatives substituted in position-2 by aryl compounds and in
position -3 by amine function with a yield of 56%.
Ping Liu et al. developed a novel tri-component reaction synthesizing of imidazo[1,2-a]pyridine
derivatives using 2-aminopyridine derivatives, aldehyde, and alkyne [114]. After 18 h of reflux in
toluene, in the presence of catalyst such as copper sulfate (CuSO4) and 4-methylbenzenesulfonic
acid (Figure 30.f), imidazo[1,2-a]pyridine derivatives are obtained with yields ranging from 28%
to 68%.
Pushpalatha B. et al. [80] synthesized imidazo[1,2- a]pyridine from 4-methyl acetophenone, 2-
amino-5-methyl pyridine and dibrome (Br2) in methanol in the presence of Lewis acid (AlCl3).
This reaction (Figure 30.g) occurred between 0 and 5°C with a 57% yield.
Figure 30: a. Synthesis method of imidazopyridine via muli components pathway according to Martna
Hieke. b. Synthesis method of the 2-substituted imidazopyridine by the multicomponent pathway according
to Katrin Groebke et al. c. Zarate-Hernández et al. synthesis method of imidazopyridine substituted N-
derivatives d. synthesis of imidazopyridine substituted N-substitutes multicomponent according to Mehdi
Adib et al. e. method of synthesis of imidazopyridine substituted N-substitutes multicomponent according
to Anneli Nordqvist et al. f. Syntheis method of 2,3-disubstituted imidazopyridine via multi-component
pathway according to Ping Liu et al. g. Pushpalatha Budumuru multi-component synthesis method of the
derivatives of 2-phenyl imidazopyridine

c. Synthesis from nitroolefins

The synthesis of the imidazo[1,2-a]pyridine core from the nitroolefins allowed to activate it in
position 3 with the nitro group. Most of these reactions occur in the presence of a catalyst.
Prashant B. Jagadhane et al. [115] were able to synthesize the imidazo[1,2-a]pyridine core by
reacting 1-(2-nitrovinyl)benzene with 2-aminopyridine in the presence of sodium dichloroiodide
(NaICl2) in the DMF at 80°C for 1 hour and 30 minutes (Figure 31.a).
This reaction was carried out in several solvents such as dimethylsulfoxide (DMSO), methanol
(MeOH), ethanol (EtOH) and acetonitrile (CH 3CN). However, using only dimethylformamide
(DMF) as a solvent resulted in better yields of 65 to 85%.
This method was developed by Litao An et al. [116]. Using the same reagents, they reacted in
acetonitrile (CH3CN) as a solvent with another catalyst, iodine–terbutylhydroperoxide–pyridine
(TBHP-Py) to obtain the imidazopyridine core in 36 to 90% yields (Figure 31.a).. The replacement
of the catalyst made it possible to increase the reaction time (12h vs. 1h30).

Figure 31: a.Synthesis method of 3-nitro-2-phenyl-midazopyridine derivatives according to Prashant B.

Jagadhane et al. b.Synthesis method of 3-nitro-2-phenyl-midazopyridine derivatives according to Litao An
et al.
d. Synthesis from α-chloro-β-diketone
In our group, Ouattara et al. [85] were able to synthesize 3-acetyl-2-methylimidazo[1,2-a]pyridine
by the reaction of 2-aminopyridine and 3-chloro-penta-2,4-dione after a reflux heterocyclic
reaction in ethanol (Figure 32). This method resulted in a ketone function at the -3 position of the
imidazo[1,2-a]pyridine core.
 Figure 32: Synthesis method of 1-(2-methylH-imidazo[1,2-a]pyridin-3-yl)ethanone via an α-chloro-β-
diketone

e. Synthesis from a pyridinium salt

A synthetic route for imidazopyridine derivatives was identified by Juan A. Vega et al. [117] from
pyridinium salt. In their research, two synthesic lines were identified. The first route is the synthesis
of 2-amino imidazo[1,2-a]pyridine derivatives by reaction of 1-alkyl-2-chloropyridinium salt
derivatives with reflux cyanamide (H2NCN) in acetonitrile in the presence of potassium carbonate
(K2CO3) for 13-20 hours with a return of 65-70% (Figure 33.a).
For the second synthetic pathway, they obtained the 2-amino imidazo[1,2-a]pyridine derivatives in
two steps. First, by converting 1-alkyl-2-chloropyridinium salt into 2-ylidencyanamidopyridine.
Secondly, after this transformation, the latter was treated, in the presence of LDA in
tetrahydrofuran (THF) for 6 to 24 h at room temperature to finally obtain the 2-amino imidazo[1,2-
a]pyridine derivatives. We noted that the best yields were obtained from this last synthesis route
(figure 33.b).
Similarly, H. Zali-Boeini et al. [118] synthesized 2,3-disubstitued imidazo[1,2-a]pyridine
derivatives, by reaction of N-alkyl pyridinium with S-alkyl thiouronium salt derivatives in water
at 75°C for 4 h in the presence of sodium hydrogen carbonate (NaHCO 3) (Figure 33.c).
Figure 33: a. Synthesis method of 2-aminoimidazopyridine derivatives from pyridinium salt according to
Juan A. Vega et al. b. Synthesis method of 2-aminoimidazopyridine derivatives from pyridinium salt
according to Juan A. Vega in two steps. c. Synthesis method of 2-aminoimidazopyridine derivatives from
pyridinium salt according to Zali-Beoini

f. Synthesis from N-oxides

The 2-substituted imidazo[1,2-a]pyridine nucleus was developed by Eric Talbot et al. from 2-
aminopyridine N-oxide. [119] They react with trifluoroacetic acid and gold dichloro-2-
pyridinecarboxylate (PicAuCl2) as catalysts, alcynes and 2-aminopyridine N-oxide at 40°C
overnight in dichloromethane (DCM) as a solvent. After treatment of the reaction medium, the
derivatives of the 2-substituted imidazo[1,2-a]pyridine are obtained with yields of 16 to 78 %.

Figure 34 : Synthesis method of 2-phenyl imidazopyridine derivatives from N-oxides

Perspectives
Antimicrobial resistance is one of the world's greatest public health threats today. Most antibiotics
lose their effectiveness over time due to the virulence of toxins secreted by bacteria in defense,
which leads to flare-ups of hospital-acquired disease. Another urgency is the widespread
emergence of drug-resistant strains Methicillin (MRSA)-resistant Staphylococcus aureus (S.
aureus). [120] The death toll from MRSA turned out to be even higher. The rapid emergence of S.
aureus strains resistant to HIV, [121] vancomycin [122], often considered the treatment of last
resort, adds to the urgency of being able to access other active ingredients. As a result, there is an
urgent need to develop new antibacterial agents that can overcome bacterial resistance, but much
more emphasis on bacterial translocation proteins. Structural modification strategies of antibiotics
with evolved resistance as an effective means of extending antimicrobial longevity are beginning
to show their limitations. Multiple compound therapy has many potential benefits, including
increased potency, reduced dosage or toxicity, and protection against development of drug
resistance. This area is of increasing interest to scientists due to the enormous (un- or mis-)explored
prospects for novel therapeutics. The development is partly guided by a biological systems
perspective recognizing that many cellular processes are difficult to control using a single drug
compound, and in part by screening multiple compounds. It is guided by high-performance
computing instruments that make it quick and inexpensive. For example, when studying
combinations of compounds in cancer chemotherapy, clinical evaluation of the benefits of
combinations is relatively straightforward. Combinations are preferred if they have acceptable side
effects and prolong long-term survival compared to alternative therapies. Therefore, the importance
of developing new types of antibacterial agents, especially those with new mechanisms of action.
Refocusing antimicrobial drug research on bacterial secretion pathways could be a big win.
Therefore, SecA, a key protein in the bacterial secretory pathway, has been investigated as a target
for the development of antibacterial agents. Synthesis and biological activity of various compounds
derived from the combination of antimicrobial pharmacophores (aminopyrimidines and
benzimidazoles) discussed in this review to form a potential SecA-inhibiting
benzimidazolylaminopyrimidine motif. Our suggest research on both scaffold aminopyrimidine
derivatives have many bioactivities, including bactericidal action and SecA inhibitors. In addition,
these compounds also contain a benzimidazole core, whose antibacterial activity is shown and
demonstrated here. An analysis of this literature concluded that pyrimidines substituted with
electron-withdrawing groups such as nitro on phenyl have stronger antibacterial activity in vitro
than chlorine atoms or methoxy groups. Nitro-substituted benzimidazolylaminopyrimidines can be
excellent active ingredients. Humans have no homologues of the SecA, so these new compounds
probably do not pose inherent toxicity problems. Selectively targeting SecA, which has no human
counterpart, seems appropriate. Furthermore, SecA is present in all bacteria, making these new
antibacterial agents effective against a broad spectrum of bacteria. After extensive review of the
medicinal chemistry literature for both pharmacophores, we could find a potential drug against
bacteria. This study addresses the following questions: how can we effectively overcome drug
resistance in bacteria? Is addition of pharmacophore will enhance the potency? Is the the best target
is translocation of protein.

Conclusion
In this review article, we attempt to summarize several biological activities and synthetic routes for
the synthesis of both heterocyclic benzimidazole and imidazo[1,2-a]pyridine compounds. The
presence of certains substituents in their derivatives indicates that they can be used as
pharmacologically molecules or drugs intermediates. Our point of view in perspespectives showed
how we would like to currently investigate the combination of both pharmacophore in this research.

Conflict of interest
The authors confirm that this article has no conflict of interest.
References

[1] Blair J. M. A., Webber M. A., Baylay A. J., Ogbolu D. O., et Piddock L. J. V., « Molecular
mechanisms of antibiotic resistance », Nature Reviews Microbiology, vol. 13, no 1, p. 42-51,
janv. 2015, doi: 10.1038/nrmicro3380.

[2] Organisation mondiale de la Santé, « Rapport sur la tuberculose dans le monde 2020 : résumé
d’orientation », 2020.

[3] Sumit T., Kalavathy R., Siong M. L., Syeed A. A. S., Vasudevan M,, et Balasubramanian N.,
« 4-(2-(1H-Benzo[d]imidazol-2-ylthio)acetamido)-N-(substituted phenyl)benzamides: design,
synthesis and biological evaluation », BMC Chemistry, vol. 13, no 1, p. 12, déc. 2019, doi:
10.1186/s13065-019-0533-7

[4] Ulviye A. C., Begum N. S., Serkan L., Derya O., Betul K. C., Yusuf O. et Zafer A. K.,
« Synthesis and AChE-Inhibitory Activity of New Benzimidazole Derivatives », Molecules, vol.
24, no 5, p. 861, févr. 2019, doi: 10.3390/molecules24050861.

[5] Sumit T., Sanjiv K. et Balasubramanian. N., « Antimicrobial potential of 1H-

benzo[d]imidazole scaffold: a review », BMC Chemistry, vol. 13, no 1, p. 18, déc. 2019, doi:
10.1186/s13065-019-0521-y.

[6] Ratika S., Alka B., et Bahadur B C., « Synthesis of methanesulphonamido-benzimidazole

derivatives as gastro-sparing antiinflammatory agents with antioxidant effect », Bioorganic &
Medicinal Chemistry Letters, vol. 27, no 13, p. 3007-3013, juill. 2017, doi:
10.1016/j.bmcl.2017.05.017.

[7] Terence N. O., Latyfa E. O., Mostafa E. G., Redouane A., Hind C., Meryem E. J., Yahia C.,
Katim A. et Amina Z., « Synthesis of Surfactants Derived from 2-Mercaptobenzimidazole and
Study of Their Acute Toxicity and Analgesic and Psychotropic Activities », Biochemistry
Research International, vol. 2019, p. 1-9, juill. 2019, doi: 10.1155/2019/9615728.

[8] Tonelli M., Paglietti G., Boido V., Sparatore F., Marongiu E., La Colla P. et Loddo R.,
« Antiviral Activity of Benzimidazole Derivatives. I. Antiviral Activity of 1-Substituted-2-
 [(Benzotriazol-1/2-yl)methyl]benzimidazoles », Chemistry & Biodiversity, vol. 5, no 11, p.
2386-2401, nov. 2008, doi: 10.1002/cbdv.200890203.

[9] Paulina F. C., José M. V. L., Rodrigo A. O., Alicia H. C., Pedro J. T. S., Lilian Y. M. et Raphael
C., « Synthesis, antiprotozoal activity, and chemoinformatic analysis of 2-(methylthio)-1 H -
benzimidazole-5-carboxamide derivatives: Identification of new selective giardicidal and
trichomonicidal compounds », European Journal of Medicinal Chemistry, vol. 137, p.
211-220, sept. 2017, doi: 10.1016/j.ejmech.2017.05.058.

[10] John O., Christel B., Kawaljit S., Godwin A.D., Linley B., Mathew N., Sergio W. et Kelly C.,
« Antimalarial Pyrido[1,2- a ]benzimidazole Derivatives with Mannich Base Side Chains:
Synthesis, Pharmacological Evaluation, and Reactive Metabolite Trapping Studies », ACS
Infectious Diseases, vol. 5, no 3, p. 372-384, mars 2019, doi: 10.1021/acsinfecdis.8b00279.

[11] Michele T., Elene G., Francesca P., Nicoletta B., Silvia P., Bruno T., Roberta L., Fabio S. et
Anna S., « Benzimidazole derivatives endowed with potent antileishmanial activity », Journal
of Enzyme Inhibition and Medicinal Chemistry, vol. 33, no 1, p. 210-226, janv. 2018, doi:
10.1080/14756366.2017.1410480.

[12] Amanda L. R., Pulane M. et Christopher J. P., « Multicomponent synthesis of imidazo[1,2-

a]pyridines using catalytic zinc chloride », Tetrahedron Letters, vol. 48, p. 4079-4082, 2007.

[13] Bagdi A. K., Santra S., Monir K., et Hajra A., « Synthesis of imidazo[1,2-a]pyridines: a
decade update », Chemical Communications, vol. 51, no 9, p. 1555-1575, 2015, doi:
10.1039/C4CC08495K.

[14] Assessment report, « For Zolpidem-containing medicinal products », European Medecines

Agency, p. 1-18, avr. 24, 2014.

[15] Cécile E. G. et Alain G., « Recent Progress in the Pharmacology of Imidazo[1,2-a]pyridines »,

Mini-Reviews in Medicinal Chemistry, vol. 7, no 9, p. 888-899, 2007

[16] Vidyacharan S., Shinde A. H., Satpathi B., et Sharada D. S., « A facile protocol for the
synthesis of 3-aminoimidazo-fused heterocycles via the Groebke–Blackburn–Bienayme
 reaction under catalyst-free and solvent-free conditions », Green Chemical, vol. 16, no 3, p.
1168, 2014, doi: 10.1039/c3gc42130a.

[17] Liu H.B., Gao W.W., Tangadanchu V.K.R., Zhou C.H., et Geng R.X., « Novel
aminopyrimidinyl benzimidazoles as potentially antimicrobial agents: Design, synthesis and
biological evaluation », European Journal of Medicinal Chemistry, no 143, p. 63-84, 2018.

[18] Zhou M., Eun Y.J., Guzei I.A. et Weibel D.B, « Structure–activity studies of divin: An
inhibitor of bacterial cell division », Medicinal Chemistry Letters, no 4, p. 880-885, 2013.

[19] Ramya V. S., Kallappa M. H., et Rangappa S. K., « Synthesis and evaluation of in vitro
anti-microbial and anti-tubercular activity of 2-styryl benzimidazoles », European Journal of
Medicinal Chemistry, vol. 44, p. 4244-4248, 2009.

[20] Muayed A. R., Baqir W. A., et Mudhafar A. M., « Synthesis, Characterization and
Antibacterial Evaluation of some Novel Benzimidazole Derivatives Containing 1,3,4-
Thiadiazole Moiety. », Oriental Journal of Chemistry, vol. 33, no 6, p. 3138-3143, déc. 2017,
doi: 10.13005/ojc/330656.

[21] Andrea B., Luka K., Ivana S., Domagoji D., Jasminka T., Martin C. T,, John M. K., Miroslav
B. et Silvana R. M., « Synthesis, anti-bacterial and anti-protozoal activities of
amidinobenzimidazole derivatives and their interactions with DNA and RNA », Journal of
Enzyme Inhibition and Medicinal Chemistry, vol. 33, no 1, p. 1323-1334, janv. 2018, doi:
10.1080/14756366.2018.1484733.

[22] Woolley D. W., « some biological effects produced by benzimidazole and their reversal by
purines », Journal of Biological Chemistry, vol. 152, no 2, p. 225-232, févr. 1944, doi:
10.1016/S0021-9258(18)72045-0.

[23] Maertens J. A., « History of the development of azole derivatives », Clinical Microbiology
and Infection, vol. 10, p. 1-10, 2004, doi: 10.1111/j.1470-9465.2004.00841.x.

[24] Mishra L., V. Singh K., Dubey N. K., et Mishra A. K., « Synthesis and Fungicidal Activity of
Some 5-Membered Heterocyclic Derivatives Containing Benzimidazoles », Bioscience,
 Biotechnology, and Biochemistry, vol. 57, no 6, p. 989-991, janv. 1993, doi:
10.1271/bbb.57.989.

[25] Gulgun A. K. et Nurten A., « Synthesis and Antifungal Properties of Some Benzimidazole
Derivatives », Journal of Chemica Turkey, vol. 30, p. 223-228, 2006.

[26] Hakan G., Canan K.¸ David W. B., Sulhiye Y. et Nurten A., « Synthesis of Some New 2-
Substituted-phenyl-1H-benzimidazole- 5-carbonitriles and Their Potent Activity Against
Candida Species », Bioorganic & Medicinal Chemistry, vol. 10, p. 2589-2596, 2002.

[27] Cheong J.E., Zaffagni M., Chung I., Xu Y., Wang Y., Jernigan F.E., Zetter B.R., et Sun L.,
« Synthesis and anticancer activity of novel water soluble benzimidazole carbamates »,
European Journal of Medicinal Chemistry, no 144, p. 372-385, 2018.

[28] Ibrahim H.A., Awadallah F.M., Refaat H.M., et Amin K.M., « Molecular docking simulation,
synthesis and 3D pharmacophore studies of novel 2-substituted- 5-nitro-benzimidazole
derivatives as anticancer agents targeting VEGFR-2 and c-Met », Bioorganic Chemistry, no 77,
p. 457-470, 2018.

[29] Refaat H. M., « Synthesis and anticancer activity of some novel 2-substituted benzimidazole
derivatives », European Journal of Medicinal Chemistry, vol. 45, no 7, p. 2949-2956, juill.
2010, doi: 10.1016/j.ejmech.2010.03.022.

[30] Salahuddin M. S., Mazumder A., et Ahsan M. J., « Synthesis, characterization and anticancer
evaluation of 2-(naphthalen-1-ylmethyl/naphthalen-2-yloxymethyl)-1-[5-(substituted phenyl)-
[1,3,4]oxadiazol-2-ylmethyl]-1H-benzimidazole », Arabian Journal of Chemistry, vol. 7, no 4,
p. 418-424, sept. 2014, doi: 10.1016/j.arabjc.2013.02.001.

[31] Abdel-Mohsen H. T., Ragab F. A. F., Ramla M. M., et El Diwani H. I., « Novel
benzimidazole–pyrimidine conjugates as potent antitumor agents », European Journal of
Medicinal Chemistry, vol. 45, no 6, p. 2336-2344, juin 2010, doi:
10.1016/j.ejmech.2010.02.011.

[32] Márquez-Navarro A., Nogueda-torres B., Hermandez-campos A., Soria-arteche O., Castillo
R, Rodriguez-Morales S., Yépez-Mulia L., Hermandez-luis F., « Anthelmintic activity of
 benzimidazole derivatives against Toxocara canis second-stage larvae and Hymenolepis nana
adults », Acta Tropica, vol. 109, no 3, p. 232-235, mars 2009, doi:
10.1016/j.actatropica.2008.11.014.

[33] Prasada R. C. M. M., Lakshmi A. J., Mani Y. G., Sudha B. S., Rekha P. B., Satyaprakash K.,
et Dhachinamoorthi D., « in vitro anthelmintic activity of novel benzimidazole derivatives
from o-phenylene diamine », World Journal Of Pharmaceutical And Medical Research, vol.
4, no 4, p. 245-248, 2018.

[34] Faruk A., Biplab K. D., Kamal S., Arpita C. et Pallab K., « synthesis, antimicrobial and
anthelmintic activity of some novel benzimidazole derivatives », International Journal of Drug
Research and Technology, vol. 4, no 3, p. 31-38, 2014.

[35] Mavrova A. T., Kamelya K. A., Dimitar I. V., Jordan A. T., Pavletta S. D., Magdalena S. K.
et Mitka K. M., « Antihelminthic activity of some newly synthesized 5(6)-(un)substituted-1H-
benzimidazol-2-ylthioacetylpiperazine derivatives », European Journal of Medicinal
Chemistry, vol. 41, no 12, p. 1412-1420, déc. 2006, doi: 10.1016/j.ejmech.2006.07.005.

[36] Mavrova A. T., Kamelya K. A., Dimitar I. V., Jordan A. T., Pavletta S. D., Magdalena S. K.
et Mitka K. M., « Antihelminthic activity of some newly synthesized 5(6)-(un)substituted-1H-
benzimidazol-2-ylthioacetylpiperazine derivatives », European Journal of Medicinal
Chemistry, vol. 41, no 12, p. 1412-1420, déc. 2006, doi: 10.1016/j.ejmech.2006.07.005.

[37] Vitale G., Corona P., Loriga M., Carta A., Paglietti G., Ibba C., Giliberti, G., Loddo R.,
Marongiu E., La Colla P., « Styrylbenzimidazoles. Synthesis and biological activity—Part 3 »,
Medicinal Chemistry, no 6, p. 70-78, 2010.

[38] Barreca M. L., Rao A., Luca De L., Iraci N., Monforte A. M., Maga G., Clercq De E.,
Pannecouque C., Balzarini J., Chimirri A., « Discovery of novel benzimidazolones as potent
non-nucleoside reverse transcriptase inhibitors active against wild-type and mutant HIV-1
strains », Bioorganic & Medicinal Chemistry Letters, vol. 17, no 7, p. 1956-1960, avr. 2007,
doi: 10.1016/j.bmcl.2007.01.025.
[39] Laura G., Erik De C., et Marinella R., « Synthesis and Antiviral/Antiproliferative Activity of
Some N-Sulphonylbenzimidazoles », Bioorganic & Medicinal Chemistry Letters, vol. 12, p.
2707-2710, 2002.

[40] Deepika S., Balasubramanian N., Pradeep K., Vikramjeet J., Rakesh N., Erik De C. et Jan B.,
« Synthesis, antimicrobial and antiviral activity of substituted benzimidazoles », Journal of
Enzyme Inhibition and Medicinal Chemistry, vol. 24, no 5, p. 1161-1168, oct. 2009, doi:
10.1080/14756360802694427.

[41] Achar K.C.S., Hosamani, K.M. et Seetharamareddy H.R., « In vivo analgesic and anti-
inflammatory activities of newly synthesized benzimidazole derivatives », European Journal
of Medicinal, no 45, p. 2048-2054, 2010.

[42] Iemura R., Kawashima T., Fukuda T., Ito K. et Tsukamoto G., « Synthesis of 2-(4-substituted
1-piperazinyl) benzimidazoles as H1-antihistaminic agents. », Journal of Medicinal Chemistry,
no 29, p. 1178-1183, 1986.

[43] Monika G., Sarbjot S., et Chander M., « Benzimidazole: An emerging scaffold for analgesic
and anti-inflammatory agents », European Journal of Medicinal Chemistry, vol. 76, p.
494-505, 2014.

[44] Kavitha C.S. A., Kallappa M. H., et Harisha R. S., « In-vivo analgesic and anti-inflammatory
activities of newly synthesized benzimidazole derivatives », European Journal of Medicinal
Chemistry, vol. 45, p. 2048-2054, 2010.

[45] Thimme G. N. R., Kavitha C. V., Kishore K. C., Omana J., Kanchugarakoppal S. R. et Sathees
C. R., « Synthesis and biological evaluation of novel 1-(4-methoxyphenethyl)-
1Hbenzimidazole- 5-carboxylic acid derivatives and their precursors as antileukemic agents »,
Bioorganic & Medicinal Chemistry Letters, vol. 19, p. 4594-4600, 2009.

[46] Mahama O., Drissa S., William Y. et Mamidou W. K., « Synthèse et criblage antiplasmodial
de quelques benzimidazolyl-chalcones », International Journal of Biological Chemical
Sciences, vol. 9, no 3, p. 1697-1710, 2015.
[47] Bandyopadhyay P., Manisha S., Sachin N. T., Ruchi Y., Pratibha S., Ashok K. et Kaushik M.
P., « Synthesis of some novel phosphorylated and thiophosphorylated benzimidazoles and
benzothiazoles and their evaluation for larvicidal potential to Aedes albopictus and Culex
quinquefasciatus », Bioorganic & Medicinal Chemistry Letters, vol. 24, no 13, p. 2934-2939,
juill. 2014, doi: 10.1016/j.bmcl.2014.04.082.

[48] José C., Arthur B., Neira G., Juan R., Rosario R., Abraham V., Robert G. et Jaime C.,
« Synthesis and biological evaluation of benzimidazole-5-carbohydrazide derivatives as
antimalarial, cytotoxic and antitubercular agents », Bioorganic & Medicinal Chemistry, vol.
19, p. 2023-2029, 2011.

[49] Divatia S. M., Rajani D. P., Rajani S. D., et Patel H. D., « Novel thiosemicarbazone derivatives
containing benzimidazole moiety: Green synthesis and anti-malarial activity », Arabian
Journal of Chemistry, vol. 12, no 7, p. 1641-1651, nov. 2019, doi:
10.1016/j.arabjc.2014.09.007.

[50] Toro P., Hugo A. K., Bruno P., Lahoz F., Pascual A., Biot C. et Arancibia R., « Organometallic
benzimidazoles: Synthesis, characterization and antimalarial activity », Inorganic Chemistry
Communications, vol. 35, p. 126-129, sept. 2013, doi: 10.1016/j.inoche.2013.06.019.

[51] Sarika S., Dhiman N., Aman M. et Gaurav K., « Synthesis And Antioxidant Activity Of The
2-Methyl Benzimidazole », Journal of Drug Delivery and Therapeutics, vol. 6, no 3, p.
100-102, 2016.

[52] Dvornikova I. A., Buravlev E. V., Fedorova I. V., Shevchenko O. G., Chukicheva I. Yu., and
Kutchin A. V. « Synthesis and antioxidant properties of benzimidazole derivatives with
isobornylphenol fragments » Russian Chemical Bulletin, International Edition, Vol. 68, No. 5, pp.
1000—1005, May, 2019

[53] Sabrina R. A., Biplab K. D., MD Shahadat H., Uttom K. and Abu S. S. R., «Synthesis and
antioxidant activity of 2-substituted-5-nitro benzimidazole derivatives». International Journal of
Pharmacy and Pharmaceutical Sciences; vol 9, No 1, pp.308-310, 2017
[54] Hobrecker F. '' Reduction-products of nitracetamide compounds'' Deut. Chem. Ges. Ber., vol.
5, p. 920-924, 1872.

[55] Montaguea L. I., « CCCXVI1.-The Formation of 2-substituted Benzimidazoles. », Journal of

the Chemical Society, p. 2393-2399, 1928.

[56] El-Gohary N. S. et Shaaban M. I., « Synthesis, antimicrobial, antiquorum-sensing and

antitumor activities of new benzimidazole analogs », European Journal of Medicinal
Chemistry, vol. 137, p. 439-449, sept. 2017, doi: 10.1016/j.ejmech.2017.05.064.

[57] Odame F., Hosten E., Betz R., Lobb K. et Tshentu Z. R., « Benzimidazole or Diamide From
a Reaction of Diamines and Carboxylic Acids or Acid Chlorides: Crystal Structures and
Theoretical Studies », Acta Chimica Slovenica, p. 986-994, déc. 2015, doi:
10.17344/acsi.2015.1703.

[58] Kiumars B., Mohammad M. K. et Iman K., « H2O2/HCl as a new and efficient system for
synthesis of 2-substituted benzimidazoles », Journal of Chemical Research, p. 783-784, 2006.

[59] K. Bahrami, M. Khodaei, et I. Kavianinia, « A Simple and Efficient One-Pot Synthesis of 2-

Substituted Benzimidazoles », Synthesis, vol. 2007, no 04, p. 547-550, févr. 2007, doi:
10.1055/s-2007-965878.

[60] K. Bahrami, M. Khodaei, et I. Kavianinia, « A Simple and Efficient One-Pot Synthesis of 2-

Substituted Benzimidazoles », Synthesis, vol. 2007, no 04, p. 547-550, févr. 2007, doi:
10.1055/s-2007-965878.

[61] Du L.-H. et Wang Y.-G., « A Rapid and Efficient Synthesis of Benzimidazoles Using
Hypervalent Iodine as Oxidant », Synthesis, vol. 2007, no 5, p. 675-678, mars 2007, doi:
10.1055/s-2007-965922.

[62] Karthikeyan C., Solomon V. R., Lee H., et Trivedi P., « Synthesis and biological evaluation
of 2-(phenyl)-3H-benzo[d]imidazole-5-carboxylic acids and its methyl esters as potent anti-
breast cancer agents », Arabian Journal of Chemistry, vol. 10, p. S1788-S1794, mai 2017, doi:
10.1016/j.arabjc.2013.07.003.
[63] Sharghi H., Mashhadi E., Aberi M., et Aboonajmi J., « Synthesis of novel benzimidazoles and
benzothiazoles via furan‐2‐carboxaldehydes, o ‐phenylenediamines, and 2‐aminothiophenol
using Cu(II) Schiff‐base@SiO 2 as a nanocatalyst », Applied Organometallic Chemistry, vol.
35, no 9, sept. 2021, doi: 10.1002/aoc.6330.

[64] Alloum B. A., Bougrin K. et Soufiaoui M., « Synthèse chimiosélective des benzimidazoles
sur silice traitée par le chlorure du thionyle », Tetrahedron Letters, vol. 44, p. 5935-5937, 2003

[65] Duvuapally M., Sadhu P., et Punniyamurthy T., « Copper(II)-Catalyzed Oxidative Cross-
Coupling of Anilines, Primary Alkyl Amines, and Sodium Azide Using TBHP: A Route to 2-
Substituted Benzimidazoles », Journal of Organic Chemistry, vol. 81, no 8, p. 3227-3234, avr.
2016, doi: 10.1021/acs.joc.6b00186.

[66] Y. Kim, M. R. Kumar, N. Park, Y. Heo, et S. Lee, « Copper-Catalyzed, One-Pot, Three-

Component Synthesis of Benzimidazoles by Condensation and C–N Bond Formation »,
Journal of Organic Chemistry, vol. 76, no 23, p. 9577-9583, déc. 2011, doi:
10.1021/jo2019416.

[67] Thanh. B. N., Bescont J. L., Ermolenko L., et Al-Mourabit A., « Cobalt- and Iron-Catalyzed
Redox Condensation of o -Substituted Nitrobenzenes with Alkylamines: A Step- and Redox-
Economical Synthesis of Diazaheterocycles », Organic Letters, vol. 15, no 24, p. 6218-6221,
déc. 2013, doi: 10.1021/ol403064z.

[68] Hobrecker F., « Ueber Reductionaprodukte der Nitracetamidverbindungen », Berichte Dtsch.

Chem. Ges, vol. 5, no 2, p. 920-924, 1872.

[69] Deepak B. N. et Bhalchandra M. B., « N-Substituted Formamides as C1-Sources for the

Synthesis of Benzimidazole and Benzothiazole Derivatives by Using Zinc Catalysts »,
SYNLETT Accounts and Rapid Communications in Chemical Synthesis, vol. 26, p. 2835-2842,
2015, doi: 10.1055/s-0035-1560319.

[70] Sissouma D., Adjou A., Touré S. A., Zoakouma S., Gnon B., et Téa G. C., Reactivity of
Amidinium Salts’ Access to Benzo[4,5]imidazo[2,1-b]Thiazoles , Phosphorus, Sulfur, and
 Silicon and the Related Elements, vol. 180, no 5‑6, p. 1375‑1378, mars 2005, doi:
10.1080/10426500590910620.

[71] Timotou A., Adjou A., Say M. V., Sissouma D., Toure S., Tea G. C. et N'Guessan Y.T., Novel
synthesis of benzimidazole by Ring Contraction Rearrangement of benzodiazepine ,
International Journal of Biological and Chemical Sciences, vol. 7, no 6, p. 2568, mai 2014,
doi: 10.4314/ijbcs.v7i6.31.

[72] Camara T. E., Coulibali S., Kone S., Adeyole T., et Adjou A., « novel synthesis of 2-
substituted benzimidazole by ring contraction rearrangement of 1, 5- benzodiazepines », World
Journal of Pharmaceutical Research, vol. 7, no 1, p. 61-84, 2017, doi: 10.20959/wjpr20181-
10512.

[73] Denise M., Philippe N., Jean-Michel L. Loubna L., Abdeslam E. A., Brahim L., El Mokhtar
E., Bouziane B., et Abdelkhalek B,, « Synthesis and structural study of N-
isopropenylbenzimidazolone », Russian Journal of Physical Chemistry, vol. 89, no 5, p.
807-811, 2015, doi: 10.1134/S0036024415050271.

[74] Vakhid A. M., Nataliya A. Z., et Oleg G. S., « Advances in the synthesis of
benzimidazolones via rearrangements of benzodiazepinones and quinoxalin(on)es »,
Mendeleev Communications, vol. 27, p. 1-11, 2017, doi: 10.1016/j.mencom.2017.01.001.

[75] Leonard N. J., David Y.C. et Karl M. B., « Sulfonate Salts of Substituted
Benzimidazoles1 », Journal America Chemical Society, vol. 69, no 10, p. 2459-2461, 1947.

[76] Hunger A., Kebrle J., Rossi A. et Hoffmann K., « Benzimidazol-Derivate und verwandte
Heterocyclen III Synthese von 1-Aminoalkyl-2-benzyl-nitro-benzimidazolen », Helvetica
Chimica Acta, vol. 43, no 4, p. 1032-106.

[77] Bhattacharaya S. C., « Synthesis and Characterization of Impurities of an Broad-spectrum

Anthelmintic Drug, Albendazole », Chemical Science Transactions, vol. 5, 2016.

[78] Asmaa S., Nada K. S., El Mokhtar E., « Synthese, Reactivite et Activités Biologiques des
Dérivés du Benzimidazole », Moroccan Journal of Heterocyclic Chemistry, vol. 18, no 3, p.
1-50, 2019.
[79] Van Allan J. A. et Deacon B. D., « 2-mercaptobenzimidazole », Organic. Synthetis, vol.
30, p. 56, 1950, doi: 10.15227/orgsyn.030.0056.

[80] Pushpalatha B., Srinivasarao G., Venkata S. S. K., Design and synthesis of novel imidazo[1,2-
a]pyridine derivatives and their anti-bacterial activity, Asian Journal of Pharmaceutical
Clinical Research, vol. 11, no 8, p. 252-258, mai 2018, doi:
http://dx.doi.org/10.22159/ajpcr.2018.v11i8.26241.

[81] Kai. L., Linhu L., Wang B., Mingliang L., Wang B., Weiyi S., Huiyuan G., Yu L., Design,
synthesis and antimycobacterial activity of novel imidazo[1,2- a ]pyridine-3-carboxamide
derivatives, European Journal of Medicinal Chemistry, vol. 137, p. 117-125, sept. 2017, doi:
10.1016/j.ejmech.2017.05.044.

[82] Akram M.H. A., Mohammed A. A. et Saeb H. A., Imidazo[1,2-a]pyridine Based Compounds
:The Hope ful Anti-Cancer Therapy, Systematic Review Pharmacy, vol. 12, no 4, p. 79-85,
2021.

[83] Gui-Ting S., Nicholas McC., Zhong-Zhu C., Xiao-Fang Y., Jiu-Hong H., Jie L., Hui-kuan L.,
Brendan F., Hong-yu L. et Zhi-Gang X., Diversity-Oriented Synthesis of Functionalized
Imidazopyridine Analogues with Anti-Cancer Activity through a Transition-Metal Free, One-
pot Cascade Reaction, Advanced Synthesis & Catalysis, vol. 360, no 19, p. 3655-3661, oct.
2018, doi: 10.1002/adsc.201800728.

[84] Nurit D. F., Candice L., Amanda L. R., Dharmendra B. Yadav , et Hajierah Davids , Charles
B. de Koning , 6-Substituted imidazo[1,2-a]pyridines: Synthesis and biological activity against
colon cancer cell lines HT-29 and Caco-2, European Journal of Medicinal Chemistry, vol. 46,
p. 4573-4583, 2011.

[85] Mahama O., Drissa S., Mamidou. W. K., et William Y., Composés á structure
imidazopyridinyl-arylpropénone, nouveaux agents anti-infectieux potentiels, Comptes Rendus
Chimie, vol. 19, no 7, p. 850-856, juill. 2016, doi: 10.1016/j.crci.2015.10.014.

[86] Hamdouchi C, Jesus de B., Mirian del P., Joseph G., Beverly A. H., et Lori V., 2-Amino-
3-substituted-6-[(E)-1-phenyl-2-(N -methylcarbamoyl)vinyl]imidazo[1,2- a ]pyridines as a
 Novel Class of Inhibitors of Human Rhinovirus: Stereospecific Synthesis and Antiviral
Activity, Journal of Medecinal Chemistry, vol. 42, no 1, p. 50-59, janv. 1999, doi:
10.1021/jm9810405.

[87] Alain G., Sylvie M., Mohammed L., Ahmed E., Robert S., Graciela A., Olivier C., Jean-
Claude T., Myriam W., Jan B., Erik De C., et Jean-Pierre C., Synthesis of Imidazo[1,2-
a]pyridines as Antiviral Agents, Journal of Medicinal Chemistry, vol. 41, no 25, p. 5108-5112,
1998, doi: 10.1021/jm981051y.

[88] Kristjan S. G., John C. D., Leroy B. T., The Condensation of 2,6-Dichloroimidazo[l,2-
a]pyridine with Ribonolactone Gives a Novel lmidazo[l,2-a]pyridine C-nucleoside with an
Unexpected Site of Ribosylation, Tetrahedron Letters, vol. 37, no 14, p. 2365-2368, 1996.

[89] Kristjan S. G., John D. W., John C. D., et Leroy B. T., Synthesis and Antiviral Activity of
Novel Erythrofuranosyl Imidazo[1,2-a]pyridine C-Nucleosides Constructed via Palladium
Coupling of Iodoimidazo[1,2-a]pyridines and Dihydrofuran, Journal of Medicinal Chemistry,
vol. 46, p. 1449-1455, 2003.

[90] Jean-Paul D. U. G., Pierre-Olivier D., Mélanie P., Claude L. C., Cédric N., Mahama O.,
Cécile E. G., Alain G. et Hassan A., Discovery of imidazo[1,2-a]pyridine-based anthelmintic
targeting cholinergic receptors of Haemonchus contortus, Bioorganic & Medicinal Chemistry,
vol. 25, no 24, p. 6695-6706, déc. 2017, doi: 10.1016/j.bmc.2017.11.012.

[91] Cyril F., Louise B., Clotilde B., Julien P., Sébastien H., Anita C., Caroline C. D., Nicolas
P., Michèle L., Magali C., Sandra B. D., Mélanie P., Alix S. S., Valère B. M., Bertrand C.,
Elisa B. R., Marc S., Rachel M., Susan W. A. H. F., Alexis V., Pascal R., Pierre V., Patrice V.,
et Nadine A.; Nongenotoxic 3-Nitroimidazo[1,2- a ]pyridines Are NTR1 Substrates That
Display Potent in Vitro Antileishmanial Activity, ACS Medecinal Chemistry Letters, vol. 10,
no 1, p. 34-39, janv. 2019, doi: 10.1021/acsmedchemlett.8b00347.

[92] Katerine. A. A., Jonathan A.G. C., Vickey L. S., Nicholas J. L., Mark J. P., Chrystala C.,
Raquel F., Carlos A., Modesto J. R., David B., Lluis B. et Gurdyal S. B., Identification of
Novel Imidazo[1,2-a]pyridine Inhibitors Targeting M. tuberculosis QcrB, PLoS One, vol. 7, no
12, p. e52951, déc. 2012, doi:10.1371/journal.pone.0052951.
[93] Moraski G. C., Lowell D. M., Philip A. H., Helena B., Sanghyun C., Scott G. F., et Marvin
J. M., Advent of Imidazo[1,2- a ]pyridine-3-carboxamides with Potent Multi- and Extended
Drug Resistant Antituberculosis Activity, ACS Medecinal Chemistry Letters, vol. 2, no 6, p.
466-470, juin 2011, doi: 10.1021/ml200036r.

[94] López-Martínez M., Salgado-Zamora H., Campos-Aldrete M.. E., Trujillo-Ferrara J. G.,
Correa-Basurto J., et Mexica-Ochoa C., Effect of the lipophilic parameter (log P) on the anti-
parasitic activity of imidazo[1,2-a]pyridine derivatives, Medecinal Chemistry Research, vol.
21, no 4, p. 415-420, avr. 2012, doi: 10.1007/s00044-010-9547-3.

[95] Pratibha S., Deepa D., Mansi P., Latha N., Divyank M., Tapasya S. et Anudeep K.
N., Exploration of Novel TOSMIC Tethered Imidazo[1,2-a]pyridine Compounds for the
Development of Potential Antifungal Drug Candidate, Research Square, p.1-23,mars 2021.
doi: 10.21203/rs.3.rs-352624/v1.

[96] Renata B. L., Cleverton K. F. d. L., Leandro L. d. S., Nelilma C. R., et Ana L. P. M., Eliezer
J. Barreiro, Carlos A. M. Fraga, Discovery of novel analgesic and anti-inflammatory 3-
arylamine-imidazo[1,2-a]pyridine symbiotic prototypes, Bioorganic & Medicinal Chemistry,
vol. 17, p. 74-84, 2009.

[97] Tschitschibabin A.E., Zur Tautomerie des α-Amino-pyridins, IV. Mitteilung: Eine
Darstellungsmethode des Pyrimidazols und seiner Homologen, Berichte der Deutschen
Chemischen Gesellschaft, vol 58, no 8, p. 1704-1706, 1925,
https://doi.org/10.1002/cber.19250580852.

[98] Mosby W. L., Heterocyclic Systems with Bridgehead Nitrogen Atoms, Part 1, Interscience
Publishers, Inc., New York, vol 15, p. 461, 1961.

[99] Andrés A. T., Gary T., Gregor J. M., Juan A. V., Ana I. d. L., Encarnación M., Aránzazu
G., María L. L., Sergio A. A. d. D., José M. A., Daniel O., Abdelah A., et Wilhelmus D., Claire
M., José I. A., Hilde L., et JoséMaría C., Imidazo[1,2-a]pyridines: Orally Active Positive
Allosteric Modulators of the Metabotropic Glutamate 2 Receptor, Journal of Medicinal
Chemistry, vol. 55, p. 2688-2701, 2012, doi: 10.1021/jm201561r. [100] Caroline C. D.,
Lucie P., Pierre V., Magali C., Christophe C., Sébastien H., Floriane T., Michèle L., Vincent
 R., Anita C., Maxime D. C., Pascal R., Nadine A. et Patrice V., Targeting the human parasite
Leishmania donovani: Discovery of a new promising anti-infectious pharmacophore in 3-
nitroimidazo[1,2-a]pyridine series, Bioorganic & Medicinal Chemistry, vol. 21, no 22, p.
7155-7164, nov. 2013, doi: 10.1016/j.bmc.2013.09.002.

[101] Brad D. M., Olivier G. B. et Kazunari O., The 14C, 13C and 15N syntheses of MON 37500,
a sulfonylurea wheat herbicide, journal of labelled compounds and radiopharmaceuticals, vol.
48, p. 397-406, 2005, doi: 10.1002/jlcr.934.

[102] Alain G., Mohammed L., Ahmed E., Robert S., Graciela A,, Olivier C., Jean-Claude T.,
Abdelali K., El Mokhtar E,, Jean-Claude D., Myriam W., Yves B., Jan B., Erik D. C., et Jean-
Pierre C., Synthesis of Acyclo-C-nucleosides in the Imidazo[1,2-a]pyridine and Pyrimidine
Series as Antiviral Agents, Journal of Medicinal Chemistry, vol. 39, no 14, p. 2856-2859, 1996.

[103] Jean-Michel C., Jan P., Vincent G., Damien C., Aure L. M. C. L., Alain G., Emmanuel M.,
Jean-Claude T., Olivier C., et Johan N., Synthesis and antiviral activity of an imidazo[1,2-
a]pyrrolo[2,3-c]pyridine series against the bovine viral diarrhea virus, European Journal of
Medicinal Chemistry, vol. 45, p. 2044-2047, 2010.

[104] Shankarappa A B., Venkatesh K. B., Yadav D. B., et Rajesh B., A novel method for the
synthesis of 6-bromo-2-(3,4-dichlorophenyl) imidazo[1,2-a]pyridine using microwave
irradiation, Molbank, p. 2, janv. 2009.

[105] Rajaa B., Angela R. A., Raphael B., Nicolas R., Mathilde C., Amelie B., Romain D., Said
Y., Patricia Melnyk et Laurence Agouridas, Design and synthesis of 2,6-disubstituted-8-amino
imidazo[1,2a]pyridines, a promising privileged structure, Bioorganic & Medicinal Chemistry,
vol. 26, no 12, p. 3296-3307, juill. 2018, doi: 10.1016/j.bmc.2018.04.057.

[106] Dongjian Z., Jiuxi C., Dengze W., Miaochang L., Jinchang D., et Huayue W., An efficient,
catalyst- and solvent-free synthesis of imidazo[1,2-a]pyridines and 2,4-disubstituted thiazoles
on grinding,Journal of chemical research, p. 84-86, 2009.
[107] Dong-Jian Z., Jiu-Xi C., Miao-Chang L., Jin-Chang D., et Hua-Yue W., Catalyst- and
Solvent-free Synthesis of Imidazo[1,2-a]pyridines, Journal of the Brazilian Chemical Society,
vol. 20, no 3, p. 482-487, 2009.

[108] Katrin G., Lutz W. et Fridolin M., Synthesis of Imidazo[1,2-a] annulated Pyridines,
Pyrazines and Pyrimidines by a Novel Three-Component Condensation, Letters Synlett, p.
661-663, 1998.

[109] Martina H., Carmen B. R., Joanna M. W., Estel la B., Holger S., Manfred S. Z., Dieter S.,
Bettina H. et Ewgenij P., SAR-study on a new class of imidazo[1,2-a]pyridine-based inhibitors
of 5-lipoxygenase, Bioorganic & Medicinal Chemistry Letters, vol. 22, no 5, p. 1969-1975,
mars 2012, doi: 10.1016/j.bmcl.2012.01.038.

[110] Carlos Z. H., Unnamatla. M. V. B., et Gámez-Montaño R., Synthesis of Imidazo[1,2-

a]pyridine-Chromones via Microwave-Assisted Groebke-Blackburn-Bienaymé Reaction,
Proceedings, vol. 41, no 1, p. 68, nov. 2019, doi: 10.3390/ecsoc-23-06652.

[111] Taleb H. Al-T. et Raed A. Al-Q., Post Groebke–Blackburn multicomponent protocol:

Synthesis of new polyfunctional imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine
derivatives as potential antimicrobial agents, European Journal of Medicinal Chemistry, vol.
45, no 12, p. 5848-5855, déc. 2010, doi: 10.1016/j.ejmech.2010.09.049.

[112] Mehdi A., Mohammad M., Mahsa A. N. et Peiman M., Catalyst-free three-component
reaction between 2-aminopyridines (or 2-aminothiazoles), aldehydes, and isocyanides in water,
Tetrahedron Letters, vol. 48, p. 7263-7265, 2007.

[113] Anneli N., Mikeal T. N., Olof L., Daniel M., Johan G., Samir Y., Luke R. O., Bachally R.
S., Mats L., Sherry L. M. et Anders K., Synthesis, biological evaluation and X-ray
crystallographic studies of imidazo[1,2-a]pyridine-based Mycobacterium tuberculosis
glutamine synthetase inhibitors, Medecinal Chemistry Communications, vol. 3, no 5, p. 620,
2012, doi: 10.1039/c2md00310d.
[114] Ping L., Li-song F., Xinsheng L., et Guo-qiang L., Synthesis of imidazo[1,2a]pyridines via
three-component reaction of 2-aminopyridines, aldehydes and alkynes, Tetrahedron Letters,
vol. 51, p. 4605-4608, 2010, doi: :10.1016/j.tetlet.2010.05.139.

[115] Prashant B. J., et Viskas N. T., lSetyternthesis of 3-Nitro-2-arylimidazo[1,2-a]pyridines

Using Sodium Dichloroiodide, Letter Synlett, vol. 25, p. 2636-2638, 2014.

[116] Litao A., Xiaojun S., Meng L., Jianfeng Z., Fengxia Z. et Hui Z., Metal-free oxidative
coupling of aminopyridines with nitroolefins to imidazo[1,2-a]pyridine in the presence of I2–
TBHP–pyridine, De Gruyter, p. 2-7, 2016, doi: DOI 10.1515/znb-2015-0171.

[117] Juan A. V., Juan J. V, Julio A. B., Jesfis E. et Hamdouchi C., A New Approach to the
Synthesis of 2- Aminoimidazo[1,2-a]pyridine Derivatives Through Microwave-Assisted N-
Alkylation of 2-Halopyridines, Tetrahedron Letters, vol. 55, p. 2317-2326, 1999.

[118] Zali-Boeini H., Norastehfara N., et Amiri Rudbaria H., One-step Synthesis of Imidazo[1,2-
a]pyridines in Water, Royal Society Of Chemistry, p. 1-16, 2016, doi: 10.1039/C6RA17065J.

[119] Eric P. A. T., Melodie R., Jeffrey M. M., et Dean F. T., Gold-Catalyzed Redox Synthesis
of Imidazo[1,2-a]pyridines using Pyridine N-Oxide and Alkynes, Advanced Synthesis and
Catalysis, vol. 356, p. 687-691, 2014, doi: DOI: 10.1002/adsc.201300996. [120] Mosby W.
L., Heterocyclic Systems with Bridgehead Nitrogen Atoms, Part One, Interscience Publishers
Inc.,.

[120] D. P. Calfee, Methicillin-resistant Staphylococcus aureus and vancomycin resistant

enterococci, and other Gram-positive in healthcare, Curr. Opin. Infect. Dis. 2012, 25, 385.
[121] Payne, D.J. Science, 2008, 321, 1644-1645.
[122] Theresa, L. S. The New England Journal of Medicine, 1999, 340, 493-501.