Costa 2016

European Journal of Medicinal Chemistry 123 (2016) 487e507
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry

journal homepage: http://www.elsevier.com/locate/ejmech
Review article
Biological importance of structurally diversified chromenes

Marta Costa a, b, Tatiana A. Dias c, Alexandra Brito c, Fernanda Proença c, *
a
Life and Health Sciences Research Institute (ICVS), University of Minho, Campus of Gualtar, Braga, Portugal
b
ICVS/3B's e PT Government Associate Laboratory, Braga, Guimara ~es, Portugal
c
Department of Chemistry, University of Minho, Campus of Gualtar, Braga, Portugal
a r t i c l e i n f o a b s t r a c t
Article history: Compounds incorporating the chromene scaffold are largely present in natural products and display a
Received 1 September 2015 wide variety of biological activities. Their low toxicity combined to the broad pharmacological properties
Received in revised form have inspired medicinal chemists in the search for new therapeutic agents.
21 June 2016
This review covers the literature between 1993 and on the biological activity of 2H- and 4H-chro-
Accepted 23 July 2016
Available online 25 July 2016
menes, both from natural and synthetic origin. Includes a section that identifies a selection of chromene-
based natural products, followed by recent literature on bioactive natural chromenes and the corre-
sponding source, covering plants and fruits. Synthetic chromenes are equally important and a separate
Keywords:
Chromene
section addresses the use of these derivatives as new leads for drug discovery. Different biological targets
Natural products were identified, namely those associated with anticancer, antimicrobial, anti-inflammatory, antith-
Synthetic analogues rombotic and antipsychotic activities.
Biological activity © 2016 Elsevier Masson SAS. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488
2. A selection of chromene-based natural products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488
3. Bioactive natural chromenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
3.1. Natural chromenes as anticancer agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
3.2. Natural chromenes as antimicrobial and antiviral agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
3.3. Natural chromenes as anti-inflammatory and antioxidant agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492
3.4. Natural chromenes for Alzheimer treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492
3.5. Natural chromenes with miscellaneous biological activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493
4. Bioactive synthetic chromenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
4.1. Synthetic chromenes as anticancer agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
4.2. Synthetic chromenes as antimicrobial and antiviral agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
4.3. Synthetic chromenes as anti-inflammatory and antioxidant agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
4.4. Synthetic chromenes as antithrombotic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
4.5. Synthetic chromenes acting on receptors of the central nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
4.5.1. Human monoamine oxidase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
4.5.2. Cannabinoid, serotonin and adenosine receptor inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
4.5.3. Dopamine and acetylcholinesterase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502
4.6. Synthetic chromenes acting on estrogen receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502
4.7. Synthetic chromenes with miscellaneous biological activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
* Corresponding author.
E-mail address: [email protected] (F. Proença).
http://dx.doi.org/10.1016/j.ejmech.2016.07.057
0223-5234/© 2016 Elsevier Masson SAS. All rights reserved.
488 M. Costa et al. / European Journal of Medicinal Chemistry 123 (2016) 487e507
1. Introduction
Chromenes are heterocyclic compounds with a benzene ring

fused to a pyran nucleus. For 2H-chromenes I, the carbon atom in
the 2-position participates in a double bond with oxygen (Z ¼ O, 2-
oxo-2H-chromene, commonly named as coumarin), nitrogen
(Z ¼ NH, 2-imino-2H-chromene) or sulfur (Z ¼ S, 2H-chromene-2-
thione) or alternatively forms two single bonds with different
substituents X,Y (II, Fig. 1).
Fig. 2. General structure of 4H-chromenes: 4,4-disubstituted (X,Y), 4-imino (Z ¼ NH)
4H-Chromenes III and IV have the sp3 hybridized carbon atom
and 4-oxo-4H-chromenes or chromones (Z ¼ O).
or a double bond to a heteroatom in the 4-position (Fig. 2).
Particularly relevant are the 4H-chromones, especially if an aro-
matic ring is present in the 2-position. These latter compounds, also products were selected and grouped in Figs. 3 and 4, according to
known as flavones, are widely present in natural products and the their substitution on C3 and/or C4-position. A number of C-2
beneficial health effects attributed to the presence of this scaffold in substituted 2H-chromenes and fused chromenes were presented in
dietary products enormously boosted the importance of this nu- Fig. 5.
cleus. The extensive work that has been developed on the synthesis Coumarins 1a-1c were isolated from the leaves of Phellodendron
and biological activity of chromones and in particular flavones, fully amurense, a tree usually found in the northern and central parts of
justifies that this subject will be separated from the present review. Taiwan (Fig. 3) [10]. Quadriseptin A (1d, Fig. 3) was obtained from
The importance of coumarins was recognized almost seven Paraphaeosphaeria quadriseptata, a rhizosphere fungus isolated
decades ago [1], in a review article that emphasized their wide from the Christmas cactus, Opuntia leptocaulis [11].
distribution in plants and extensively discussed the synthetic In more recent years, Ayapin (2a, Fig. 3) was isolated from Hel-
methods available for their preparation. Another review on the lianthus annuus, a major oil seed [12,13]. Two regioisomeric struc-
literature of natural coumarins published between 1988 and 1994 tures, 2b and 2c, were isolated from a chloroform extract of the
mainly covers their separation and identification from plant ex- aerial parts of Pterocaulon virgatum [14].
tracts and in some cases the chemical synthesis [2]. Acetonide 3, prenylcoumarins 4a-f and bis-prenylcoumarins 5
The variety and relevance of the pharmacological properties of and 6 (Fig. 3) were first isolated from the ethyl acetate soluble
natural coumarins has been emphasized over the years in reviews fraction of Fatoua pilosa, a small plant distributed throughout
and articles [3,4]. The book series “The Chemistry of Heterocyclic Philippines, Moluccas, New Guinea and Taiwan [15].
Compounds” [5] dedicated an entire volume to the synthesis and 6-Acylcoumarin 7 was isolated in Gua Musang, from an extract
biological relevance of chromenes, chromanones and chromones. collected of Mesua racemosa, a large tree widely distributed in
The collections “Comprehensive Heterocyclic Chemistry” [6] and tropical Asia (Fig. 4) [16].
“Comprehensive Heterocyclic ChemistryII” [7] also contemplate Coumarins 8e10 were isolated from the ethyl acetate soluble
reviews on the structure, synthesis and applications of pyrans and fraction of the stem bark and the fruits of the Calophyllum dispar
their benzo derivatives. (Fig. 4) [17].
The low toxicity of the natural compounds and their broad Compound 11 is an Alternariol derivative isolated from an un-
pharmacological properties are attractive features for medicinal identified fungal culture of an undisclosed Chinese mangrove
chemists and a source of inspiration for the design of novel ther- habitat [18e20]. Aspergiolide A and B (12a and 12b, Fig. 4) were
apeutic agents. The pharmaceutical industry is also deeply aware of isolated from cultures of the marine-derived fungus Aspergillus
this important scaffold in the search for new drug candidates. glaucus, collected from the mangrove roots in the Fujian province of
This review is organized in three sections. The first section China.
presents an overview of chromene-based natural products, iden- Ocimarin 13a and 13b (Fig. 4) were isolated from the n-butanol
tifying their origin and relevance, complementing recent reviews extract of the leaves of holy basil, Ocimum sanctum [21].
[8,9] on this subject. This is followed by a discussion on the bio- The lysilactones A-C (14a-c, Fig. 4) were isolated from the
logical applications of natural and synthetic chromene derivatives. ethanolic extract of aerial parts of Lysimachia clethroides, a tradi-
tional Chinese folk medicine which is widely distributed in many
provinces of China [22].
2. A selection of chromene-based natural products
Polycarcin 15 has been isolated from a culture extract of Strep-
tomyces polyformus [23,24].
A wide range of novel chromene-based natural products were
Gilvocarcins (16a-c, Fig. 4) are metabolites of certain Strepto-
reported during the last two decades. 2H-Chromenes and in
myces species. These naturally occurring C-aryl glycosides have the
particular 2-oxo-2H-chromenes, also known as coumarins, are
sugar moiety linked to the para position of a fused phenolic group
among the most studied and reported class of these compounds.
[25].
Some examples of 2-oxo-2H-chromenes identified in natural
Arahypin-5 (17, Fig. 5) was isolated from peanut seeds chal-
lenged by an Aspergillus caelatus strain [26,27].
Xanthyletin (18a), xanthoxyletin (18b), seselin (19) and atala-
phyllidine (22b) (Fig. 5) were isolated from Citrus sinensis grafted
on Citrus limonia, which is the key rootstock for citriculture in Brazil
[28]. Calanone 20 was isolated from Calophyllum teysmannii
[29,30]. The prenylated chromene 21 was isolated from an extract
from New Zealand endemic brown alga Perithalia capillaris [31,32].
Azacridone A 22a is the first naturally occurring aza-acridone
alkaloid, isolated from the roots of Citrus paradise [33,34].
Fig. 1. General structure of 2H-chromenes: 2,2-disubstituted (X,Y), 2-imino (Z ¼ NH),
2-thione (Z ¼ S) and 2-oxo-2H-chromenes or coumarins (Z ¼ O).
M. Costa et al. / European Journal of Medicinal Chemistry 123 (2016) 487e507 489
Fig. 3. Natural products containing the 2-oxo-2H-chromene moiety.
Fig. 4. Natural products containing the C3 and/or C4 substituted 2-oxo-2H-chromene moiety.

Fig. 5. Natural products containing the C-2 substituted 2H-chromene moiety.
3. Bioactive natural chromenes (Fig. 6). These isoprenylated dihydroxycoumarins showed EC50
values that, in general, were lower than 10 mM for human breast
3.1. Natural chromenes as anticancer agents tumor T47D cells and prostate tumor PC-3 cell line. Coumarins
bearing a 6-prenyl-8-(3-methyloxobutyl) substituent demon-
Coumarins 23 and 24 (Fig. 6) isolated from the fruit and stem strated enhanced inhibition of HIF-1 [42].
bark of Calophyllum dispar distributed in the tropical rain forest), Natural coumarins 33a-c (Fig. 6) were evaluated for their DNA
showed cytotoxic effect against KB cell lines. These compounds cleavage potency, since DNA strand scission agents demonstrated
inhibited 50% of the cellular growth at a concentration ranging to be valuable antitumor agents. These compounds were extracted
from 4 to 8 mg/mL [35]. from the roots of Mallotus resinosus and although the potency of
The dichloromethane extract from the stem bark of Kielmeyera these molecules for DNA cleavage was not exceptional, the authors
albopunctata, a plant that can be found in the Brazilian plateau, led considered that these compounds were valuable leads for synthetic
to the isolation of coumarins 25a and 25b (Fig. 6). These com- derivatives, due to the simplicity of their structure [43].
pounds were active against several human cancer cell lines (Lu1, Psoralidin 34 (Fig. 6), a naturally occurring chromene isolated
Col2, KB and LNCaP) with ED50 from 11.1 to 19.8 mg/mL [36]. from Psoralea corylifolia, was identified as a potent anticancer
Neo-tanshinlactone 26 (Fig. 6) was isolated as a minor compo- agent, exhibiting cytotoxic effects on gastric, colon and breast
nent from the ethanol extract of the root of Salvia miltiorrhiza. This cancer cell lines [44,45]. This chromene also exhibited antioxidant
chromene was analyzed for its antitumor activity against several [46], antibacterial [47] and antidepressant activity [48].
human breast cancer cell lines of clinical significance and exhibited Thiaplidiaquinones A (35) and B (36) (Fig. 6) were isolated from
low ED50 values (0.2e0.6 mg/mL) for two ERþ (MCF-7 and ZR-75-1) the ascidian Aplidium conicum available along Sardinia coast (Italy)
and for one ER-/HER-2 (SK-BR-3) overexpressing cell line [37,38]. [49]. These complex compounds were studied for their cellular
The authors also established a synthetic route for this molecule. toxicity using human leukemia T cell line with propidium iodide
Feliciano et al. extracted 17 chromene-based compounds from (PI) staining and flow cytometry. The treated cells showed a sig-
the leaves of Marila pluricostata, a tree distributed throughout the nificant loss of nuclear DNA (chromatinolysis) and both compounds
regions of Panama, Costa Rica and Colombia. Compounds 27a, 27b induced a strong production of intracellular reactive oxygen species
and 28 (Fig. 6) with R1 ¼ H and R2 ¼ CH2CHC(CH3)2 were newly (ROS). Thiaplidiaquinones 35 and 36 were considered to induce cell
identified molecules and chromenes 28, 29 and 9 examples of death by apoptosis.
chromenes 30 were identified as known mammeisin derivatives.
This set of compounds exhibited anticancer activity in human 3.2. Natural chromenes as antimicrobial and antiviral agents
cancer cell lines MCF-7, H-480 and SF-268, showing GI50 as low as
0.1 mg/mL [39]. Coumarins 37 and 38 (Fig. 7) were isolated from the leaves of
Chromenes 31a-e (Fig. 6) were isolated from the fungal endo- Aesculus pavia and Amyris texana respectively, and showed anti-
phyte Alternaria sp. of the Egyptian plant Polygonum senegalense. fungal activity [50,51]. Pavietin was analyzed for various fungal
These natural compounds were evaluated for their cytotoxic ac- pathogens and showed the highest activity for Guignardia aesculi at
tivity against L5178Y mouse lymphoma cells and especially com- the three concentrations tested (50, 100 and 200 mM), suggesting
pounds 31a-c proved to be active, with EC50 values of 1.7e7.8 mg/ that this compound displayed a defensive role against this fungal
mL. A study of the in vitro inhibitory potential of the extracted attack [50]. Chromene 38 was tested against Botrytis cinerea and
chromenes against 24 different protein kinases showed that the showed moderate activity. This compound was also evaluated as an
compounds successfully inhibited several enzymes, with promising algicidal agent and demonstrated selectivity toward Planktothrix
IC50 values (lower than 10 mg/mL) [40,41]. perornata (LCIC of 10.0 mM and IC50 of 2.3 mM) compared with
Coumarins 32, isolated from tropical/subtropical plant Mammea Selenastrum capricornutum (LCIC of 100.0 mM and IC50 of 12.6 mM)
americana were found to inhibit the activation of HIF-1 (hypoxia- [51].
inducible factor-1) in human breast and prostate cancer cell lines Asphodelin A 39 and the glucoside derivative 40 (Fig. 7) were
Fig. 6. Natural products with anticancer activity.
isolated from the bulbs and roots of Asphodelus microcarpus, Gramniphenols 43, 44a and 44b (Fig. 7) were fully characterized
collected in Egypt [52]. These chromenes exhibited antimicrobial and tested for their antiviral activity, showing anti-tobacco mosaic
activity for Staphylococcus aureus, Escherichia coli and Pseudomonas virus activity with IC50 values of 20.8, 40.8 and 57.7 mM respectively.
aeruginosa and compound 39 showed the highest potency with The compounds were also investigated as anti-HIV agents,
minimal inhibitory concentration (MIC) values of 4e16 mg/mL. The although only a moderate effect was detected.
compounds were also tested for their antifungal activity against Several coumarins were extracted from the leaves of Galipea
Candida albicans and Botrytis cinerea and Asphodelin A (MIC values panamensis, a small tree found in eastern Panama and northwest
of 64 and 128 mg/mL respectively) was more efficacious than the Colombia. The ethyl acetate extract afforded chromenes 45a-c
naturally occurring compound 40 (moderate/low activity). (Fig. 7) and these compounds were tested for their activity against
Chromenes 41a,b and 42 (Fig. 7), extracted from grapefruit oil, Leishmania panamensis [55]. Chromenes 45a and 45b proved to be
were identified as moderate/good antibacterial agents, treating the most active, with EC50 of approximately 10 mg/mL. The EC50
methicillin-resistant Staphyloccus aureus bacterial strain [53]. value for 45c was slightly higher (14.1 mg/mL).
Coumarins 41b and 42 were isolated as a mixture (2:1) that could 5-Methylcoumarins 46a,b (Fig. 7), isolated from Vernonia bra-
not be separated and the compounds were synthesized to be chycalyx, were also investigated for their activity against protozoa,
evaluated separately. Compound 41a enhanced the susceptibility of namely Leishmania major promastigotes and Plasmodium falcipa-
methicillin-resistant Staphyloccus aureus strains to ethidium bro- rum schizonts, in concentrations that do not significantly inhibit
mide and norfoxacin, to which these micro-organisms are usually human lymphocyte proliferation [56]. Coumarin 46b displayed the
resistant. best IC50 values (13.4 mM) for L. major and both compounds pre-
Natural chromene-based compounds were also isolated from sented values above 50 mM for two strains of P. falciparum.
Arundina gramnifolia, a plant belonging to the orchid family [54]. Another example of chromene derivatives active against
Fig. 7. Chromene derivatives from natural sources, with antimicrobial and antiviral activity.
protozoa parasites, isolated from the roots, stems and leaves of halotolerant fungus Penicillium citrinum B-57 and presented IC50
Piper gaudichaudianum were the gaudichaudianic acid enantiomers values from 10.6 to 58.7 mM, except for compound 52 that was
47 (Fig. 7) [57]. The pure enantiomers and their racemic mixtures inactive [61].
were evaluated against the Y-strain of Trypanosoma cruzi and the
racemic mixture turned out to be the most active (IC50 ¼ 55.8 mM)
with a maximum synergistic effect.
3.4. Natural chromenes for Alzheimer treatment
3.3. Natural chromenes as anti-inflammatory and antioxidant
agents The alkaloid Taspine 56 (Fig. 9) was extracted from the leaves of
Magnolia x soulangiana and detected for the first time in this species
Chromene-based compounds 48a-c (Fig. 8) were isolated from [61]. This compound was tested as AChE inhibitor in an enzyme
the fruits of Melicope semecarpifolia, a tree that grows at low alti- assay showing an IC50 of 0.33 mM and proving that this chromene
tude in the forest of Taiwan and Philippines [58]. These compounds derivative was even more active than the used positive control
were tested for their anti-inflammatory activity, using the inhibi- (Galanthamine, IC50 ¼ 3.20 mM) [62].
tion effect on superoxide anion generation and elastase release by Glabridin 57 (Fig. 9), an isoflavane, was isolated from the roots of
human neutrophils in response to fMet-Leu-Phe/Cytochalasin B. A Glycyrrhiza glabra and its effects on cognitive functions and
moderate effect was observed, with IC50 between 7 and 31 mg/mL. cholinesterase activity were studied in mice [63]. The results sug-
Cheng and co-workers investigated the extract of soft coral gest this is a promising drug candidate for memory improvement to
Sinularia capillosa and isolated a set of compounds including cap- be explored in the management of Alzheimer patients. Glabridin
illobenzopyranol 49 (Fig. 8) [59]. The in vitro anti-inflammatory was also recently reported as an anti-obesity agent [64] and it is
activity was determined for this chromene, using LPS-stimulated widely used in the cosmetic industry.
cells (RAW 264.7 cells). Chromene 49 did not inhibit COX-2 pro- Compound 58 and Macluraxanthone 59 (Fig. 9) were also
tein expression but it significantly inhibited iNOS protein evaluated for AChE inhibitory effect. Chromene 58 was extracted
(approximately 36% inhibition at 10 mM). This compound was also from Garcinia livingstonei and Ki values for competitive inhibition
tested as an anticancer agent using mouse lymphocytic leukemia proved to be quite interesting (1.9 mM) [65]. Macluraxanthone 59
cell line P-388 and an ED50 value of 12.7 mM was determined. was isolated from nonpolar fractions of the methanolic extract,
Compounds 50 to 55 (Fig. 8) were tested for their antioxidant from the root bark of Maclura pomifera and investigated for the
activity, using DPPH as model radical to evaluate the radical scav- in vitro AChE and butyrylcholinesterase (BChE) enzyme inhibitory
enging properties of the molecules. Ubichromenol 50 could be activity [66]. This naturally occurring compound proved to be a
isolated from various animal tissues and presented a weak effect as specific inhibitor of AChE with an IC50 value of 8.47 mM and a Ki of
antioxidant [60]. Chromenes 51 to 55 were obtained from 3.43 mM.
Fig. 8. Natural chromenes with anti-inflammatory and antioxidant properties.
Fig. 10. Bioactive chromenes present in nature.
Fig. 9. Chromene derivatives as AChE inhibitors.
This compound inhibited endothelin converting enzyme with an

IC50 value of 9 mM and has potential therapeutic use in hyper-
3.5. Natural chromenes with miscellaneous biological activities
tension treatment through the reduction of endothelin
production.
Kim and co-workers isolated Scopoletin 60 (Fig. 10), the main
(þ)-Calanolide A 62 was isolated from Calophyllym lanigerum, a
bioactive constituent of flower buds from Magnolia fargesii, and
native tree of the Malaysian rain forest and ()-calanolide B 63
studied the use of this compound for the treatment of sugar cat-
from the latex of the tropical rainforest tree Calophyllum teysmannii
aracts, that can lead to human blindness [67]. The inhibition of
(Scheme 10) [71]. These compounds were evaluated for their HIV-1
aldose reductase, an enzyme linked to cataract induction in dia-
inhibitory activity and proved to be potent candidates, with ED50
betic patients, was studied and proved that Scopoletin 60 delayed
values in the nano-molar range, as documented in several publi-
the progression of the cataracts that were induced by dietary
cations [71e73].
galactose. This investigation concluded that Scopoletin 60 pre-
The extract of the leaves and twigs of Rhododendron daur-
vented changes in lens morphology induced by galactose and the
icum, growing in the northern part of China, eastern part of
protective effect against sugar cataracts was mediated by inhib-
Siberia, and Hokkaido, exhibited significant anti-HIV activity.
iting both aldose reductase activity and oxidative stress. This
Daurichromenic acid 64 (Fig. 10) was isolated from this extract
compound has also been studied by other groups, that explored
[74]. The anti-HIV potential of this compound was evaluated
the antioxidant properties and the potential use as an AChE in-
using acutely infected H9 and showed promising results: EC50
hibitor [68,69]. This compound was also identified as a potential
value of 0.00567 mg/mL, IC50 value of 21.1 mg/mL and a good
anticancer agent [43].
therapeutic index (3.710).
A chemical examination of the roots of the plant Dalea fili-
ciformis led to the isolation of Daleformis 61 (Scheme 10) [70].
4. Bioactive synthetic chromenes and nano-molar concentration range.

4-Arylcoumarins 65 (Fig. 11) were prepared and tested for their
4.1. Synthetic chromenes as anticancer agents anticancer potential [75]. Compounds bearing the substituents
R2 ¼ H, R3 ¼ OMe, R4 ¼ OH and R1 ¼ H or R1 ¼ OMe led to the best
A large number of chromene derivatives have been prepared results inhibiting the growth of CEM leukemia cell line at a low
with interesting anticancer properties and several examples concentration (0.083 and 0.52 mM respectively). These two com-
showed cytotoxic effects on cancer related cell lines in the micro pounds demonstrated inhibition of tubulin assembly inducing
Fig. 11. Synthetic chromene derivatives with anticancer properties.

apoptosis but they also triggered cell death via a non-apoptotic methyl or ethyl group in the R3 position led to the best inhibition of
pathway. cell growth and also to the best selectivity values, indicating that
Chromene derivatives 66 (Fig. 11), bearing an amine moiety in the substitution pattern in the furan and the neighboring aromatic
the 4 position, were tested for their ability to inhibit DNA synthesis ring strongly influenced the activity. This compound showed ED50
(Ehrlich cells) and cell growth (HeLa cells) [76]. This study showed of 0.45 mg/mL for MCF-7 and 0.18 mg/mL for ZR-75-1. In a different
that some compounds were only active in one of these tests and work, the same research group investigated a new set of neo-
that the results of the two tests could not be correlated. In general, tanshinlactone analogues 73, varying the substitution pattern in
several molecules were identified as antiproliferative and cytotoxic different ring positions [86]. Once again several chromenes were
agents, with low IC50 values (1.74e12.9 mM) and the activities identified as promising anti-cancer agents with low ED50 values
depended on both the amine moiety and the substituent in the (lower than 1 mg/mL). The methyl group in the R1 position and alkyl
aromatic ring of the chromene. The phenylamino and cyclo- groups in R3 led once again to the best results.
alkylamino groups proved to be the most effective amino sub- Analogous chromenes 74 (Fig. 11), bearing an amine moiety in
stituents and the presence of an additional aromatic ring in the the 4 position instead of a furan ring, were evaluated as growth
chromene moiety, providing a tricyclic nucleus, also enhanced the inhibition agents against a set of tumor cell lines [87]. These
biological activity. included breast cancer (ZR-75-1, MDA MB-231, SK-BR-3), non small
Griffin and co-workers prepared a series of DNA-dependent cell lung cancer (A549), prostate cancer (DU145), nasopharyngeal
protein kinase (DNA-PK) inhibitors as agents to enhance cytotox- carcinoma (KB) and vincristine-resistant KB subline (KB-VIN) cell
icity of DNA-damaging therapies used in the treatment of cancer lines. The substituents in the amine moiety were of aliphatic, aro-
[77]. Chromenes 67 (Fig. 11) bearing a heterocyclic amine (mor- matic and heterocyclic nature. The aromatic substitution pattern
pholine or piperidine) in the 4 position were analyzed and the in- proved to be the most convenient, since it led to low ED50 values
hibition, expressed by the IC50 value, varied between 1.75 and (0.01e5.8 mM), in the tested cell lines. The 4-methoxy and 3-
11.31 mM. The best IC50 value (1.75 mM) was obtained for the methylphenyl moiety with R1 ¼ H led to the best ED50 values,
chromene bearing a morpholine group in position 4 and a methoxyl from 0.01 to 0.76 mM, favoring the inhibition of cell growth. Similar
group in C6 of the aromatic ring. chromenes 75 were also prepared by the same authors (Fig. 11)
Inhibitors of endothelial cell proliferation are important for the [88]. These compounds included a five or six-membered ring
treatment of pathologies associated with angiogenesis, including attached to the aromatic chromene moiety, instead of a second
solid tumors. Nonesteroidal chromene derivatives 68a and 68b aromatic ring as for chromenes 74. The effect of the amine sub-
(Fig. 11) were reported as specific inhibitors of endothelial cell stituent was also studied. Compounds incorporating a six-
proliferation after evaluation using primary human vein endothe- membered ring and a 4-methoxyphenyl group in the amine unit,
lian cells [78]. These molecules are structural analogues of Alter- with R3 ¼ H or Me, were highly active against several human tumor
nariol 31a and other natural derivatives 31 (Fig. 6), also exhibiting cell lines from different tissues, with ED50 values from 0.32 to
anticancer activity. 0.008 mM.
Novobiocin analogues 69 and 70 (Fig. 11) were tested by Blagg The inhibition of hyperplasia formation by compound 76
et al. [79e81] and by Bras and co-workers [82] as antiproliferative (Fig. 11) was studied using estradiol-induced rat uterine hyper-
agents and potential heat shock protein 90 (Hsp90) inhibitors, a plasia [89]. It is known that estrogen hormones induced changes in
promising target for the development of anticancer agents. Blagg the structure of the tissue in the uterus lead to atypical hyperplasia
et al. proved that chromene derivative 69, bearing a methyl group and subsequent cancer formation in the endometrium. The ovari-
in R2 and in the 8 position of the aromatic ring (R1), were potent ectomized rats were treated with 100 and 200 mg/kg of compound
inhibitors of the Hsp90 protein-folding process [79]. These authors 76 and this chromene proved to induce apoptosis via the intrinsic
studied the antiproliferative activity of chromenes 69 bearing a pathway (interfered with Akt activation and decreased X-linked
substituted biaryl or 2-indolyl groups using several cell lines of inhibitor of apoptosis protein expression) and to inhibit estradiol-
breast (SkBr3, MCF-7), colon (HCT116), pancreatic (PL45) and induced hyperplasia formation in rat uterus.
prostate (LNCaP, PC-3) cancer. Several promising compounds were Over the last few years, Xing et al. investigated the cytotoxicity
identified, with low IC50 values [80,81]. Derivatives 70, lacking the of 4H-chromene 77 and derivatives for cancer cell lines (Fig. 11).
noviose moiety, were tested by Bras and co-workers. Substituents These authors were particularly interested in compounds that
in position 4 and 7 were crucial and a tosyl moiety in these posi- selectively target drug-resistant cancer cells to overcome this
tions led to the best results. These compounds not only led to cell problem. Compound 77, with R1 ¼ R2 ¼ Et and R3 ¼ H, was tested on
death (MCF-7 cell line), but also to degradation of Hsp90 client cancer cells overexpressing the antiapoptotic Bcl-2 family proteins
proteins [82]. Coumermycin A1 derivatives 71 (Fig. 9) were also and was found to act as an antagonist, demonstrating selective
analyzed and demonstrated inhibitory activity against Hsp90 pro- cytotoxicity toward malignant cells, overcoming drug resistance
tein folding process [83]. [90,91]. This compound induced cell death trough the endo-
Compounds 72 (Fig. 11) were also identified as antiproliferative plasmatic reticulum (ER) pathway, inducing ER stress and ER Ca2þ
agents and inhibitors of heat shock protein 90, through the sup- release. Inhibition of ATPase activity of sarcoplasmic/endoplasmic
pression of HIF-a client protein. These chromenes exhibited activ- reticulum Ca2þ-ATPase was also observed. Compound 77 with
ities in the nano-molar range in the non-small-cell lung cancer R1 ¼ R2 ¼ Et and R3 ¼ 3,5-OMe led to more promising results and
H1299 cell line. The antiangiogenic activities were also measured demonstrated lower micromolar cytotoxicity against a wide-range
using zebrafish embryos and a dose dependent manner was of hematologic and solid tumor cells (over 11 different cancer cell
observed [84]. lines) [92,93]. The behavior of this chromene was also studied in
A series of neo-tanshinlactone analogues 73 (Fig. 11) were pre- camptothecin (CCRF-CEM/C2) and mitoxantrone (HL-60/MX2)
pared and tested for their anticancer activity in several breast resistant cancer cells and selectively killed drug-resistant cells over
cancer cell lines (MCF-7, ZR-75-1, MDA MB-231, HS 587-T, SK-BR-3), parent cancer cells. A structure-activity relationship analysis led to
non small cell lung cancer (A549), skin cancer (A431), prostate the development of other analogues of compound 77, bearing the
cancer (LN-CaP and PC-3), colon cancer (SW620), nasopharyngeal same substitution pattern in R3, but with R1 ¼ R2 ¼ CH2C^CH [93].
carcinoma (KB) and vincristine-resistant KB subline (KB-VIN) [85]. This compound showed enhanced activity, with an IC50 value of
Chromene 73 bearing a methyl group in the R1 position and a 640 nM in the multi-drug resistant HL60/MX2 cell line.
The activation of hypoxia inducible factor pathway (HIF) helps alkyl chain led to an ED50 value in the nano-molar range (32.5 nM)
tumor cells to adapt to hypoxia conditions and leads to therapeutic but a low therapeutic index (102e308), when tested against 100
resistance and has become an important target in cancer treatment. TCID50 HIVADA infection in a pseudovirus-based assay. The best
2H-Chromenes 78 (Fig. 11) were identified as inhibitors of HIF-1, results were obtained for the second substitution pattern, were a
when tested under hypoxia conditions using human glioma cell lower ED50 value (2.85 nM), together with a successful therapeutic
line LN229-HRE-Lux [94,95]. The effect of the substitution pattern index (higher than 10000) anticipate a better anti-HIV-1 activity
in the sulfonamide group was studied. For R1 ¼ 3,4- [102]. Coumarins 84 were tested against wild-type HIV-1 cells and
dimethoxyphenyl and R2 ¼ cyclopropane, an IC50 value of proved to be potent anti-HIV agents against MT-4 cells [103]. Low
500 nM was found. On the other hand, when R2 was the phenyl EC50 values (9 mM/mL) were obtained for 3 compounds, bearing
group and the R1 substituent was a the 3,4-dimethoxyphenyl, 4- the substituents R1 ¼ 7,8-Me, R2 ¼ H, R3 ¼ NO2 and R1 ¼ 7-OH,
methoxyphenyl or 3,5-dimethylphenyl moiety, IC50 values in the R2 ¼ H, R3 ¼ NO2 or Cl.
nM range were also determined. It was established that compound Chromenes 85 (R1 ¼ Ph or CH]CH-Ph, Fig. 12) were evaluated
78, bearing a 3,4-dimethoxyphenyl in the sulfone group and an as anti-picornavirus agents, against human rhinovirus (HRV) se-
aromatic ring in the amine moiety (IC50 value of 650 nM) did not rotypes 1B and 14 and enterovirus (EV) 17 [104]. The tested com-
alter the levels of HIF-1, but interfered with the ability of HIF-1a/ pounds proved to affect the replication of picornaviruses, although
HIF-1b to interact with cofactors p300/CBP to form an active they were more effective against the HRVs. The best activity results
transcriptional complex. were found for the chromene derivative where R1 ¼ R2 ¼ H and
2H-Chromene 79 (Fig. 11), bearing a thiazolidine-2,4-dione, R3 ¼ CH ¼ CHPh and IC50 values of 0.20 and 1.30 mM were deter-
rhodamine or hydantoin moiety in C3, were also studied for their mined for HRV 1B and HRV 14, respectively. This compound seemed
anticancer properties, using human alveolar basal epithelial to affect functions related to the viral capsid, such as the virus
adenocarcinoma (A549), human chronic myelogenous leukemia attachment to cell membrane and probably the uncoating of viral
(K562), human breast adenocarcinoma (MCF-7) and human acute genome. A slightly higher IC50 value (12.50 mM) was determined for
lymphoblastic leukemia (MOLT-4) cell lines [96]. Chromene 79 EV 71.
bearing a bromine atom in position 6 of the aromatic ring and the Angelicin derivatives 86 (Fig. 12) were tested under an anti-
hydantoin moiety (X ¼ O, Y ¼ NH and R2 ¼ H) in the 3-position, led influenza drug discovery program [105]. Compound 86 bearing a
to the best results with IC50 values comparable to cisplatin, a phenyl ring as R1 and a 2-thienyl moiety as R2 was a lead com-
standard antitumor agent. pound, with an IC50 value of 70 nM when tested in the A/WSN/33
A series of coumarins 80 bearing the hydrazide-hydrazone (H1N1) strain. This molecule showed also promising activity on
moiety was synthesized and evaluated in vitro against human other strains of influenza A and B, keeping the nano-molar activity.
drug-resistant pancreatic carcinoma (Panc-1) cells and drug- A preliminary study on the mechanism of action pointed towards
sensitive (hepatic carcinoma; Hep-G2 and leukemia; CCRF) cell viral ribonucleoprotein as the molecular target.
lines. The 6-Brominated derivatives were more potent than doxo- The search for antibacterial/antimocrobial agents continues to
rubicin (DOX) against resistant Panc-1 cells. In particular, derivative be important due to the prevalence of drug-resistant bacterial in-
80 with R1 ¼ 6-Br and R2 ¼ 2-thiophen showed significant cyto- fections. Chromenes 85e91 (Fig. 13) were also evaluated as anti-
toxicity against all tested cells (IC50: 3.60e6.50 mM) as well as bacterial or antimicrobial agents. The antimicrobial activity of
induced the expression of apoptotic- and cell cycle arrest (G2/M)- chromenes 85 was determined using the agar diffusion technique,
genes in resistant Panc-1 cells. Moreover, it induced the up- gram positive Staphylococcus aureus and gram negative Escherichia
regulation of CDKN1A, DDIT4, GDF-15 and down-regulation of coli strains. These chromenes showed moderate antimicrobial ac-
CDC2, CDC20, CDK2 genes [97]. tivity, when compared to Streptomycin [106]. Chromenes 86 and 87
Coumarin derivatives 81 containing the 4,5-dihydropyrazole were tested against several gram positive and gram negative bac-
moiety have been reported as potential telomerase inhibitors. For teria and showed that the substituent in the aromatic ring was
example, compound 81 with R1 ¼ H, R2 ¼ COMe and R3 ¼ Ph determinant for the antimicrobial activity [107]. Compound 86
exhibited high activity against human gastric cancer cell SGC-7901 with a p-bromine atom in R3 showed efficacy when inhibiting
with an IC50 value of 2.69 ± 0.60 mg/mL. Furthermore, this com- S. aureus growth and compound 87 bearing chlorine and fluorine
pound together with derivative 81 with R1 ¼ Br, R2 ¼ COMe and atoms in R3 were especially active against Serratia marcescens and
R3 ¼ Ph can strongly inhibit telomerase exhibiting IC50 values of Proteus mirabilis, when compared with Ampicillin.
2.0 ± 0.07 and 1.8 ± 0.35 mM, respectively [98]. Compound 81 Compounds 88 exhibited promising activity against gram
bearing R1 ¼ H, R2 ¼ COCH2N(nPr)2, R3 ¼ 4-CF3C6H4 showed a negative Pseudomonas aeruginosa and E. coli and also against gram
potent inhibitory activity with an IC50 value of 0.98 ± 0.11 mM. The positive S. aureus, with MIC values of 25 or 50 mg/mL, when
in vivo evaluation results indicated the potential for this compound compared to Chloramphenicol, Ciprofloxacin and Ampicillin [108].
to inhibit the growth of S180 and HepG2 tumor-bearing mice be- Chromenes 89, with a thiazole moiety, proved to be active against
sides having significantly increased the survival rate of mice S. aureus, Bacillus subtilis, E. coli and P. aeruginosa microorganisms in
bearing EAC tumor [99]. concentrations above 4 mg/mL, comparable to the standard drug
Compound 81 with R1 ¼ H, R2 ¼ COCH2S(CH2)4CH3, R3 ¼ 4- Ceftriaxone [109]. Also 4H-chromenes 90a and 90b inhibited the
CF3C6H4 presented strong telomerase inhibitory activity with an growth of several bacterial strains. Chromene 90a proved to be
IC50 value of 0.92 ± 0.09 mM [100]. especially active against gram negative bacteria Vibrio cholerate
(MIC ¼ 12.5 mg/mL) whereas 90b was more active against gram
4.2. Synthetic chromenes as antimicrobial and antiviral agents positive Streptococcus pneumonia (MIC ¼ 12.5 mg/mL), as compared
to Ampillicin (MIC ¼ 100 mg/mL for both strains) [110]. Coumarins
Chromenes 82e84 (Fig. 12) were synthesized and evaluated for 91 proved to be effective inhibitors against Bacillus anthracis and
their anti-HIV potential. Benzo[c]chromen-6-ones 82 were slightly S. aureus. The most potent compound with R1 ¼ R3 ¼ Me, R2 ¼ 4-
active on HIV aspartyl protease with IC50 values from 10 to 50 mM chloro-1,10 -biphenyl, R4 ¼ OH and n ¼ 2 was reported to have
[101]. Calanolide A derivatives 83 showed promising activity IC50 values of 1.5 and 1 mM against the DNA duplex strand-
against HIV-1, especially when R1 ¼ n-C3H7, R2 ¼ H and R1 ¼ n- unwinding activities of both B. anthracis and S. aureus helicases,
CH2Br, R2 ¼ H. In the former compound, the extended hydrophobic respectively. This compound was also potent against multiple
Fig. 12. Chromenes as antiviral agents.
Fig. 13. Chromene-based compounds with antibacterial activity.
Ciprofloxacin-resistant MRSA strains with low MIC values [111]. higher than the standard drug Rifampicin (MIC ¼ 40 mg/mL) [113].
Mycobacterium tuberculosis is a human pathogen responsible for Chromenes 95 also proved to be promising antitubercular agents,
tuberculosis and associated with a high mortality rate. Chromene- especially the compound bearing a methoxyl group in position 9,
based molecules (Fig. 14) were identified as antitubercular agents. that showed MIC95 of 89 mM for M. tuberculosis and M. bovis and
Compound 92 presented a MIC value of 2.0e4.0 mg/mL against also proved to be non-toxic to mammalian cells (VERO cells) [114].
M. bovis [112]. 4H-Chromenes 93 and 94 were tested against 2H-Chromenes 96 and 97 (Fig. 15) were evaluated against the
M. tuberculosis H37Rv and derivatives with R1R2 ¼ eCH]CHCH]N- promastigote form of Leishmania major using the MTT assay [115].
and R3 ¼ R4 ¼ H proved to have a MIC value of 62.5 mg/mL, slightly All the tested compounds presented in vitro anti-leishmanial
R2 ¼ OH, R3 ¼ H; R1 ¼ CO2Et, R2 ¼ R3 ¼ H and R1 ¼ CO2Et, R2 ¼ OH,

R3 ¼ OCO(3-Cl-C6H4)) and 100 induced 48.7e58.9% protection
against carrageenin induced rat paw edema. Derivatives 104 with
R1 ¼ H, R2 ¼ piperidinyl and R1 ¼ H, R2 ¼ morpholinyl inhibited
75.7 and 77.7%, respectively, carrageenin induced raw paw edema.
Several 6,7 or 7,8-fused dioxolane coumarins 105 and 106
(Fig. 16) were evaluated for their antioxidant and anti-
inflammatory potential [119]. All compounds displayed moderate
antioxidant activity in the DPPH assay. Compounds 106 (R1 ¼ Et,
R2 ¼ CO2Et and R1 ¼ Me, R2 ¼ Ph) were screened in vivo (0.01 mmol/
kg) for their anti-inflammatory potential and both induced
55e57.4% protection against carrageenan-induced paw edema,
presenting a higher activity than the reference drug, indomethacin
(47%). Additional studies were carried out based on the ferrous-ion
stimulated peroxidation of linoleic acid and compounds 106, with
R1 ¼ Me, R2 ¼ Ph, were the most active.
a,b-Unsatured 2H-chromenes 107 with R1 ¼ COCH]CHAr
(Fig. 17) were selected by Hamdi et al. to be tested as antioxidant
and antibacterial agents. Compounds 107 with R1 ¼ COCH]CH-(p-
Br-C6H4), R2 ¼ OH, R3 ¼ R4 ¼ R5 ¼ H and R1 ¼ COCH]CH-(p-
N(Me)2eC6H4), R2 ¼ OH, R3 ¼ R4 ¼ R5 ¼ H were identified as the
most potent antioxidant structures [120]. Balabani et al. incorpo-
Fig. 14. Chromene-based antitubercular agents. rated the 3-pyrroline nucleus into the coumarin derivatives and
examined their free radical scavenging activity [121]. Compounds
107 with R4 ¼ 2,5-dihydro-1H-pyrrolyl, R5 ¼ Me, R1 ¼ R2 ¼ R3 ¼ H;
R3 ¼ pyrrolyl, R4 ¼ Me, R1 ¼ R2 ¼ R5 ¼ H and R2 ¼ 2,5-dihydro-1H-
pyrrolyl, R1 ¼ R3 ¼ R4 ¼ R5 ¼ H presented the highest soybean
lipoxygenase inhibitory activity and also a promising antioxidant
potential. 4-Hydroxy-di-coumarin 108 (R1 ¼ H, R2 ¼ Me, R3 ¼ OMe)
showed a moderate antioxidant activity and strong radical scav-
enging activity towards the DPPH radical, comparable to that of 108
where R1 ¼ R2 ¼ R3 ¼ H (Fig. 17) [122].
Structures 109 (Fig. 17) were tested for the scavenger activity in
a peroxyoxalate-hydrogen peroxide model system due to their
chemiluminescence characteristics [123]. The strongest scavenger
activity was found at 104 mol/L for 109 (R1 ¼ R3 ¼ H, R2 ¼ OH) and
the authors claimed that the presence of an electron-donating
substituent in the side chain of the aromatic ring should be
Fig. 15. 2H-Chromenes with anti-parasite activity.
responsible for the biological response.
A series of 2H-chromene-based TNF-a converting enzyme
(TACE) inhibitors (110, Fig. 18) was prepared to study their struc-
activity at a concentration lower than 3 mM and they were non- tural optimization as inhibitors on S10 pocket. Compound 110
toxic at the tested concentrations. These compounds were (R1 ¼ R3 ¼ H, R2 ¼ Me, R4 ¼ N,N-diethylaminoethyl, n ¼ 1) showed
considered to be promising leads for these protozoan infections. the most promising in vitro and in vivo results, with in vitro inhib-
Chromenes 98 were identified as lead antimalarial agents since itory activities of IC50 ¼ 0.28 nM and IC50 ¼ 60 nM for TACE inhi-
several compounds were evaluated against Plasmodium falciparum bition and cellular TNF-a inhibition, respectively. This derivative
strains 3D7 and K1 and showed MIC values lower than 5 mM also inhibited paw edema in rat carrageenan model [124].
including in the nano-molar range (Fig. 15) [116]. The oral avail- 2-Oxo-2H-chromenes 111 bearing a propanamide moiety were
ability of the best compounds was analyzed and proved to be low evaluated in vitro as cyclooxygenase inhibitors (Fig. 18) [125].
due to poor ADME properties. Molecular docking studies indicated Compound 111 (R1 ¼ H, R2 ¼ isoquinolin-1(2H)-one) showed a
a possible binding of these molecules to the active site of falcipain-2 balanced selectivity towards COX-2 over COX-1 inhibition and good
enzyme. docking scores when docked into the COX-2 protein.
Setileuton 112 (Fig. 18) presented an IC50 ¼ 3.9 nM in the H5-LO
(enzyme 5-lipoxygenase) assay, an IC50 ¼ 52 nM in the HWB (hu-
4.3. Synthetic chromenes as anti-inflammatory and antioxidant man whole blood) assay together with a relatively low affinity for
agents the hERG (human ether-a-go-go gene) channel [126]. Considering
its overall profile this compound was selected for clinical
Nicolaides et al. evaluated the antioxidant and anti- development.
inflammatory activities of some benzo[1]khellactone derivatives Timonen et al. synthesized 7-hydroxycoumarine derivatives and
99e102 (Fig. 16) [117]. All the tested compounds interacted with investigated their anti-inflammatory effects. Six structures 113
1,1-diphenyl-2-picrylhydrazyl stable free radical (DPPH) in a con- (a:R1 ¼ R2 ¼ Me, R3 ¼ R4 ¼ H; b:R1 ¼ R2 ¼ R3 ¼ Me, R4 ¼ H;
centration and time-dependent manner. Derivatives 101e102 and c:R1 ¼ Et, R2 ¼ Me, R3 ¼ R4 ¼ H; d:R1 ¼ R3 ¼ R4 ¼ H, R2 ¼ Ph;
coumarin Mannich-bases 103 and 104 (Fig. 16) revealed to be e:R1 ¼ R3 ¼ R4 ¼ H, R2 ¼ 2-FC6H4 and f:R1 ¼ R3 ¼ H, R2 ¼ Ph,
potent HO_ scavengers, competing with DMSO, and inhibited soy- R4 ¼ OMe) inhibited LPS-induced NO production at 100 mM con-
bean lipoxygenase in vitro [118]. Compounds 99 (R1 ¼ CO2Et, centrations (Fig. 18) [127]. iNOS protein expression was inhibited by
Fig. 16. 2-Oxo-2H-chromenes with antioxidant and anti-inflammatory potential.
Fig. 17. 2-Oxo-2H-chromenes with antioxidant potential.
more than 80% at 100 mM concentration and more than 45% at highly active [128]. Analogues bearing R1 ¼ 7-OCH2-pyridinyl, 8-Me
10 mM for molecules 113c-f. Compounds 113a-e inhibited IL-6 and R1 ¼ 7-OCH2CH2-morpholidinyl, 8-Me were notably more
production by more than 80% at 100 mM. Derivatives 113a-c effective than the reference compounds (Milrinone and Cilostazol).
revealed to inhibit LPS-induced iNOS mRNA expression and nuclear The in vitro activity of these two chromenes on human platelet
translocation of NF-kB, by more than 50% and 65%, respectively. aggregation, induced in platelet-rich plasma by ADP, collagen and
A23187, was measured and the IC50 values varied from 0.284 to
2.5 mM. The authors studied the mechanism of action of these
4.4. Synthetic chromenes as antithrombotic agents
promising compounds and evaluated the inhibitory activity on
phosphodiesterase 3 (PDE3) isolated from human platelets. For
A series of chromene compounds were synthesized and evalu-
R1 ¼ 7-OCH2-pyridinyl, 8-Me an IC50 value of 0.037 mM was found
ated for their antithrombotic activity (Fig. 19). Substituted chro-
and this chromene proved to be a more potent PDE3 inhibitor than
menes 114 were tested for their in vitro activity as platelet
the compound with R1 ¼ 7-OCH2CH2-morpholidinyl, 8-Me
aggregation inhibitors and most of the compounds showed to be
chromenes 117, bearing an amide group in the 3 position [131]. For

R1 ¼ 6,8-dichloro, R2 ¼ 3,5-dimethyl and R1 ¼ 6-chloro, 8-bromo,
R2 ¼ H, IC50 values of 4.3 and 4.4 mM, respectively, were obtained
towards FXIIa. These derivatives were selective to FXIIa, since no
inhibition was detected for THR, FXa, TF/FVIIa and kallikrein.
4.5. Synthetic chromenes acting on receptors of the central nervous

system
4.5.1. Human monoamine oxidase inhibitors

A large series of chromenes have been synthesized and tested
in vitro for their human monoamine oxidase A and B (hMAO-A and
hMAO-B) inhibitory activity (Fig. 20) [132]. 7-Oxycoumarin de-
rivatives 119e120 were evaluated for their MAO-A and B inhibitory
effect and showed high in vitro affinity and selectivity towards
MAO-A isoenzyme, with Ki values on the picomolar range. In the
in vitro tests, the acetohydrazide derivative 120b showed an inhi-
bition of MAO-A activity of 5.01 pM and a comparable inhibitory
activity was determined for 7-oxycoumarin derivatives 119, with
R2 ¼ (CH2)2eN-diethylamino (5.18 pM). However, in vivo tests
proved that compounds 119 bearing R1 ¼ Me, R2 ¼ H, X ¼ O and
R1 ¼ H, R2 ¼ H, X ¼ S presented a higher anti-MAO effect and
Fig. 18. 2-Oxo-2H-chromenes with anti-inflammatory potential.
displayed ED50 values of 7.85 and 7.95 nM, respectively. A new
series of 3-, 4- and 7-polysubstituted coumarins 121 (Fig. 20) have
been evaluated for their MAO-A and MAO-B inhibitory potency.
Most of the compounds acted as MAO inhibitors, with IC50 values in
the picomolar range. The coumarin scaffold with R1 ¼ OCH2C6H4(3-
Cl), R2 ¼ H and R3 ¼ Me exhibited outstanding MAO-B affinity
(pIC50 ¼ 8.29) and a high MAO-B selectivity (DpIC50 ¼ 3.39)
[133,134]. In general, the authors observed that derivatives with
R1 ¼ OCH2Ar bearing halogen substituents in the aromatic moiety
led to improved activity [135]. Later, the same research group re-
ported that coumarin 121 with R1 ¼ OCH2C6H4(3-Cl), R3 ¼ H and
R2 ¼ CH2NHMe or R2 ¼ CHO inhibited competitively MAO B with Ki
values in the 0.1e0.5 mM range, 30e700 fold lower than those
observed with MAO A [136]. The in vivo experiments for these
compounds were performed and a rapid blood brain barrier
penetration capacity was observed when administered both
parenterally and orally. This chromene behaved as a potent
(ED50 ¼ 0.24 mg/kg po), reversible and short-acting MAO-B in-
hibitor with no significant effect on MAO-A [137]. Chromene 121
with R1 ¼ H, R2 ¼ nPr, R3 ¼ R4 ¼ C4H4 (Fig. 20) proved to be a se-
lective MAO-A inhibitor with an IC50 value of 2.28 mM and an in vivo
profile in mice consistent with antidepressant-like effects
[138,139].
Chromene derivatives 122 (Fig. 20) were analyzed as inhibitors
Fig. 19. Chromenes with antithrombotic activity.
of hMAO and in general these compounds showed selectivity to-
wards hMAO-B with IC50 values in the micromolar range. Com-
(IC50 ¼ 0.078 mM). pounds bearing R1 ¼ H, R2 ¼ NH-(4-F-C6H4) and R1 ¼ H, R2 ¼ NH-
The anticoagulant Tecarfarin 115 (Fig. 19) was orally adminis- (4-SO2MeeC6H4) proved to be potent and selective inhibitors of
trated to rabbits or dogs and selectively reduced the levels of the hMAO-B with IC50 values of 0.067 and 0.0014 mM, respectively
vitamin K-dependent coagulation factors (factors II, VII, IX and X) [140]. Compounds 122 with R1 ¼ H, R2 ¼ NH-(3-MeC6H4) and
[129]. This chromene derivative prolonged the prothrombin time R1 ¼ H, R2 ¼ SCH2-(2-furan) presented IC50 values of 0.93 mM and
and attenuated venous and arterial thrombosis, an effect compa- 0.21 mM, respectively. The MAO-B selectivity with respect to the
rable to the oral anticoagulant Warfarin. MAO-A isoform was 64.5-fold vs. 1-fold for the amide derivative
Activated factor FXIIa has been an attractive target for the pre- and 189.2-fold vs 1-fold for the thioester [141].
vention and treatment of thromboembolic diseases and chromenes
116 and 117 were considered potent and selective inhibitors 4.5.2. Cannabinoid, serotonin and adenosine receptor inhibitors
de
(Fig. 19). Fre rick et al. demonstrated that 3,6-disubstituted cou- A series of 3-benzylcoumarins were synthesized and tested at
marins 116 were effective for the inhibition of THR (thrombin) and cannabinoid receptors CB1 and CB2 in radioligand binding assays
FXa, two enzymes implicated in the common pathway of the and cAMP (30 -50 -cyclic adenosine monophosphate) accumulation
coagulation cascade [130]. The substituents R1 ¼ 2,5- studies (Fig. 21) [142]. The most potent chromene derivatives
dichlorophenyl and R1 ¼ 3-chlorophenyl enhanced the potency of include compound 123a, a selective CB1 antagonist (Ki
116 on THR and FXa. The same research group synthesized CB1 ¼ 0.022 mM), 123b a dual CB1/CB2 agonist (CB1 Ki ¼ 0.032 mM,
EC50 ¼ 0.056 mM; CB2 Ki ¼ 0.049 mM, EC50 ¼ 0.014 mM), 123c, a dual
Fig. 20. Chromenes as human monoamine oxidase inhibitors.
Fig. 21. Chromenes tested for several receptors of the central nervous system.
CB1/CB2 ligand that blocks CB1 but activates CB2 receptors (CB1 subnanomolar affinity for the CB2 receptor was exhibited by a 9-
Ki ¼ 0.244 mM; CB2 Ki ¼ 0.210 mM, EC50 ¼ 0.054 mM) and 123d, a hydroxyl analog 124a (CB2 Ki ¼ 0.82 nM) while the 9-methoxy
selective CB2 receptor agonist (CB1 Ki ¼ 1.59 mM, CB2 Ki ¼ 0.068 mM, analog 124b (CB2 Ki ¼ 6.7 nM) presented a 54-fold CB2 selectivity.
EC50 ¼ 0.048 mM). Compound 124c showed good affinity to the CB2 receptor
Compounds 124 (Fig. 21) are structurally related to Cannabinol (Ki ¼ 3.1 nM), but a poor selectivity profile.
125, a natural constituent of cannabis with modest CB2 selectivity Compounds 126 (Fig. 21) were tested for their affinity for 5-
[143]. Optimal receptor subtype selectivity of 490-fold and hydroxytryptamine (5-HT) receptor [144]. Chromene 126 with
R1 ¼ H and R2 ¼ CH2-morpholino proved to be the most promising 129 (R1 ¼ NHCH2CH2NHPh) proved to be the most active in the
compound and showed selectivity to rat 5-HT1B receptor, acting as in vitro tests and a Ki value of 5.8 nM was determined for the D4.2
an antagonist. The binding profile showed a 13-fold preference for receptors. In vivo studies showed increased DOPA (ʟ-3,4-
rat 5-HT1B (Ki ¼ 47 nM) vs bovine 5-HT1B (Ki ¼ 630 nM) receptors. dihydroxyphenylanine) accumulation (51% in the hippocampus
This compound was also evaluated in other monoaminergic re- and 23% in the striatum) in rat brains when dosed orally at 20 mg/
ceptors (adrenoreceptors, dopamine and muscarinic), but low af- kg.
finity was observed. The biological evaluation of molecules 130 (Fig. 22) proved that
The combination of indole-butylamine and chromenonyl- these compounds were good and selective hAChE inhibitors, in the
piperazine moieties led to compounds 127 (Fig. 21) [145]. This low micromolar range [148]. Chromene derivative 130 (R1 ¼ 3-
scaffold showed to be equally potent at the 5-HT1A receptor and at OMe, 4-OH) demonstrated high potency with an IC50 for hAChE
5-HT transporter. The nitrogen functionalities introduced in posi- of 0.33 mM. Kinetic studies showed that this compound behaved as
tion 3 of the chromene led to compounds acting as agonists at the a mixed type inhibitor for EeAChE (Ki ¼ 81 nM). An excellent
5-HT1A receptor (IC50 ¼ 0.1e9.1 nM) and as 5-HT re-uptake in- antioxidant profile was also determined by the ORAC experiment.
hibitors (IC50 ¼ 0.2e19 nM). Compounds 130 with R1 ¼ 2,4-OMe, 4-NO2, 3,4,5-OMe and 3,4-Cl
Several chromene based compounds 128 (Fig. 21) were phar- showed a good permeability profile for the blood brain barrier as
macologically tested for their affinity at adenosine receptors [146]. determined in the PAMPA assay and low toxicity in HepG2 cells.
In general, compounds 128 were selective for A2A receptors over Significant neuroprotective effects were observed against mito-
the A1, A2B and A3 receptor subtypes, in the submicromolar con- chondrial chain blockers-induced cell death and no neurotoxic ef-
centration range. Chromenes with X ¼ NH demonstrated higher fects were registered at concentrations lower than 50 mM.
affinity than the compounds bearing an oxygen atom in this posi- Chromenes 131 and 132 were synthesized and tested for AChE
tion. Compound 128 (R1 ¼ R3 ¼ H and R2 ¼ OMe) showed the inhibition (Fig. 22) [149]. Derivative 131a was the first compound
highest affinity for A2A (pKi ¼ 7.1) receptors, but no selectivity was published to bind both anionic sites of the human acetylcholines-
observed towards the other receptor subtypes. The selectivity was terase, allowing the simultaneous inhibition of the catalytic and the
further improved with the introduction of linear/cyclic alkyl chains amyloid-b pro-aggregating activities of AChE. This compound
or substituted imidazole moieties in the 3-carboxamide substituent presented a Ki value for AChE inhibition of 44.5 nM and was used as
(R1). lead for the synthesis of derivatives 131b,c and 132. These new
compounds presented comparable IC50 values (Ki ¼ 10.5e62.1 nM).
4.5.3. Dopamine and acetylcholinesterase inhibitors

Chromene derivatives were also found to be active as dopamine 4.6. Synthetic chromenes acting on estrogen receptors
(DA) and acetylcholinesterase inhibitors and may be considered
promising candidates for the treatment of Schizophrenia and Alz- The endogenous steroid estrogen is a critical mediator of many
heimer diseases (Fig. 22). physiological functions related to development, growth, and
Several 2-oxo-2H-chromenes 129 demonstrated high affinity maintenance of a large number of tissues in both females and
(<20 nM, Ki) for the dopamine D4 receptor when tested in cloned males. A series of chromene derivatives were found to be selective
human DA D2ʟ, D3 and D4.2 receptor subtypes, expressed in Chi- estrogen receptor (ER) modulators (Fig. 23).
nese hamster ovary K1cells (Fig. 22) [147]. In general, these com- Substituted di-chromene derivatives 133 (Fig. 23) were pre-
pounds showed selectivity for dopamine D4.2 versus D2ʟ receptors pared and evaluated as estrogen receptor modulators [150]. The
and showed antagonist activity at the D4.2 receptors. Compound pure S and R enantiomers were tested in vitro for their estrogenic
Fig. 22. Bioactive chromenes for Schizophrenia and Alzheimer treatment.

Fig. 23. Chromenes tested on estrogen receptors.
and antiestrogenic activities. The pure R enantiomer of 133 A series of coumarins 138 were reported as aldose reductase 2
(R1 ¼ COC(Me)3) was the most promising compound and in vivo (ALR2) inhibitors. Aldose reductase (alditol: NADPþ 1-
tests showed an agonistic effect on bone and lipid and an antago- oxidoreductase, EC 1.1.1.21, ALR2) and sorbitol dehydrogenase (L-
nist effect on mammary glands and uterus. This compound also iditol: NADþ 5-oxidoreductase, EC 1.1.1.14, SDH) play key roles in
alleviates hut flushes and increases the amount of vaginal fluid. the polyol pathway involved in the glucose metabolism, which in
Chromene derivatives 134 (Fig. 23) showed binding affinity for turn has been linked to long-term diabetic complications. The
ERa and ERb as low as 1.6e200 nM and demonstrated antagonist suppressive effect on the accumulation of galactitol in the rat lens
behavior in the MCF-7 human breast adenocarcinoma cell line as as well as the ALR2 selectivity profile of compounds 138 against
well as in Ishikawa cell line, with IC50 values in the range sorbitol dehydrogenase and aldehyde reductase (ALR1) was eval-
0.2e360 nM [151]. In general, compounds with absolute configu- uated. The authors concluded that he potency toward ALR2 was
ration R were significantly more potent in antiuterotropic assays. enhanced when R3 ¼ OH, while R4 ¼ OH interfered with ALR1 in-
Compounds 134 with piperidine, thiomorpholine, pyrrolidine and hibition activity. Furthermore, the presence of a phenyl group as
azepane substituents were potent antagonists in Ishikawa and the R2 substituent improved both potency and selectivity. Com-
MCF-7 cell based functional assays. The in vivo studies proved that pound 138 with R1 ¼ H, R2 ¼ Ph, R3 ¼ R4 ¼ OH inhibited galactitol
compounds 134 bearing the pyrrolidine and azepane substituents accumulation in a dose-dependent manner [154].
exhibited the ideal profile for the treatment of postmenopausal The chromene nucleus was selected from a 2500-member small
symptoms. molecule library and a SAR study was performed using a 15-
Compounds 135 and 136 (Fig. 23) were tested for their affinity member collection with a tetracyclic skeleton. At 10 mM, Ampki-
and selectivity for ERa and ERb [152]. Several chromene derivatives none 139 (R1 ¼ 7-OMe, 8-OH, R2 ¼ Me, R3 ¼ 4-benzoylphenyl,
were found to be potent and selective ERb agonists. Modifications Fig. 22) induced 322% activation of AMPK (adenosine 5’-mono-
in the substituents were introduced in both aromatic rings led to phosphate activated protein kinase) [155]. This compound was
compounds with ERb < 10 nM and >100 fold selectivity over ERa. identified as an indirect activator of AMPK with potential antidia-
Chromenes 135 with substituents such as H and Me (R1-R5) betic and antiobesity effects.
demonstrated the lowest IC50 values for ERb (4.1e7.8 nM). For 2H-Chromenes 140e142 (Fig. 24) were screened using mast cell
compounds 136 substituents such as H and Me for R1 and R2 and H, (MC) degranulation assay to further evaluation as adjuvants for use
Me and Et for R3 and R4 were favorable and IC50 values of 2.3e8 nM in mucosal vaccine strategies. Twelve derivatives bearing benzyl-
were determined for ERb. amine, chalcones or cyanostilbene motifs were identified to induce
at least 5% MC/9 degranulation [156]. The best result (10.1%) was
4.7. Synthetic chromenes with miscellaneous biological activities achieved for 2H-chromene 140 with R1 ¼ 5-OBn and incorporating
the 8-CH2NHCH2Ph subunit. For chalcone-based chromenes, com-
6-Sulfonyl-2H-chromenes 137 (Fig. 24) were studied for their pound 141 with R1 ¼ 2-OH, 4-Br was the most active (8.4%). Among
ability to act as KATP-Channel Openers (KCOs) by Salamon et al. the cyanostilbene subset of chromenes, 142 with 6-CH]C(CN)Ph
[153]. Structure-activity studies indicated that the 2-, 4- and 6- and R1 ¼ H, presented the highest activating potential (7.4%).
positions of the benzopyran core have a great effect on the bio- Starcevic et al. tested 6- and 7-phenyl coumarins 143 (Fig. 25) as
logical activity. Bimakalin (138, Fig. 22) bearing a 4-pyridone moi- selective nonsteroidal inhibitors of 17b eHSD1 (17b-hydroxysteroid
ety was used as a template for 2H-chromenes 137, which were dehydrogenase type 1) [157]. A series of mimetics of steroidal
mainly sulfonamide derivatives and proved to be active. Compound structures with improved inhibition of 17b eHSD1 was evaluated.
137 (R1 ¼ H, R2 ¼ Ph) was the most potent member of this series, Biologically active 7 phenyl-coumarins 143 with R1 ¼ 7-Ph, 7-(4-
binding more effectively than Bimakalin 137 (R2 ¼ CN) both in MeC6H4), 7-(4-OMeC6H4), 7-(4-OHC6H4), 7-(4-FC6H4), 7-(4-
cardiac membranes and in aortic smooth muscle cells. ClC6H4); R2 ¼ COMe, CO2Et, H; R3 ¼ H did not inhibit 17b eHSD2
Fig. 24. 2H-Chromenes tested for different biological activities.
Fig. 25. 2-Oxo-2H-chromenes displaying different biological activities.
at 60 mM, which makes them selective inhibitors for 17b eHSD1 over 17b eHSD2 and a and b estrogen receptors.
over 17b eHSD2 receptor. Compound 143 (R1 ¼ 7-(4-OHC6H4); Coumarin derivatives 143 were also reported as a novel class of
R2 ¼ COMe; R3 ¼ H) displayed the highest activity with an inhibitors of the metalloenzyme carbonic anhydrase (CA) by Mar-
IC50 ¼ 270 nM in addition to a very good selectivity of 17b eHSD1 esca et al. (Fig. 25). The interaction of several substituted coumarin
derivatives with 13 mammalian CA isoforms was explored [158]. displayed the highest activity with ki/KI ¼ 1.1 105 M1s1.
The activities ranged between the low nanomolar and micromolar From the screening of a molecule-library, Li and co-workers
and selective isoform inhibitors were detected. identified the 3-piperazinyl coumarin core as antagonist of CKLF1
Hydroxycoumarins 143, 144 and 145 (Fig. 25) were developed to (chemokine-like factor 1) [165]. Compound 150 (R1 ¼ Me, Fig. 25)
be tested as a-glucosidase inhibitors [159]. The dimeric structure with and IC50 ¼ 21.2 nM blocked the calcium mobilization and
144 was the most effective a-glucosidase inhibitor with chemotaxis induced by CKLF1-C27, reduced the asthmatic patho-
IC50 ¼ 860 nM and its potency was approximately 14 times superior logic changes in the lung tissue of CKLF1-transfected mice and
to Genistein, a known a-glucosidase inhibitor. Both compounds 144 ameliorated pathological changes via inhibition of NF-kB signal
and 145 were specific a-glucosidase inhibitors with 145 being a pathway.
competitive inhibitor (Ki ¼ 4.81 mM) and 144 a noncompetitive Coumarin-dihydropyridine hybrids 151 and 152 (Fig. 25) dis-
inhibitor (Ki ¼ 587 nM). played potent osteoblastic bone formation in vitro and prevented
Chromenes 146 bearing a phenylsulfonamide moiety exhibited ovariectomy-induced bone loss in vivo [166]. Structure 152 with
inhibitory activities with IC50 values from 64.5 nM to 26.7 mM. The R1 ¼ sec-butyl, R2 ¼ Me, R3 ¼ Et, R4 ¼ H was the most promising
authors observed that most derivatives with R2 ¼ Me showed bone anabolic agent, with an EC50 ¼ 1.2 mM. In vivo studies of this
higher activities compared to those bearing R2 ¼ H and compound compound showed that at 1 (mg/kg)/day body weight increased
146 with R1 ¼ 6-OMe, 7-OH, R2 ¼ Me was the most potent a- bone mass density and volume, expression of osteogenic genes
glucosidase inhibitor on the series [160]. (RUNX2, BMP-2 and ColI) bone formation rate and mineral appo-
Asymmetric 143 and symmetric 4-hydroxycoumarins 147 sition rate in an ovariectomized rodent model postmenopausal
(Fig. 25) were evaluated as inhibitors of human NAD(P)H quinone osteoporosis. This compound also improved the trabecular micro-
oxidoreductase-1 (NQO1), in the presence and absence of BSA architecture and decreased bone turn over markers (osteocalcin
[161]. Compounds 147 with R1 ¼ 6,7-Me, R2 ¼ H; R1 ¼ 7,8-C4H4, and CTx). These findings demonstrated comparable osteoprotective
R2 ¼ H and R1 ¼ 7,8-Me, R2 ¼ H displayed IC50 values of 0.41, 0.18 effects of 152 to the known osteogenic agent, parathyroid hormone
and 0.42 nM, in the absence of protein, and were significantly more (PTH).
potent than compound 147 (R1 ¼ R2 ¼ H) with an IC50 ¼ 2.6 nM,
used as standard. Regarding the activities, in the presence of pro- 5. Conclusion
tein, the same molecules showed better IC50 values of 233, 370 and
96 nM respectively, compared to the standard, whose This review updates and emphasizes the importance of the
IC50 ¼ 404 nM. In addition, derivative 147 with R1 ¼ 5-OMe, R2 ¼ H chromene scaffold in bioactive compounds. The chromene unit is
presented an IC50 ¼ 38 nM. Asymmetric molecules 143 with present in a wide range of natural products and was found to
R1 ¼ 6,7-Me, R2 ¼ CH2(1-naphtyl), R3 ¼ OH; R1 ¼ 7,8-C4H4, interact with various biological targets, usually with a high thera-
R2 ¼ CH2(2-naphtyl), R3 ¼ OH; R1 ¼ 7,8-Me, R2 ¼ CH2(3,4-MeC6H3), peutic index. Activities such as anticancer, antimicrobial, antiviral,
R3 ¼ OH had IC50 values of 167, 255 and 192 nM, respectively. anti-inflammatory, antioxidant, etc. were assigned to diverse
A series of coumarin derivatives associated to a pyrimidine core chromene derivatives.
were tested in vivo for analgesic and anti-pyretic activities by Keri This is certainly a source of inspiration for medicinal chemists
and co-workers [162]. Compounds 148 (Fig. 25) with R1 ¼ 5-6- and pharmaceutical companies, as current knowledge constitutes
benzo, R2 ¼ OH; R1 ¼ 6-Cl, R2 ¼ SH; R1 ¼ 5-6-benzo, R2 ¼ NH2 only part of the high potential of this compound family. For re-
presented significant analgesic activity when compared to the searchers dedicated to this topic, there is still a wide unexplored
standard drug, Analgin. Structures 148 with R1 ¼ 6-Me, R2 ¼ OH; area to be investigated, especially in the search for new molecules
R1 ¼ 6-Me, R2 ¼ NH2; R1 ¼ 7-Me, R2 ¼ NH2; R1 ¼ 6-Cl, R2 ¼ NH2 and with enhanced biological activity.
also R1 ¼ 5-6-benzo, R2 ¼ NH2 showed significant anti-pyretic ac-
tivity, comparable with the standard drug, Aspirin. The qualitative Acknowledgement
QSAR study indicated that the anti-pyretic and analgesic activities
are enhanced by the presence of an amino-group at the 2-position We acknowledge the financial support from University of
of the pyrimidine ring and compounds bearing hydroxyl and thiol Minho, FCT through the Portuguese NMR network (RNRMN),
groups increased DNA cleavage activities. Project F-COMP-01-0124-FEDER-022716 (ref. FCT PEst-C/QUI/
A series of ester and amide derivatives of coumarin 149 (Fig. 25) UI0686/2011) FEDER-COMPETE and for the postdoctoral grant
were evaluated in vitro for the inhibitory activity against bovine a- awarded to Marta Costa (SFRH/BPD/79609/2011).
chymotrypsin [163]. The authors verified that the presence of the
ester moiety enhanced inhibition for the serine protease when
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European Journal of Medicinal Chemistry 123 (2016) 487e507

Contents lists available at ScienceDirect

European Journal of Medicinal Chemistry

Biological importance of structurally diversiﬁed chromenes

Chromenes are heterocyclic compounds with a benzene ring

Fig. 3. Natural products containing the 2-oxo-2H-chromene moiety.

Fig. 4. Natural products containing the C3 and/or C4 substituted 2-oxo-2H-chromene moiety.

Fig. 5. Natural products containing the C-2 substituted 2H-chromene moiety.

Fig. 6. Natural products with anticancer activity.

Fig. 8. Natural chromenes with anti-inﬂammatory and antioxidant properties.

Fig. 10. Bioactive chromenes present in nature.

Fig. 9. Chromene derivatives as AChE inhibitors.

This compound inhibited endothelin converting enzyme with an

4. Bioactive synthetic chromenes and nano-molar concentration range.

Fig. 11. Synthetic chromene derivatives with anticancer properties.

Fig. 12. Chromenes as antiviral agents.

Fig. 13. Chromene-based compounds with antibacterial activity.

R2 ¼ OH, R3 ¼ H; R1 ¼ CO2Et, R2 ¼ R3 ¼ H and R1 ¼ CO2Et, R2 ¼ OH,

Fig. 16. 2-Oxo-2H-chromenes with antioxidant and anti-inﬂammatory potential.

Fig. 17. 2-Oxo-2H-chromenes with antioxidant potential.

chromenes 117, bearing an amide group in the 3 position [131]. For

4.5. Synthetic chromenes acting on receptors of the central nervous

4.5.1. Human monoamine oxidase inhibitors

Fig. 20. Chromenes as human monoamine oxidase inhibitors.

4.5.3. Dopamine and acetylcholinesterase inhibitors

Fig. 22. Bioactive chromenes for Schizophrenia and Alzheimer treatment.

Fig. 23. Chromenes tested on estrogen receptors.

Fig. 24. 2H-Chromenes tested for different biological activities.

Fig. 25. 2-Oxo-2H-chromenes displaying different biological activities.

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