Journal Description
Drugs and Drug Candidates
Drugs and Drug Candidates
is an international, peer-reviewed, open access journal on drug discovery, development, and knowledge, published quarterly online by MDPI.
- Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 21.5 days after submission; acceptance to publication is undertaken in 6.6 days (median values for papers published in this journal in the first half of 2024).
- Recognition of Reviewers: APC discount vouchers, optional signed peer review, and reviewer names published annually in the journal.
- Drugs and Drug Candidates is a companion journal of Pharmaceuticals.
Latest Articles
A Comprehensive Review of the Ethnobotanical Uses, Pharmacological, and Toxicological Profiles of Piper capense L.f. (Piperaceae)
Drugs Drug Candidates 2024, 3(3), 598-614; https://doi.org/10.3390/ddc3030034 - 9 Sep 2024
Abstract
Commonly known as wild pepper, Piper capense (P. capense) is a culinary herb mainly used as a secret in preparation of “Nkui” and “Nah poh” in Bayangam, West Cameroon. However, it also has many interesting pharmacological properties,
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Commonly known as wild pepper, Piper capense (P. capense) is a culinary herb mainly used as a secret in preparation of “Nkui” and “Nah poh” in Bayangam, West Cameroon. However, it also has many interesting pharmacological properties, which is why the people of sub-Saharan Africa so highly prize it for the treatment of multiple human pathologies. This study aimed to highlight the traditional uses, phytochemical composition, biological activities, and toxicological profile of the P. capense plant, to draw the attention of pharmaceutical companies to its enormous potential for the development of future phyto- or pharmaceutical products. Documentary research was meticulously carried out in the Web of Sciences, Scopus, Pubmed/Medline, and Google Scholar databases according to PRISMA 2020 guidelines. The results show that extracts and compounds isolated from Piper capense have interesting anticancer, antibacterial, antimalarial, hypoglycemic, anti-epileptic, and antidepressant activities. Methanolic extracts and essential oils from P. capense exhibit no harmful effects when directly applied to normal human hepatocytes, umbilical cord cells, intestinal cells, and keratinocyte cell lines. Additionally, methanolic extracts administered acutely or subchronically at low doses (≤250 mg/kg body weight) in Wistar rats also demonstrate no adverse effects. In conclusion, given its interesting activities, P. capense is a viable option for developing new antimalarial, anticancer, antibacterial, hypoglycemic, anti-epileptic, and antidepressant drugs. However, many avenues still need to be explored before translation into drugs.
Full article
(This article belongs to the Section Drug Candidates from Natural Sources)
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Open AccessArticle
Enhanced Lung Cancer Therapy via Co-Encapsulation of Docetaxel and Betulinic Acid
by
Trideep Saikia, Prakash Rajak, Bhanu P. Sahu and Lima Patowary
Drugs Drug Candidates 2024, 3(3), 566-597; https://doi.org/10.3390/ddc3030033 - 29 Aug 2024
Abstract
Docetaxel (DTX) and betulinic acid (BA) co-encapsulated poly-lactic co-glycolic acid (PLGA) nanoparticles (NPs) were developed for enhanced lung cancer activity in vitro. Poly (lactic-co-glycolic acid) (PLGA) was used as an encapsulating polymer along with polyvinyl alcohol (PVA) as a stabilizing base to formulate
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Docetaxel (DTX) and betulinic acid (BA) co-encapsulated poly-lactic co-glycolic acid (PLGA) nanoparticles (NPs) were developed for enhanced lung cancer activity in vitro. Poly (lactic-co-glycolic acid) (PLGA) was used as an encapsulating polymer along with polyvinyl alcohol (PVA) as a stabilizing base to formulate NPs with the double-emulsion solvent evaporation method to study the size and potential, along with the surface morphology and in vitro release, of NPs. Cell culture studies like in vitro cellular uptake, apoptosis, and cell cycle arrest were performed in an in vitro cytotoxicity study to access the NP’s effect in the A549 human lung cancer cell line. The emulsification solvent evaporation technique produced smooth spherical nanoparticles of small sizes with a relatively narrow size distribution (147.2 ± 12.29 nm). On the A549 cell line, the formulation showed higher cytotoxicity (6.43 ± 0.11, 4.21 ± 0.32, and 1.17 ± 0.23 µmol for 24, 48, and 72 h, respectively) compared to the free drug due to an increase in vitro cellular uptake. Apoptosis and cell cycle analysis also confirmed the effectiveness of the prepared NPs. In vitro studies have proven the tumor-targeting potential of DTX-BA-NPs in A549 cell lines and could be future medication for lung cancer treatment.
Full article
(This article belongs to the Section Preclinical Research)
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Open AccessArticle
Microwave and Radiofrequency Ablation: A Comparative Study between Technologies in Ex Vivo Tissues
by
Fabio Lobascio, Rocco Di Modugno, Marco Fiore, Nicola Di Modugno, Cristian Bruno, Thomas De Nicolo, Rossella Veronica Barberis, Karine Cabiale and Marilena Radoiu
Drugs Drug Candidates 2024, 3(3), 550-565; https://doi.org/10.3390/ddc3030032 - 6 Aug 2024
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In this paper, we report on the use of a purpose-built hybrid solid-state microwave and radiofrequency generator operating at frequencies of 2.45 GHz and/or 480 kHz for cancer ablation in various tissues. The hybrid generator was tested ex vivo on chicken breast and
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In this paper, we report on the use of a purpose-built hybrid solid-state microwave and radiofrequency generator operating at frequencies of 2.45 GHz and/or 480 kHz for cancer ablation in various tissues. The hybrid generator was tested ex vivo on chicken breast and bovine liver and has demonstrated that the high accuracy of the power delivered to the sample can be achieved by controlling the emitted power versus the temperature profile of the treated sample. In particular, the hybrid generator incorporates control systems based on impedance or reflected power measurements that allow controlled ablation without causing unwanted carbonization and without including areas where tissue damage is not desired. The results of the ex vivo tests showed that radiofrequency ablation (RFA) could be effective for performing controlled ablations with minimally invasive probes, such as cardiac pathologies, small lesions, and tissues with particular composition, while microwave ablation (MWA) could be optimal for performing large ablations in highly vascularized tissues, such as liver cancer, where it is necessary to achieve higher temperatures.
Full article
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Open AccessArticle
Design of Marine Cyclodepsipeptide Analogues Targeting Candida albicans Efflux Pump CaCdr1p
by
Ricardo Ribeiro, Sara Fortes, Lia Costa, Andreia Palmeira, Eugénia Pinto, Emília Sousa and Carla Fernandes
Drugs Drug Candidates 2024, 3(3), 537-549; https://doi.org/10.3390/ddc3030031 - 1 Aug 2024
Abstract
Fungal infections are a significant threat to human health and the environment. The emergence of multidrug-resistant strains of fungi and the growing prevalence of azole resistance in invasive fungal infections exacerbate the problem, with efflux pumps being a major cause of antifungal resistance
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Fungal infections are a significant threat to human health and the environment. The emergence of multidrug-resistant strains of fungi and the growing prevalence of azole resistance in invasive fungal infections exacerbate the problem, with efflux pumps being a major cause of antifungal resistance and a prime target for several counteractive strategies. In Candida albicans, the ATP-binding cassette superfamily transporter CaCdr1p is the predominant efflux pump involved in azole resistance. Marine organisms have unique phenotypic characteristics to survive in challenging environments, resulting in biologically active compounds. The cyclodepsipeptides unnarmicin A and C have shown promising results as inhibitors of rhodamine 6G efflux in cells expressing CaCdr1p. Herein, a series of unnarmicin analogues were designed and docked against a CaCdr1p efflux pump based on the cryogenic electron microscopy structure available to select the most promising compounds. Analogue 33 was predicted to be the best considering its high affinity for the efflux pump and pharmacokinetic profile. These results pave the way for further synthesis and in vitro biological studies of novel unnarmicins seeking a synergistic effect with fluconazole.
Full article
(This article belongs to the Collection Chirality in Drugs and Drug Candidates)
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Open AccessArticle
Indazole–Quinolone Hybrids as Anti-Virulence Agents against Pseudomonas aeruginosa
by
Marie Hanot, Marine Duplantier, Céline Dalle, Yani Ren, Sophie Da Nascimento, Jean-Paul Becker, Nicolas Taudon, Elodie Lohou and Pascal Sonnet
Drugs Drug Candidates 2024, 3(3), 512-536; https://doi.org/10.3390/ddc3030030 - 19 Jul 2024
Abstract
Antibiotic resistance is a critical public health issue. Among the multi-drug resistant microorganisms in question, Pseudomonas aeruginosa has been designated by the WHO as a priority threat. Its virulence is orchestrated through quorum sensing (QS). This sophisticated communication network relies on the release
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Antibiotic resistance is a critical public health issue. Among the multi-drug resistant microorganisms in question, Pseudomonas aeruginosa has been designated by the WHO as a priority threat. Its virulence is orchestrated through quorum sensing (QS). This sophisticated communication network relies on the release and perception of autoinducers acting as population density indicators. Therefore, the interest of a quorum silencing pharmacological approach has unfolded to quench bacterial pathogenicity without impairing growth. In this article, we reported the development of a family of indazole–quinolone hybrids as anti-virulence agents. These new biaromatic compounds were designed as potential specific QS quenchers against P. aeruginosa. Our transdisciplinary research methodology included their synthesis using palladocatalyzed cross-coupling reactions, as well as their in silico physicochemical and in vitro biological evaluation. The hit 7-chloro-2-indazolyl-4-quinolone Ie shows a promising anti-biofilm and anti-pyocyanin efficiency (35% inhibition at 25 µM and 35% inhibition at 100 µM, respectively) without an anti-pseudomonal bacteriostatic effect. It also demonstrated a moderate eukaryotic cytotoxicity. Its anti-QS properties have been investigated using metabolomic and molecular modelling studies.
Full article
(This article belongs to the Section Medicinal Chemistry and Preliminary Screening)
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Open AccessReview
Biological Profile of Synthetic and Natural Indole Derivatives: Paving New Paths in Cancer Treatment
by
Ana Margarida Janeiro and Carolina S. Marques
Drugs Drug Candidates 2024, 3(3), 488-511; https://doi.org/10.3390/ddc3030029 - 19 Jul 2024
Abstract
The indole scaffold is considered a privileged framework in the design and synthesis of several active pharmaceutical ingredients, particularly as promising anticancer agents. Its presence in several bioactive natural compounds has caught the attention of the scientific community, which has been committed to
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The indole scaffold is considered a privileged framework in the design and synthesis of several active pharmaceutical ingredients, particularly as promising anticancer agents. Its presence in several bioactive natural compounds has caught the attention of the scientific community, which has been committed to unveiling its biosynthetic pathways and generating multiple derivatives with innovative synthetic routes. The large variety of structural derivatives enhances their use in multiple bioapplications and pharmacological activities. In this review, the reader will have easy access to some examples of natural and synthetic indole derivatives with antimicrobial, antidepressant, anti-inflammatory, antiviral, antimigraine, and antiemetic activity. However, the main topic of this review is related to cancer and the importance of indole derivatives as promising anticancer drugs. Two of the reasons why cancer is considered a massive problem worldwide are attributed to the struggle to develop target-specific drugs while avoiding drug resistance. Among countless drugs targeting specific proteins involved in tumorigenesis, prompting life quality in the treatment of several cancer types, protein kinases, desoxyribonucleic acid topoisomerases, and P-glycoprotein have been shown to be the main targets when it comes to the development of novel anticancer agents. Furthermore, indole and its derivatives are also studied regarding affinity to other targets related to cancer. This review aims to highlight the utility of the indole scaffold in anticancer drug design, inspiring the creation and synthesis of new derivatives that target specific proteins and address drug resistance challenges.
Full article
(This article belongs to the Section Medicinal Chemistry and Preliminary Screening)
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Open AccessArticle
Study of the Effects of Novel Analogs of Calebin-A on Melanogenesis
by
Shilpi Goenka, Kalyanam Nagabhushanam and Muhammed Majeed
Drugs Drug Candidates 2024, 3(3), 471-487; https://doi.org/10.3390/ddc3030028 - 15 Jul 2024
Abstract
In our previous study, we documented the anti-melanogenic efficacy of calebin-A (CBA), which is a curcuminoid analog. The effects of its newly synthesized analogs, i.e., bisdemethoxy calebin (BD), demethoxycalebin-1 (DA1), demethoxycalebin-2 (DA2), and tetrahydrocalebin-A (THCBA), on melanogenesis have not been examined yet. Herein,
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In our previous study, we documented the anti-melanogenic efficacy of calebin-A (CBA), which is a curcuminoid analog. The effects of its newly synthesized analogs, i.e., bisdemethoxy calebin (BD), demethoxycalebin-1 (DA1), demethoxycalebin-2 (DA2), and tetrahydrocalebin-A (THCBA), on melanogenesis have not been examined yet. Herein, we evaluated these four CBA analogs to determine their impacts on the enzymatic activity of mushroom tyrosinase. Additionally, we examined their effects on melanogenesis and the tyrosinase activity in B16F10 mouse and MNT-1 human melanoma cells. The antioxidant activity of the analogs was also assessed. Our results revealed that BD was ineffective, while DA1 and DA2 showed similar antioxidant activities, with THCBA exhibiting the greatest antioxidant activity. Next, the diphenolase activity assay results revealed that DA1 showed the most excellent inhibitory efficacy, DA2 and BD showed similar inhibition profiles, and THCBA was ineffective. In addition, the results of the monophenolase activity showed a similar pattern, except that THCBA suppressed the activity. The four analogs were evaluated for any cytotoxicity over a 48 h duration in B16F10 and HaCaT keratinocytes, where DA1 exerted cytotoxicity at the concentration of 50 µM. Based on this, the analogs were evaluated over a 10–50 µM concentration range, while DA1 was evaluated over 10–35 µM. BD showed the greatest efficacy at multiple concentrations in significantly diminishing melanogenesis in hormone-stimulated B16F10 cells, while DA1 and DA2 suppressed melanin at 35 and 50 µM, respectively, and THCBA stimulated melanogenesis at 50 µM. In addition, BD and DA1 suppressed tyrosinase activity in B16F10 cells, with no effect in the case of DA2 and THCBA analogs. However, in MNT-1 cells, only DA1 showed efficacy in suppressing melanin production while the other three analogs were ineffective. Interestingly, BD and DA1 suppressed MNT-1 cell tyrosinase activity. Collectively, our results indicate that of the four analogs, DA1 merits further investigation as a potential compound for hyperpigmentation skin disorders. Additional research is necessary to delineate the molecular mechanisms underlying the melanogenesis-inhibitory effect of CBA analogs and examine their efficacy in diminishing melanogenesis in normal human melanocytes.
Full article
(This article belongs to the Section Preclinical Research)
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Open AccessArticle
Synergistic Solutions: Exploring Clotrimazole’s Potential in Prostate and Bladder Cancer Cell Lines
by
Mariana Pereira and Nuno Vale
Drugs Drug Candidates 2024, 3(3), 455-470; https://doi.org/10.3390/ddc3030027 - 28 Jun 2024
Abstract
Clotrimazole (CLZ), traditionally an antifungal agent, unveils promising avenues in cancer therapy, particularly in addressing bladder and prostate cancers. In vitro assessments underscore its remarkable efficacy as a standalone treatment, significantly diminishing cancer cell viability. Mechanistically, CLZ operates through multifaceted pathways, including the
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Clotrimazole (CLZ), traditionally an antifungal agent, unveils promising avenues in cancer therapy, particularly in addressing bladder and prostate cancers. In vitro assessments underscore its remarkable efficacy as a standalone treatment, significantly diminishing cancer cell viability. Mechanistically, CLZ operates through multifaceted pathways, including the inhibition of Ca2+-dependent K+ channels, suppression of glycolysis-related enzymes, and modulation of the ERK-p65 signaling cascade, thus underscoring its potential as a versatile therapeutic agent. Our investigation sheds light on intriguing observations regarding the resilience of UM-UC-5 bladder cancer cells against high doses of paclitaxel (PTX), potentially attributed to heightened levels of the apoptosis-regulating protein Mcl-1. However, synergistic studies demonstrate that the combination of Doxorubicin (DOXO) and CLZ emerges as particularly potent, especially in prostate cancer contexts. This effectiveness could be associated with the inhibition of drug efflux mediated by multidrug resistance-associated protein 1 (MRP1), underscoring the importance of exploring combination therapies in cancer treatment paradigms. In essence, our findings shed light on the anticancer potential of CLZ, emphasizing the significance of tailored approaches considering specific cancer types and molecular pathways in drug repurposing endeavors. While further validation and clinical exploration are warranted, the insights gleaned from this study offer promising prospects for enhancing cancer therapy efficacy.
Full article
(This article belongs to the Section Marketed Drugs)
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Open AccessReview
The Multifaceted Therapeutic Potential of Saffron: An Overview Based on Research and Patents
by
Yahya Ramadan Elfardi, Reda El Boukhari, Ahmed Fatimi and Latifa Bouissane
Drugs Drug Candidates 2024, 3(3), 437-454; https://doi.org/10.3390/ddc3030026 - 21 Jun 2024
Abstract
Plants and plant extracts have long been acknowledged as valuable resources for the development of therapeutic formulations for various diseases. Among them, numerous plants and plant-derived products have demonstrated cytotoxic and/or anti-tumor properties. Saffron, particularly due to its major compounds, namely crocin, crocetin,
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Plants and plant extracts have long been acknowledged as valuable resources for the development of therapeutic formulations for various diseases. Among them, numerous plants and plant-derived products have demonstrated cytotoxic and/or anti-tumor properties. Saffron, particularly due to its major compounds, namely crocin, crocetin, and safranal, stands out as a promising candidate in this regard. Our research undertakes a literature review, reaffirming the antioxidant, anti-inflammatory, and, notably, anti-tumor properties of saffron and its major constituents. Additionally, this study examines relevant patent documents, highlighting innovative applications for saffron and its major compounds in cancer therapy. The review discusses the progress in purifying the compounds extracted from saffron and assesses their impact on cytotoxic trial outcomes, the potential synergies between certain saffron compounds and established cytotoxic molecules, and the limitations of the patents examined, particularly concerning reported clinical evidence. Researchers who focus on advances in oncology will know from our findings the evolution of the patent landscape regarding cytotoxic and/or anti-tumor therapeutic applications using saffron or its main compounds. Moreover, investigators can draw inspiration from patents leveraging traditional knowledge, particularly from Chinese medicine, to clarify specific active molecules and their mechanisms of action and can expedite the translation of these findings into clinically relevant interventions, potentially enhancing cancer therapy outcomes.
Full article
(This article belongs to the Section Medicinal Chemistry and Preliminary Screening)
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Open AccessArticle
Cyclocurcumin, a Minor Curcuminoid, Is a Novel Candidate for Hypopigmentary Skin Disorders with Melanogenesis-Stimulating Capacity
by
Shilpi Goenka
Drugs Drug Candidates 2024, 3(2), 410-436; https://doi.org/10.3390/ddc3020025 - 17 Jun 2024
Abstract
Effective therapies to treat skin hypopigmentation disorders caused by diminished melanin synthesis or export are limited due to potential side effects. In this work, we explored if cyclocurcumin (CYC), a curcuminoid found in minor amounts in turmeric rhizomes, might enhance the process of
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Effective therapies to treat skin hypopigmentation disorders caused by diminished melanin synthesis or export are limited due to potential side effects. In this work, we explored if cyclocurcumin (CYC), a curcuminoid found in minor amounts in turmeric rhizomes, might enhance the process of melanogenesis. CYC did not demonstrate antioxidant activity as evaluated by the DPPH assay. At noncytotoxic concentrations, CYC robustly enhanced melanin synthesis and melanin export in B16F10 mouse melanoma cells, which was correlated to increased cellular tyrosinase activity. The melanogenesis-stimulating efficacy of CYC was enhanced in B16F10 cocultures with HaCaT cells. Next, our results in MNT-1 human melanoma cells confirmed that CYC is a stimulator of both melanin synthesis and melanin export and acts by upregulating microphthalmia transcription factor (MITF) protein, although CYC did not alter tyrosinase protein or tyrosinase activity in MNT-1 cells. Moreover, the examination of CYC in MNT-1:HaCaT cocultures continued to show a more potent effect on stimulating melanin synthesis, as well as its export to recipient keratinocytes. Finally, CYC was shown to demonstrate a potent capacity to stimulate melanin production in primary human melanocytes from a Caucasian donor (HEMn-LP cells), although the effects on cellular tyrosinase activity were biphasic. Taken together, this is the first study to report the novel finding that CYC is a potent promelanogenic candidate that exhibits potential utility in the therapeutic management of skin disorders arising due to hypopigmentation in humans. Future studies that examine the molecular mechanisms and elucidate the promelanogenic efficacy of CYC in vivo are necessary.
Full article
(This article belongs to the Section Preclinical Research)
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Graphical abstract
Open AccessReview
Two-Dimensional and Spheroid-Based Three-Dimensional Cell Culture Systems: Implications for Drug Discovery in Cancer
by
Anali del Milagro Bernabe Garnique, Natália Sudan Parducci, Lívia Bassani Lins de Miranda, Bruna Oliveira de Almeida, Leonardo Sanches and João Agostinho Machado-Neto
Drugs Drug Candidates 2024, 3(2), 391-409; https://doi.org/10.3390/ddc3020024 - 13 Jun 2024
Abstract
The monolayer (two-dimensional or 2D) cell culture, while widely used, lacks fidelity in replicating vital cell interactions seen in vivo, leading to a shift toward three-dimensional (3D) models. Although monolayers offer simplicity and cost-effectiveness, spheroids mimic cellular environments better. This is due to
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The monolayer (two-dimensional or 2D) cell culture, while widely used, lacks fidelity in replicating vital cell interactions seen in vivo, leading to a shift toward three-dimensional (3D) models. Although monolayers offer simplicity and cost-effectiveness, spheroids mimic cellular environments better. This is due to its nutrient gradients, which influence drug penetration and provide a more accurate reflection of clinical scenarios than monolayers. Consequently, 3D models are crucial in drug development, especially for anti-cancer therapeutics, enabling the screening of cell cycle inhibitors and combination therapies vital for heterogeneous tumor populations. Inhibiting processes like migration and invasion often require drugs targeting the cytoskeleton, which can exhibit dual functionality with cell cycle inhibitors. Therapeutic approaches with promising anti-cancer potential often exhibit reduced efficacy in 3D cell culture compared to their performance in monolayer settings, primarily due to the heightened complexity inherent in this system. In the face of this scenario, this review aims to survey existing knowledge on compounds utilized in both 2D and 3D cell cultures, assessing their responses across different culture types and discerning the implications for drug screening, particularly those impacting the cell cycle and cytoskeletal dynamics.
Full article
(This article belongs to the Section Preclinical Research)
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Graphical abstract
Open AccessArticle
Essential Oil of Psidium glaziovianum Kiaersk Alleviates the Effects of Complete Freund’s Adjuvant (CFA)-Induced Arthritis by Regulating Inflammation and Oxidative Stress
by
Wêndeo Kennedy Costa, João Victor de Oliveira Alves, Beatriz Meyruze Barros Da Fonseca, Valquíria Bruna Guimarães Silva, Rafael Jardim Ferreira, Thiago Henrique Napoleão, Patrícia Maria Guedes Paiva, Maria Tereza dos Santos Correia, Alisson Macário de Oliveira and Márcia Vanusa da Silva
Drugs Drug Candidates 2024, 3(2), 380-390; https://doi.org/10.3390/ddc3020023 - 7 May 2024
Cited by 1
Abstract
Rheumatoid arthritis (RA) is a chronic and debilitating condition that affects a significant number of individuals worldwide. Unfortunately, the currently available therapeutic approaches often yield unsatisfactory results and may be accompanied by harmful side effects. A medicinal plant called Psidium glaziovianum Kiaersk has
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Rheumatoid arthritis (RA) is a chronic and debilitating condition that affects a significant number of individuals worldwide. Unfortunately, the currently available therapeutic approaches often yield unsatisfactory results and may be accompanied by harmful side effects. A medicinal plant called Psidium glaziovianum Kiaersk has potential benefits in the treatment of this condition due to its anti-inflammatory and analgesic properties. In this study, our objective was to investigate the potential therapeutic effects of P. glaziovianum essential oil (PgEO) in alleviating arthritis symptoms in mice induced by Complete Freund’s Adjuvant (CFA). The effect of P. glaziovianum essential oil was evaluated in mice with Complete Freund’s Adjuvant (CFA)-induced arthritis. Edema sizes, macroscopic and radiographic images, cytokine levels, and oxidative stress were evaluated. Administration of PgEO at dosages of 50 and 100 mg/kg effectively prevented CFA-induced osteoarticular changes in arthritic mice, resulting in a significant reduction in joint damage. Additionally, the PgEO treatment exhibited the ability to minimize edema, a common symptom associated with arthritis. Furthermore, PgEO can modulate the levels of pro-inflammatory cytokines and oxidative stress, both of which play crucial roles in the progression of the disease. In conclusion, our study suggests that PgEO holds great potential as a natural therapeutic agent for rheumatoid arthritis.
Full article
(This article belongs to the Section Preclinical Research)
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Open AccessArticle
Preclinical Testing of Chronic ICA-1S Exposure: A Potent Protein Kinase C-ι Inhibitor as a Potential Carcinoma Therapeutic
by
Christopher A. Apostolatos, Wishrawana S. Ratnayake, Sloan Breedy, Jacqueline Kai Chin Chuah, James Alastair Miller, Daniele Zink, Marie Bourgeois and Mildred Acevedo-Duncan
Drugs Drug Candidates 2024, 3(2), 368-379; https://doi.org/10.3390/ddc3020022 - 7 May 2024
Abstract
Protein kinase C-iota (PKC-ι) is an oncogene overexpressed in many cancer cells including prostate, breast, ovarian, melanoma, and glioma cells. Previous in vitro studies have shown that 5-amino-1-((1R,2S,3R,4R)-2-3-dihydroxy-4-(hydroxymethyl)cyclopentyl)-1H-imidazole-4-carboxamide (ICA-1S), a PKC-ι-specific inhibitor, has low toxicity in both acute and sub-acute mouse model toxicological
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Protein kinase C-iota (PKC-ι) is an oncogene overexpressed in many cancer cells including prostate, breast, ovarian, melanoma, and glioma cells. Previous in vitro studies have shown that 5-amino-1-((1R,2S,3R,4R)-2-3-dihydroxy-4-(hydroxymethyl)cyclopentyl)-1H-imidazole-4-carboxamide (ICA-1S), a PKC-ι-specific inhibitor, has low toxicity in both acute and sub-acute mouse model toxicological testing and is an effective therapeutic against several cancer cell lines showing significant reductions in tumor growth when treating athymic nude mice with xenografted carcinoma cell lines. To further assess ICA-1S as a possible therapeutic agent, chronic mouse model toxicological testing was performed in vivo to provide inferences concerning the long-term effects and possible health hazards from repeated exposure over a substantial part of the animal’s lifespan. Subjects survived well after 30, 60, and 90 days of doses ranging from 50 mg/kg to 100 mg/kg. Heart, liver, kidney, and brain tissues were then analyzed for accumulations of ICA-1S including the measured assessment of aspartate transaminase (AST), alkaline phosphatase (ALK-P), gamma-glutamyl transferase (GGT), troponin, and C-reactive protein (CRP) serum levels to assess organ function. Predictive in vitro/in silico methods were used to predict compound-induced direct hepatocyte toxicity or renal proximal tubular cell (PTC) toxicity in humans based on the high-content imaging (HCI) of compound-treated cells in combination with phenotypic profiling. In conclusion, ICA-1S shows low toxicity in both acute and chronic toxicology studies, and shows promise as a potential therapeutic.
Full article
(This article belongs to the Section Preclinical Research)
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Open AccessArticle
Toxicity and Teratogenic Potential of Piplartine from Piper tuberculatum Jacq. during Embryonic Development in Mice (Mus musculus)
by
Giulliano Rezende Silva, Lívia Thaís Gontijo Miranda, Shirley Aline da Costa Arteaga da Silva, Laise Rodrigues de Andrade, Natanael Carvalho de Souza, Bruno Silva Sá, Elivaldo Ribeiro de Santana, Andreanne Gomes Vasconcelos, Daniel Carneiro Moreira, Aline Pic-Taylor, Alessandra Durazzo, Massimo Lucarini, Lydia Fumiko Yamaguchi, Massuo Jorge Kato, Amilcar Sabino Damazo, Daniel Dias Rufino Arcanjo, José Roberto de Souza de Almeida Leite and José Eduardo Baroneza
Drugs Drug Candidates 2024, 3(2), 353-367; https://doi.org/10.3390/ddc3020021 - 30 Apr 2024
Abstract
Piplartine, also known as piperlongumine, is a natural and biologically active amide alkaloid found in various Piper species within the Piperaceae family. It possesses numerous beneficial properties that can be leveraged in the development of nanotechnological and pharmaceutical products. However, information on the
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Piplartine, also known as piperlongumine, is a natural and biologically active amide alkaloid found in various Piper species within the Piperaceae family. It possesses numerous beneficial properties that can be leveraged in the development of nanotechnological and pharmaceutical products. However, information on the effects of piplartine on mammalian embryonic development is scarce. This study aims to assess the general toxicity and teratogenic potential of piplartine during the embryonic development of mice. Pregnant mice received daily treatments of 25, 50, or 100 mg/kg of piplartine via gavage from the sixth day of gestation (implantation) to the eighteenth. On the eighteenth day, the mice were euthanized, and whole organs, blood samples (for hematological and biochemical analyses), and bone marrow cells (for DNA fragmentation and cell cycle assays) were collected. The uterus was examined for implantation sites and embryo resorptions. Additionally, fetuses were collected to assess for fetal anomalies. Piplartine did not result in maternal or embryo-fetal toxicity, induce fetal anomalies, cause hematological and biochemical alterations, or lead to DNA fragmentation. The oral administration of piplartine is safe and does not exhibit toxicity or teratogenic effects in mice. This finding opens avenues for the development of piplartine-based biotechnological products for therapeutic interventions in disease treatment.
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(This article belongs to the Section Preclinical Research)
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Open AccessArticle
Relaxant Activity of 4H-Pyran and 1,6-Dihydropyridine Derivatives on Isolated Rat Trachea
by
Samuel Estrada-Soto, Soledad Alemán-Pantitlán, Emmanuel Gaona-Tovar, Fernando Hernández-Borja, Yolanda Alcaraz, Rafael Villalobos-Molina and Miguel A. Vázquez
Drugs Drug Candidates 2024, 3(2), 342-352; https://doi.org/10.3390/ddc3020020 - 11 Apr 2024
Abstract
Derivatives of 4H-pyrans and 1,6-dihydropyridines have generated considerable attention due to their interesting biological and therapeutic values. Their pharmacological activities include vasorelaxant, anticarcinogenic, antimicrobial, and antioxidant activities. Thus, the aim of the current work is to determine the relaxant effect of synthesized 4H-pyran
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Derivatives of 4H-pyrans and 1,6-dihydropyridines have generated considerable attention due to their interesting biological and therapeutic values. Their pharmacological activities include vasorelaxant, anticarcinogenic, antimicrobial, and antioxidant activities. Thus, the aim of the current work is to determine the relaxant effect of synthesized 4H-pyran and 1,6-dihydropyridine derivatives with potential anti-asthmatic properties on the smooth muscle airway, with a possible Ca2+-channel blockade as a mechanism of action due to their analogy with 1,4-dihidropyridines. 4H-pyrans and 1,6-dihydropyridines were achieved using multicomponent reactions by microwave and conventional heating. Also, test samples were evaluated ex vivo to determine their relaxant effect on isolated rat tracheal rings pre-contracted with carbachol. All compounds evaluated showed a significant relaxant effect on carbachol-induced contraction in tracheal rat rings. Compounds 4b, 4e, 7a, and 8d were the most potent from the entire series and were also more potent than theophylline, used as a positive control. In conclusion, in the current work some relaxant compounds of the airway smooth muscle with potential to be developed as anti-asthmatic drugs were obtained.
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(This article belongs to the Section Medicinal Chemistry and Preliminary Screening)
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Open AccessReview
Sebetralstat: A Rapidly Acting Oral Plasma Kallikrein Inhibitor for the On-Demand Treatment of Hereditary Angioedema
by
Edward P. Feener, Rebecca L. Davie, Nivetha Murugesan, Stephen J. Pethen, Sally L. Hampton, Michael D. Smith, Paul K. Audhya and Chris M. Yea
Drugs Drug Candidates 2024, 3(2), 328-341; https://doi.org/10.3390/ddc3020019 - 7 Apr 2024
Abstract
Sebetralstat is a novel, potent, and selective oral plasma kallikrein inhibitor drug candidate in clinical development for the on-demand treatment of hereditary angioedema (HAE). Upon binding, sebetralstat induces a conformational change in the active site of plasma kallikrein, which contributes to its high
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Sebetralstat is a novel, potent, and selective oral plasma kallikrein inhibitor drug candidate in clinical development for the on-demand treatment of hereditary angioedema (HAE). Upon binding, sebetralstat induces a conformational change in the active site of plasma kallikrein, which contributes to its high potency (Ki 3 nM) and selectivity (>1500 fold) against other serine proteases. Its physiochemical properties promote both rapid dissolution in the stomach and rapid absorption in the upper intestine that contribute to its fast and efficient absorption. A single oral administration of sebetralstat rapidly provides near-complete inhibition of plasma kallikrein and blockade of high-molecular-weight kininogen cleavage as early as 15 min, which drives its clinical efficacy. In a phase 2 clinical trial, sebetralstat significantly reduced the time to beginning of symptom relief (p < 0.0001) with median times of 1.6 h (95% CI: 1.5–3.0) with sebetralstat versus 9.0 h (4.0–17.2) with placebo. KONFIDENT (NCT05259917) is a phase 3 clinical trial assessing the on-demand use of sebetralstat for HAE. If successful, this trial could support the approval of sebetralstat as the first noninvasive, on-demand treatment option to rapidly halt HAE attacks and provide fast symptom relief.
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(This article belongs to the Special Issue Drugs of the Kallikrein-Kinin System)
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Open AccessFeature PaperReview
Zilucoplan: A Newly Approved Macrocyclic Peptide for Treatment of Anti-Acetylcholine Receptor Positive Myasthenia Gravis
by
Lia Costa and Carla Fernandes
Drugs Drug Candidates 2024, 3(2), 311-327; https://doi.org/10.3390/ddc3020018 - 27 Mar 2024
Abstract
Zilucoplan is a synthetic macrocyclic peptide approved by the Food and Drug Administration (FDA), in October 2023, for the treatment of generalized myasthenia gravis. It is considered as an orphan drug that causes the inhibition of terminal complement cascade activation with a dual
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Zilucoplan is a synthetic macrocyclic peptide approved by the Food and Drug Administration (FDA), in October 2023, for the treatment of generalized myasthenia gravis. It is considered as an orphan drug that causes the inhibition of terminal complement cascade activation with a dual mechanism of action preventing the formation of the membrane attack complex (MAC) and the destruction of the neuromuscular junction. This drug has been demonstrated to be able to treat the generalized myasthenia gravis without significant adverse effects, with good efficacy, safety, and tolerability profile. Zilucoplan is not only innovative and promising in the therapeutics of generalized myasthenia gravis, but it could also be beneficial for the treatment of other diseases as well as a model for synthesis of analogues to improve pharmacological profile.
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(This article belongs to the Section Marketed Drugs)
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Open AccessArticle
DFT Calculations, Pro-Apoptotic Effects, and Anti-Infective Investigations of Alkaloids Isolated from the Stem Bark Extract of Enantia chlorantha
by
Vincent O. Imieje, Ahmed A. Zaki, Mansour A. E. Bashar, Islam Rady, Mohamed A. M. El-Tabakh, Mohamed A. E. Abd El-Aziz, Eman. S. Abou-Amra, Shahd Yasser, Ibraheem M. M. Gobaara, Mohammed A. S. Abourehab, Reham M. Samra, Hussein A. El-Naggar and Abiodun Falodun
Drugs Drug Candidates 2024, 3(1), 291-310; https://doi.org/10.3390/ddc3010017 - 7 Mar 2024
Cited by 1
Abstract
Fractionation of the stem bark of Enantia chlorantha Oliv yields three alkaloids, palmatine (1), jatrorrhizine (2), columbamine (3), and β-Sitosterol (4). In this investigation, density functional theory (DFT) calculations were carried out to evaluate
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Fractionation of the stem bark of Enantia chlorantha Oliv yields three alkaloids, palmatine (1), jatrorrhizine (2), columbamine (3), and β-Sitosterol (4). In this investigation, density functional theory (DFT) calculations were carried out to evaluate the electronic structure and properties of 1–4 by DFT-B3LYP/6-31G level of theory using Gaussian 09 software. The highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), HOMO-LUMO energy difference (band gap), hardness (η), softness (S), dipole moment (μ), electronegativity (χ), hydrophobicity (logP), topological surface area (TPSA), and energy gap (Eg) were calculated. The in vitro cytotoxicity of the compounds was investigated against MCF-7 and HCT116 cancer cell lines using Wi-38 cells as a control. The compounds inhibited the proliferation of the MCF-7 and HCT116 cell lines and induced apoptosis via upregulation of caspase-3, Bax, PARP cleavage, and downregulation of Bcl-2. DFT analyses revealed that compounds 1 and 3 have smaller energy gaps, 0.072 and 0.071eV, respectively, with the highest dipole moments; hence, these compounds are more chemically reactive and exhibit better modulation of caspase-3 enzyme and inhibitory activities of the MCF-3 and HCT116 cell lines. The antimicrobial and antiparasitic evaluation of 1–4 showed moderate efficacy against the bacterial strains and moderate antiparasitic activity against Cichlidogyrus tilapia.
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(This article belongs to the Section Drug Candidates from Natural Sources)
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Open AccessArticle
Development of Paclitaxel Proliposomal Dry Powder Inhaler (PTX-PLM-DPI) by Freeze-Drying Method for Lung Cancer
by
Chinmoyee Borah, Trideep Saikia, Alakesh Bharali, Madhuchandra Lahan, Nikhil Biswas and Bhanu P Sahu
Drugs Drug Candidates 2024, 3(1), 275-290; https://doi.org/10.3390/ddc3010016 - 5 Mar 2024
Abstract
Despite various efforts, a successful selective delivery system for chemotherapeutic agents for lung cancer is still lacking. Dry powder inhaler (DPI) systems based on proliposomes (PLMs) could be a potential system for the efficient delivery of paclitaxel to lungs. PLM-based DPI prepared with
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Despite various efforts, a successful selective delivery system for chemotherapeutic agents for lung cancer is still lacking. Dry powder inhaler (DPI) systems based on proliposomes (PLMs) could be a potential system for the efficient delivery of paclitaxel to lungs. PLM-based DPI prepared with a freeze-drying method can therefore be an alternative. Paclitaxel-loaded PLM-based DPI (PTX-PLM-DPI) powders were prepared using the method of thin film deposition on a carrier followed by freeze drying. These were prepared using soya phosphatidylcholine (SPC) and cholesterol as the lipids and mannitol as the carrier. The reconstituted liposomes were evaluated in terms of size, morphology, drug entrapment, release and cytotoxicity. The DPI powders were evaluated for their flow property, surface topography, dose uniformity and in vitro lung deposition. Stable and free-flowing PTX-PLM-DPI powder was obtained that could be reconstituted into homogenous liposomal vesicles < 200 nm as confirmed by TEM and SEM studies. The liposomes showed drug entrapment of 92.64 ± 1.4% and diffusion-controlled release of up to 28% in 24 h. These liposomes showed better dose-dependent cytotoxicity in A549 cells in comparison to paclitaxel suspension with IC50 values of 46 ± 0.87 ng/mL and 154.9 ± 3.64 ng/mL, respectively. In vitro lung deposition studies of the PTX-PLM-DPI showed sufficient deposition with the fine particle fraction (FPF) of 50.86 ± 2.8% of particles with an aerodynamic diameter less than 5 µ. Hence, it canbe concluded that PLM-based DPI prepared by freeze drying can be a promising, stable, safe and free-flowing system for the enhanced lung delivery of paclitaxel.
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(This article belongs to the Section Preclinical Research)
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Open AccessArticle
Anti-Shigellosis Activity and Mechanisms of Action of Extracts from Diospyros gilletii Stem Bark
by
Audrey Carrel Nguelo Talla, Eugénie Aimée Madiesse Kemgne, Vincent Ngouana, Bijou-Lafortune Noumboue Kouamou, Listone Monelle Nzeye Ngameni, Brice Rostan Pinlap, Yanick Kevin Dongmo Melogmo, Branly-Natalien Nguena-Dongue, Boniface Pone Kamdem, Paul Keilah Lunga and Fabrice Fekam Boyom
Drugs Drug Candidates 2024, 3(1), 256-274; https://doi.org/10.3390/ddc3010015 - 1 Mar 2024
Abstract
Shigellosis is a pathological condition that affects the digestive system and possibly causes diarrhoea. Shigella species, which are responsible for this disease, are highly contagious and spread through contaminated food and water. The increasing development of resistance by Shigella species necessitates the urgent
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Shigellosis is a pathological condition that affects the digestive system and possibly causes diarrhoea. Shigella species, which are responsible for this disease, are highly contagious and spread through contaminated food and water. The increasing development of resistance by Shigella species necessitates the urgent need to search for new therapies against diarrhoea-causing shigellosis. The scientific validation of medicinal plants, such as Diospyros gilletii, which is used for the traditional treatment of diarrhoeal conditions is worthwhile. The present study aims to investigate the antibacterial activity of extracts from D. gilletii against selected Shigella species. Extracts from D. gilletii stem bark were prepared by maceration using various solvents. The antibacterial activity of D. gilletii extracts was evaluated in Shigella dysenteriae, S. flexneri, S. boydii, and S. sonnei using a microdilution method, whereas a cytotoxicity test was performed on Vero and Raw cells using resazurin-based colorimetric assays. Bacterial membrane-permeability studies were evaluated using propidium iodide (PI)- and 1-N-phenyl-naphthylamine (NPN)-uptake assays, whereas inhibition and eradication tests on bacterial biofilms were carried out by spectrophotometry. As a result, methanol, ethanol and hydroethanol (water: ethanol; 30:70, v/v) extracts of D. gilletii inhibited the growth of S. boydii, S. flexneri and S. sonnei, with minimum inhibitory concentration (MIC) values ranging from 125 to 500 µg/mL, without toxicity to Vero and Raw cells. Time-kill kinetics revealed bactericidal orientation at 2 MIC and 4 MIC and a bacteriostatic outcome at 1/2 MIC. The mechanistic basis of antibacterial action revealed that D. gilletii extracts inhibited and eradicated Shigella biofilms and promoted the accumulation of NPN and PI within the inner and outer membranes of bacteria to increase membrane permeability, thereby causing membrane damage. This novel contribution toward the antibacterial mechanisms of action of D. gilletii extracts against Shigella species substantiates the use of this plant in the traditional treatment of infectious diarrhoea.
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(This article belongs to the Section Drug Candidates from Natural Sources)
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