Letters in Drug Design & Discovery - Volume 15, Issue 11, 2018

Background: Oxime K033 was considered a promising drug candidate originally developed for the treatment of nerve agent poisoning. This study summarizes its potency to reactivate in vitro acetylcholinesterase inhibited by several nerve agents (tabun, sarin, cyclosarin, soman, VX, Russian VX), mimic agent (DFP) and organophosphorus pesticide (chlorpyrifos) to show whether this compound might be used in cases of nerve agent or pesticide poisoning and considered as a so-called “broad spectrum reactivator”. Methods: Moreover, docking studies of tested oxime with human AChE (HssAChE) complexed with several OPs were performed in order to verify its stability, binding modes and ability to adopt favourable conformations and to perform the reactivation reaction with each OP under experimental study. Results & Conclusion: According to the obtained results, K033 could not be considered a universal antidote due to its poor reactivation activity in the case of tabun-, soman- and DFP-inhibited rat acetylcholinesterase. On the contrary, its very good in vitro potency in human-relevant doses for cyclosarin inhibition is highlighted.

Background: Considering the limitations of current cholinesterase inhibitor drugs for the treatment of Alzheimer's disease, there is ongoing research activities to find out alternative drug candidates. The aryl-spacer-N-benzyl pharmacophore model has been effectively utilized to design various types of cholinesterase inhibitor molecules, including donepezil. Within this research study, we have questioned the significance of the benzyl group within this pharmacophore employing the urolithin derivatives. Urolithins are benzo[c]chromene analogue metabolites of ellagitannins, abundantly found in pomegranate and berry fruits. Methods: Employing the previous experience that urolithin-spacer-N-benzyl yielded out potent cholinesterase inhibitors, we have designed novel benzo[c]chromene derivatives either lacking the benzyl group or possessing benzyl group in isoquinoline moiety lacking free N-C bond rotation. Following the synthesis and structure identification studies the compounds were screened for their potential to inhibit cholinesterase enzymes. Furthermore, the title compounds were also evaluated for their potential to prevent cholinesterase-accelerated amyloid beta aggregation. In the final, the most active compound was examined to find out its interactions with the cholinesterase enzyme employing a molecular docking study. Results: The title compounds displayed varying cholinesterase inhibitory potential. Some of the compounds were found more / comparable activity to the activity of the current drugs employed in clinic. The potential of the title molecules to inhibit amyloid beta aggregation was found poor. Conclusion: The title compounds displayed varying cholinesterase inhibitory potential, implying that the benzyl group is not a must in each design. This was also shown with the molecular docking studies. On the other hand, the beta amyloid aggregation studies have pointed out that cholinesterase inhibition does not guarantee the prevention of cholinesterase-accelerated amyloid beta aggregation.

Background: Ferrocene is a potential pharmacophore for drug design and drug discovery. Methods: Based on our previous good achievements (Med. Chem. commun., 2014,7,968-972), nineteen novel structures of 1,1'-ferrocene diformates bearing isoxazole moiety (3a-3s) were firstly synthesized in the current work and characterized by 1H NMR, 13C NMR, ESI-MS. Then, their cytotoxicity to A549, HCT116 and MCF-7 cell lines was evaluated using the MTT method. Results: The results showed that most compounds exhibited higher potent cytotoxicity to A549, HCT116 and MCF-7 cell lines. Conclusion: Especially, 3b, 3h, 3k, 3l, 3m, 3n, 3o, 3p and 3s simultaneously exhibited stronger inhibitory activity towards A549, HCT116 and MCF-7 cell lines than that of the reference drug cisplatin, which can be regarded as very promising metal-based lead compounds for anticancer agents.

Background: Sinapic Acid (SA), as a natural phenolic compound, is widely spread in plants. Objectives: In this study, the radioprotective effect of SA was investigated against genotoxicity and apoptosis induced by ionizing radiation in human lymphocytes. Methods: In this experimental study, peripheral blood samples were collected from human volunteers and incubated with SA at different concentrations (50-1000 μM) for three hours. The whole blood samples were exposed to X-ray at the dose of 1.5 Gy. Lymphocytes were cultured with mitogenic stimulation to determine the micronuclei in cytokinesis-blocked binucleated lymphocyte. The apoptotic lymphocytes were evaluated by flow cytometry in SA treated and/or irradiated samples. The antioxidant activities of SA were assayed by two different methods. Results: SA significantly decreased the frequency of micronuclei and apoptosis in human lymphocytes exposed to ionizing radiation. The maximum protection and higher decrease in the frequency of micronuclei in lymphocytes were observed at 1000 μM of SA with 73% of efficacy. SA exhibited strong free radical scavenging and antioxidant activity at a concentration-dependent antioxidant activity. Conclusion: This data provides that SA is a powerful radioprotective agent that can protect human normal cells against the genetic damage and apoptosis induced by ionizing irradiation.

Background: A series of 2-substituted benzoxazoles and their possible metabolites, N-(2-hydroxy-4(or 5)-nitrophenyl)benzamides and phenylacetamides, which were previously synthesized by our group, were investigated for their inhibitory activities on both eukaryotic DNA topoisomerase I (Topo I) and II (Topo II). Methods: DNA topoisomerase I and II inhibitory activity of compounds were determined by relaxation assay which could measure the conversion of supercoiled pBR322 plasmid DNA to its relaxed form. Results: According to DNA topoisomerase relaxation assay results, four derivatives (1c, 1f, 2b, 2e) among tested 21 compounds inhibited human Topo I, whereas three compounds (1c, 1e, 1f) inhibited human Topo IIα. 2-(4'-bromophenyl)-6-nitrobenzoxazole (1f) was observed to be the most effective Topo II inhibitor with the lowest IC50 value of 71 μM and 2-(4'-tert-butyl-phenyl)-6- nitrobenzoxazole (1c) with the IC50 value of 104 μM was considered the most effective Topo I inhibitor. However, it is noteworthy that these two compounds affected both Topo I and II enzymes. When the relationship between chemical structures and biological activities of the compounds were examined, the following two results were obtained: (i) CH2 bridge seems to decrease the Topo I and II inhibitions and (ii) bulky groups at R1 position increased both Topo I and II inhibitions for benzoxazole derivatives while small groups at R1 position increased the Topo I inhibition for benzamide derivatives. Conclusion: Biological activity and SAR results of tested derivatives may provide some predictions in order to design novel topoisomerase inhibitors.

Background: Averrhoa bilimbi has been used in the traditional medicine for treatment of hypertension, diabetes and as an antihypercholesterolemic. This study investigated the inotropic and chronotropic effects of Averrhoa bilimbi aqueous extract (AqE) on the guinea pig atrium. Methods: Left and right atria isolated from guinea pig were used to evaluate the atrial contractility and atrial rate, respectively. Results: In left atria, AqE showed a negative inotropic effect and delaying the time to peak without change relaxation time. In right atria, AqE reduced the atrial rate (67%). Furthermore, AqE induced a rightward shift in the concentration-effect curve of CaCl2 and reduced by 61% the Bowditch phenomenon. To evaluate the mechanism involved in the effects evoked by AqE, concentration-effect curves were obtained in the presence of atropine (M2 muscarinic receptor antagonist) and TEA (non-selective potassium channels blocker). The results revealed that these antagonists shifted rightward the concentration-effect curve of AqE. Conclusion: In conclusion, AqE reduces both atrial contractility and heart rate by activation of M2 receptors increasing potassium efflux associated with decreased calcium entry in cardiomyocyte. These effects are important for its future pharmacological applications being a source of new drugs that can be use in treatment of cardiovascular disease.

Background: Tyrosinase is a copper-containing enzyme that involves in melanine biosynthesis and fruits enzymatic browning pathways. Chemical inhibitors of tyrosinase could have potential applications in cosmetics, medicine and food industry. In this study, we evaluated 6-Methoxy-3,4-dihydronaphthalenone chalcone-like derivatives as potent tyrosinase inhibitors and radical scavengers. Methods: A series of ten 2-arylidene-6-methoxy-3,4-dihydronaphthalenone derivatives as tyrosinase inhibitors and potential antioxidants were designed and synthesized by aldol condensation reaction. Furthermore, tyrosinase inhibitory activity of the compounds was evaluated and to indicate the binding mode of some of the synthesized compounds, the molecular docking analysis was performed using AutoDock 4.2 software. The antioxidant activity of these compounds against DPPH radical scavenging was also investigated. Results: Results indicated that the compound bearing 3´-ethoxy and 4´-hydroxy (P5) was found to be potential competitive tyrosinase inhibitor with IC50 value of 6.19 ± 1.05 μM that exhibited higher tyrosinase inhibitory activity than the positive control, kojic acid, with IC50 value of 9.28 μM. Docking results confirmed that the active inhibitors were well accommodated in the mushroom tyrosinase active site. Compounds P5 and P8 exhibited potential radical scavenging activities with EC50 values of 27.02 ± 0.84 and 20.40 ± 2.36 μM, respectively. Conclusion: Therefore, P5 could be introduced as a potent tyrosinase inhibitor with radical scavenging activity that might be a promising compound in the field of drug discovery.

Background: Bioavailability is a major area of concern in drug development. It has been shown that poor oral bioavailability of molecules reduces the chances of converting a suitable lead into drug candidate. Objective: As part of our efforts to increase the likeliness of anticancer natural products reaching drug development phase, a study was designed which judges the oral absorption of these chemical molecules. Methods: A set of ~5000 compounds derived from three anticancer databases has been examined for their oral bioavailability. We have analyzed three critical factors: Lipophilicity, aqueous solubility and permeability of the molecule using twelve rules and descriptors, with the aim of exploring the oral absorption quotient of anticancer phytochemicals. Results: Our results showed that for three-fourth of the studied compounds, the computed parameters fall within the accepted range. In addition, the three anticancer libraries have maximum number of molecules which are lipophilic and cell permeable. However, molecules showing aqueous solubility were present only in NPACT and CancerHSP. Conclusion: We hope that the screened naturally occurring plant-based anticancer molecules will facilitate selection of lead that are orally bioavailable and thereby will help in reducing time and effort involved in anticancer drug development.

Introduction: Dihydropyrimidine scaffold represent an important class of pharmacologically active nitrogen containing heterocyclic compounds. A wide range of molecules with dihydropyrimidine moieties have important role in medicinal chemistry on account of their potential biological activities. Methodology: A series of 3,4-dihydropyrimidine-2(1H)-thione derivatives have been designed and synthesized in a concise way through condensation of variously substituted chalcones with thiourea in alkaline alcoholic solutions. In order to investigate their biological significance, these compounds were tested for their in vitro antimicrobial potential against various bacterial and fungal strains. Moreover, the experimental results were supported by molecular docking studies. Results and Discussion: The newly synthesized compounds were characterized by the usual spectroscopic techniques In case of antibacterial activity, the compounds 5 (40.3±0.44 mm), 12 and 13 (almost 35 mm) exhibited highest zone of inhibitions against Methicillin-resistant Staphylococcus auerus (MRSA) bacterial strain as compared to the standard drug Cefixime. These compounds displayed moderate to good activities against all attempted fungal strains. In docking analysis, it has been observed that compounds 8 (-6.4017 Kcal/mol) and 10 (-6.1319 Kcal/mol) revealed significant binding affinity against penicillin binding protein (PDB ID: 1VQQ), while compounds 1 (-143.23 Kcal/mol) and 2 (-146.99 Kcal/mol) showed best activity for shikimate dehydrogenase (PDB ID: 3DON). Conclusion: In conclusion, we have designed, synthesized and characterized an interesting series of biologically active dihydropyrimidine derivatives. Remarkably, most of the synthesized compounds were found more active against all tested bacterial strains in comparison to the standard drug Cefixime as manifested by experimental as well as theoretical results.

Background: In the current study, a series of novel thiophene chalcones (3a-g) and pyrazole containing thiophene derivatives (6a-g) were designed as potential anti-fungal agents and evaluated in silico for drug-likeness behavior. Methods: The titled compounds were synthesized using Claisen–Schmidt reaction of 3-methyl-2- thiophenecarboxaldehyde (1) with several acetophenone derivatives (2a-g) followed by cyclization reactions using hydrazine hydrate to form new compounds (6a-g) in good to excellent yield. All the synthesized compounds were characterized by IR, 1H NMR, 13C NMR and Mass spectral analysis. All the synthesized chalcones (3a-g) and pyrazole derivatives (6a-g) were screened for antifungal potency using Candida albicans (MTCC 3958) and Aspergillus niger (MTCC 9933) using fluconazole as standard drug. Results & Conclusion: The assay results revealed interesting finding that, compound 6c showed significant activity against both the tested fungal strains.

Background: Trk A kinase plays a crucial role in the cell cycle events including survival, proliferation and differentiation in normal and neoplastic neuronal cells. Thus, it has been proved as an important target for cancer pharmaceutical. Methods: A series of twenty-three Trk A inhibitors containing 7-azaindole scaffold were studied based on a combination of two computational techniques, the Three-Dimensional Quantitative Structure Activity Relationship (3D-QSAR) following by molecular docking. The Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) were developed using eighteen molecules having pIC50 ranging from 5.777 to 2.499. The best generated CoMFA and CoMSIA models show conventional determination coefficients R2 of 0.98 and 0.98 as well as their leave-one-out cross-validation determination coefficients Q2 of 0.51 and 0.64, respectively. The predictive ability of those models was evaluated by the external validation using a test set of five compounds with predicted determination coefficients R2 test of 0.74 and 0.80, respectively. Results: The most and the least active compounds from the dataset were docked into the active site of the protein (PDB ID: 4aoj) to interpret those results obtained from 3D-QSAR models and to elucidate the binding mode between this type of compounds and the Trk A protein. Conclusion: These satisfactory results are not offered help only to understand the binding mode of substituted azaindoles into this type of targets, but provide information to design new potent Trk A inhibitors. According to the good concordance between the CoMFA/CoMSIA contour maps and docking results, the obtained information was explored to design novel molecules.

Background: 2-aminoselenazoles became an important core in medicinal chemistry after the discovery of Ebselen and Ethaselen. Therefore, many researchers have reported the synthesis of small selenazole intermediates via Hantzsch cyclization using a wide array of methodologies and catalysts. Methods: In this work, we investigated the formation of 2-aminoselenazoles on various organic solvents and in water, under catalyst-free conditions. Moreover, these molecules and their 2-aminothiazoles analogues were assessed in vitro for their antitubercular activity against Mycobacterium tuberculosis and the results compared. Results: Instant reactions were observed when using polar aprotic solvents and all selenazoles were synthesized in water using sonochemistry. Furthermore, two selenazoles and one thiazole displayed activity in the μM range and the selenium heterocycles seems to be more potent than their sulphur analogues. Conclusion: This is the first study of selenazoles against M. tuberculosis. It is noteworthy that 2-amino-1,3-selenazoles are interesting synthetic intermediates that could be incorporated into novel prototypes against tuberculosis.

Background: Oxidative stress and inflammation are important processes involved in cardiovascular disease. Antioxidant agents, like drugs or natural products from plants or plant-based food, represent a promising approach to treat these pathologies. Methods: In light of this, a gemfibrozil-stilbene hybrid (GEM-STIL) was synthesized as a strategy to combine the well-known antioxidant activity of stilbenes with the reported antioxidant and antiinflammatory actions of fibrates such as gemfibrozil. The physicochemical properties, including aqueous solubility, partition coefficient, chemical stability and enzymatic hydrolysis of GEM-STIL have been studied and indicated that it is stable and has a good lipophilicity. The biological activity was also evaluated for its effect on C2C12 cell line viability and antioxidant activities. Results: The results indicated that GEM-STIL was well tolerated and induced a reduction of cell viability only at higher concentration (100 μg/ml). On the other hand, also at lower nontoxic concentrations (5, 25 and 50 μg/ml) exhibited a significant reduction of ROS production as well as a protective effect against the induced oxidative stimulus. Conclusion: These findings suggest that GEM-STIL is a potential new antioxidant agent useful in oxidative stress-related pathologies.