Letters in Drug Design & Discovery - Volume 17, Issue 3, 2020

Nitric Oxide (NO), an important biological mediator, is involved in the regulation of the cardiovascular, nervous and immune systems in mammals. Synthesis of NO is catalyzed by its biosynthetic enzyme, Nitric Oxide Synthase (NOS). There are three main isoforms of the enzyme, neuronal NOS, endothelial NOS and inducible NOS, which have very similar structures but differ in their expression and activities. NO is produced in the active site of the enzyme in two distinct cycles from oxidation of the substrate L-arg (L-arginine) in nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reaction. NOS has gained considerable attention of biochemists due to its complexity and unique catalytic mechanism. The review focuses on NOS structure, its function and catalytic reaction mechanism. In particular, the review is concluded with a discussion on the role of all three isoforms of NOS in physiological and pathological conditions and their inhibitors with a focus on the role of computational techniques in their development.

Background: QSAR study of p-substituted aromatic hydrazones was performed to estimate the quantitative effects of selected topological descriptors on their antimicrobial activity. None of the hydrazones inhibited the growth of the Aspergillus spp., while the data obtained with regard to the antifungal activity of the compounds against Candida utilis were insufficient to develop reliable statistical QSAR models. Therefore, the investigation was focused on developing QSAR models for predicting the antibacterial activity of the compounds against Bacillus subtilis. Methods: A set of substituted hydrazones were tested for their in vitro growth inhibitory activity against Candida utilis, Bacillus subtilis and Aspergillus niger and the diameter of the inhibition zone (mm) was measured. The inhibitory activity data, determined in μg/mL, were transformed to the negative logarithms of molar MICs (log1/CMIC). Using Marvinsketch software package, 28 topological descriptors were calculated. Statistical parameters, such as R2, Sd, F-test, R2 adj, Q, SPRESS, PSE and Q2, were used to test the quality of the developed two-, three-, four-parametric and higher QSAR models. Results and Conclusion: Statistical evaluation of the data used to test the quality of the obtained QSAR models indicated that the two-parametric model involving the descriptors Atom Count (AC) and Maximal Projection Area (MAPA) was statistically significant when all the statistical parameters were summarized. The two parameters, AC and MAPA, had opposite input in modeling the antimicrobial activity of the selected hydrazones against Bacillus subtilis.

Background: In the present study, eight new cephalosporin conjugated sulfonamides were synthesized to investigate the anticancer activity. Methods: All the compounds were characterized on the basis of FTIR, 1HNMR, MS and elemental analysis (CHN). The new compounds were evaluated against the Vero and Hep G2 cancer cell lines for their anticancer activities. Cytotoxicity of all the compounds was determined against brine shrimp at 20 μg concentration. Results and Conclusion: The results revealed that ceftriaxone conjugated sulfonamide was the most potent and showed cytotoxicity (86.4 %) comparable to the standard reference drug actinomycin D (90.0 %). The compounds with lower cLogP value showed more antiproliferative effect due to their higher cell permeability. Ceftriaxone conjugated with 4-acetamido benzene sulfonyl was the most active compound against both cell lines with IC50 3.95 μM (Vero) and 5.11 μM (Hep G2) values whereas its activity was comparable with 5-fluorouracil used as reference drug (IC50 = 2.84 μM).

Background: Plant-derived natural compounds have a unique molecular structure and rich biological activity, hence, they are treated as important raw materials for the development of drugs. Methods: A natural compound (-)-β-pinene was used as a raw material, and twenty-six novel derivatives with amide or acylthiourea groups were synthesized based on the molecular hybridization method. In vitro antitumor activity of these derivatives on human breast cancer cell line MCF7 and human colon cancer cell line SW1116 were tested by MTT method. The effects of the synthesized derivatives on the morphology of MCF7 and SW1116 were observed by fluorescent inverted microscope. Results: The preliminary structure-activity relationship analysis demonstrates that the position and species of substituents on the aromatic ring of derivatives have an effect on the antitumor activity of derivatives. Observation of the cell morphology reveals that derivatives with antitumor activity can lead to rounding of the cell morphology, a decrease in cell volume and cell density, and ultimately inhibition of the proliferation of MCF7 and SW1116 cells. The antitumor activity evaluation results show that among these derivatives, compounds 5c, 5e, 5h, 7c, 7b and 7e exhibit good antitumor activity against MCF7, and compounds 5c, 5e, 5h and 7j exert moderate antitumor activity against SW1116. Conclusion: This study hopes to promote the high value-added utilization of natural compounds β-pinene and the development of novel antitumor drugs.

Background: Limonoids represent an important class of natural products which possess a broad range of biological activities. Albeit their enormous potentials as therapeutic candidates, they usually suffer from low bioavailability, poor aqueous solubility and relatively weak biological activities which result in significant challenges in the clinic applications. Therefore, the exploration and development of novel limonin derivatives with improved drug-like properties through the structural modifications recently have attracted great attention in the biological and medicinal chemistry field. Methods: Based on the structural modifications of C17-furan ring in limonin, a series of limonin derivatives was designed, synthesized and screened for their anti-inflammatory and analgesic activities in vivo. Results and Conclusion: Preliminary pharmacological studies revealed that most tested compounds exhibited more potent anti-inflammatory and analgesic efficacies than lead molecule limonin. Especially, for compound 3f, it exhibited a stronger anti-inflammatory effect than that of naproxen and comparable analgesic potency with aspirin. In the formalin test, 3f showed an obviously attenuated phase-II pain response which indicated that it may produce an anti-inflammatory effect in the periphery. Furthermore, the significantly low hERG inhibition (IC50 >100 μM) and high LD50 value of target molecule 3f further demonstrated it as a promising analgesic/anti-inflammatory candidate with excellent drug-like profiles.

Background: Due to the extensive use of a single fungicide to control crop diseases, the increase of resistant individuals leads to control failures. The search for molecules with fungicidal activity is still ongoing. Strobilurin is one of the most popularly used fungicides in the agrochemical field. A large number of strobilurin derivatives with both high activity and low toxicity have been developed. Methods: In the present study, a series of novel ortho-substituted benzyl carboxylates were efficiently synthesized by the reaction of (E)-methyl 2-(2-(bromom-ethyl)phenyl)-2-methox-yiminoaceta with various carboxylic acids. Their structures were confirmed and characterized by 1H NMR, 13C NMR, and ESI-MS analysis. Their fungicidal activities against common phytopathogenic fungi from six major cash crops were screened based on the pesticides guidelines for the laboratory bioactivity tests. Results: The primary fungicidal activity test results indicate that all compounds showed a certain inhibitory effect on the growth of 13 plants pathogenic fungi at a concentration of 100 ppm, and Compd. 3 has the most obvious inhibitory effect on all fungi. Further fungicidal activity studies indicate that some of these novel strobilurin derivatives containing carboxylate unit exhibited potential in vitro fungicidal activities at the dosage of 6.25 mg/L-1. Conclusion: A series of the ortho-substituted benzyl carboxylates derivatives containing β- methoxyacrylate moiety were designed and synthesized by modifying the side chain of traditional strobilurin fungicide. Compd. 3, Compd. 2 and Compd. 16 were identified as the most promising candidates for further study.

Background: Hydrazones, frequently occurring motifs in many bioactive molecules, have attracted a great deal of interest as potent antimicrobial agents. Objective: The aim of this work was to design and synthesize new hydrazone-based antimicrobial agents. Methods: 4-[2-((5-Arylfuran-2-yl)methylene)hydrazinyl]benzonitrile derivatives (1-10) were obtained via the reaction of 4-cyanophenylhydrazine hydrochloride with 5-arylfurfurals. Compounds 1-10 were evaluated for their antimicrobial effects using a broth microdilution method. Their cytotoxic effects on NIH/3T3 mouse embryonic fibroblast cell line were determined using XTT assay. The most effective antimicrobial agents were investigated for their genotoxic effects using Ames MPF assay. In silico docking and Absorption, Distribution, Metabolism and Excretion (ADME) studies were also performed using Schrödinger’s Maestro molecular modeling package. Results: The antifungal effects of the compounds were more significant than their antibacterial effects. Compound 5 bearing 3-nitrophenyl moiety was the most potent antifungal agent against Candida albicans, Trichoderma harzianum and Fusarium species, whereas compound 10 bearing 4- chloro-2-nitrophenyl moiety was the most effective antifungal agent on Aspergillus ochraceus. According to XTT and Ames MPF assays, these compounds were neither cytotoxic nor genotoxic at the concentrations tested. Docking studies suggested that these compounds showed good affinity to the active site of lanosterol 14α-demethylase (CYP51) (PDB code: 5V5Z) and interacted with the key residues such as Hem601 and Cys470. Based on in silico ADME studies, the compounds are expected to have high oral bioavailability. Conclusion: According to the in vitro and in silico studies, compounds 5 and 10 stand out as potential orally bioavailable antifungal agents for further studies.

Background: The bromodomain and extra-terminal proteins (BET), in particular BRD4, has recently emerged as a potential therapeutic target for the treatment of many human disorders such as cancer, inflammation, obesity and cardiovascular disease, which draw more and more attention to discover potent BRD4 inhibitors in the past years. In this article, we described the discovery process of an entirely new chemotype of BRD4 inhibitors. Methods: A fragment-based drug discovery strategy was employed in attempting to find a novel chemotype of BRD4 inhibitors. Thus, the potential hits were firstly identified by docking study with KAc binding pocket and AlphaScreen assay. Then the elected hit was further structurally optimized based on the interaction revealed by the docking study and the Structure-Activity Relationship (SAR). Results: A 1-(2-hydroxyphenyl)ethan-1-one fragment was first identified as an efficient hit to BRD4 with a weak inhibition activity and high ligand efficiency (IC50 = 8.9 μM, LE > 0.5) based on virtual screening and biochemical assay. Then, two-rounds optimization of the hit by a fragmentbased drug discovery approach enabled the discovery of a potent BRD4 inhibitor 9, which exhibit nanomolar potency in biochemical assays (IC50 = 0.18 μM). Conclusion: The title compounds displayed potent inhibitory activity to BRD4, implying acetophenone core is an effective KAc residue mimic, suggesting acetophenone derivatives as a new chemotype may be promising for developing novel BRD4 inhibitors.

Introduction: Heterocyclic compounds are vital to life, since they constitute the most interesting part of the pharmacologically active drugs. Dihydropyrimidine-2-one/thione (DHPM) as the heterocyclic nucleus is the basic part of the most natural as well as synthetic drugs. Synthesis of new derivatives of DHPM and screening their pharmacological potential appear to be an important goal. Methodology: In this study, we have synthesized 15 derivatives of 3,4-dihydropyrimidin-2(1H)- ones/thiones through simple one-step synthetic method comprising one-pot condensation of variously substituted benzaldehydes, urea/thiourea and ethyl acetoacetate using ammonium chloride in methanol as well as under solvent-free conditions. In comparison, the former methodology was proved more efficient, convenient and gave higher yields. Moreover, those compounds were screened for their potential against bacterial strains (S. aureus and E. coli) and fungal strains (C. albicans and C. parapsilosis). Results and Discussion: The experimental results revealed that the synthesized compounds are more active against C. albicans fungus as compared to other tested microbes. Amongst all the synthesized derivatives, compound 3 showed significant non-competitive potential antifungal activity in vitro antimicrobial assay. Theoretically, molecular docking studies showed that these compounds can bind effectively to oxidoreductase enzyme of E. coli and CYP-51 oxidoreductase of C. albicans. Conclusion: Herein, we report improved and high yield reaction conditions for the synthesis of biologically active dihydropyrimidine-2-one, and-thione derivatives. Remarkably, most of the synthesized compounds demonstrated moderate to very good antifungal activity in comparison to the antibacterial activity.

Background: Colony Stimulating Factor-1 Receptor (CSF-1R) is associated with malignancy, invasiveness and poor prognosis of tumors, and pyrimidine derivatives are considered as a novel class of CSF-1R inhibitor. Methods: To explore the relationship between the structures of substituted pyrimidine derivatives and their inhibitory activities against CSF-1R, CoMFA and CoMSIA analyses, and molecular docking studies were performed on a dataset of forty-four compounds. Results: We found in CoMFA model including steric and electrostatic fields for the training set, the cross-validated q2 value was 0.617 and the non-cross-validated r2 value was 0.983. While, the crossvalidated q2 value was 0.637 and the non-cross-validated r2 value was 0.984 in CoMSIA Model which include steric, electrostatic and hydrophobic fields. 3D equipotential maps generated from CoMFA and CoMSIA along with the docking binding structures provided enough information about the structural requirements for better activity. Conclusion: The data generated from the present study helped us to predict the activity of new inhibitors and further design some novel and potent CSF-1R inhibitors.

Background: Applying of "double-drug" strategy to 5-nitrofuran derivatives has been proposed. Methods: A small library of 5-Nitrofuran-2-yl Thiohydrazones was developed, and initial screening demonstrated good activity against bacteria and fungi of ESKAPE panel. Results and Conclusion: The synthesis of the desired thiohydrazones was carried out via condensation of 5-nitrofuran-2-carbaldehyde with thiohydrazides of substituted oxamic acids.