Letters in Drug Design & Discovery - Volume 18, Issue 1, 2021

Background: Due to the increasing number of cases of invasive fungal infections (IFIs), there is an urgent need to identify potent antifungal agents capable of combating IFIs. Pyrazolines are one such class of therapeutically active agents that could be considered to fulfill this need. Objective: In this context, this paper aims to identify two new series of bis-pyrazolines endowed with potent antifungal activity against Candida albicans and Aspergillus niger. Methods: Two new series of bis-pyrazolines (4a-i, 5a-e) were synthesized through an efficient and versatile synthetic procedure. The compounds were screened for their antifungal effects on C. albicans and A. niger using a broth microdilution method. Their cytotoxic effects on NIH/3T3 mouse embryonic fibroblast cells were determined using MTT assay. Molecular docking studies were performed in the active site of lanosterol 14 α-demethylase (CYP51) to shed light on their antifungal effects using Schrödinger’s Maestro molecular modeling package. Results: 5,5'-(1,4-Phenylene)bis[1-(2-(5-phenyl-1,3,4-oxadiazol-2-yl)thio)acetyl)-3-(2-thienyl)-4,5- dihydro-1H-pyrazole] (4a) and 5,5'-(1,4-phenylene)bis[1-(2-(4-(2-hydroxyethyl)-1-piperazinylthiocarbamoyl) thio)acetyl)-3-(2-thienyl)-4,5-dihydro-1H-pyrazole] (5a) were found as the most promising antifungal agents in this series. Compounds 4a and 5a showed pronounced antifungal activity against C. albicans (MIC= 0.016 mg/mL) and A. niger (MIC= 0.008 mg/mL). Based on MTT assay, their antifungal effects were selective (IC50 > 0.500 mg/mL for NIH/3T3 cell line). Molecular docking studies suggested that compounds 5a-e might show their anticandidal effects via CYP51 inhibition in regard to their stronger interactions in the active site of CYP51. Conclusion: Compounds 4a and 5a stand out as potential antifungal agents for the management of IFIs caused by C. albicans and A. niger.

Background: Matrix metalloproteinase-8 (MMP-8) participates in the degradation of different types of collagens in the extracellular matrix and basement membrane. Up-regulation of the MMP-8 has been demonstrated in many disorders including cancer development, tooth caries, periodontal/ peri-implant soft and hard tissue degeneration, and acute/chronic inflammation. Therefore, MMP-8 has become an encouraging target for therapeutic procedures for scientists. We carried out a molecular docking approach to study the binding affinity of 29 flavonoids, as drug candidates, with the MMP-8. Pharmacokinetic and toxicological properties of the compounds were also studied. Moreover, it was attempted to identify the most important amino acids participating in ligand binding based on the degree of each of the amino acids in the ligand-amino acid interaction network for MMP-8. Methods: Three-dimensional structure of the protein was gained from the RCSB database (PDB ID: 4QKZ). AutoDock version 4.0 and Cytoscape 3.7.2 were used for molecular docking and network analysis, respectively. Notably, the inhibitor of the protein in the crystalline structure of the 4QKZ was considered as a control test. Pharmacokinetic and toxicological features of compounds were predicted using bioinformatics web tools. Post-docking analyses were performed using BIOVIA Discovery Studio Visualizer version 19.1.0.18287. Results and Discussion: According to results, 24 of the studied compounds were considered to be top potential inhibitors for MMP-8 based on their salient estimated free energy of binding and inhibition constant as compared with the control test: Apigenin-7-glucoside, nicotiflorin, luteolin, glabridin, taxifolin, apigenin, licochalcone A, quercetin, isorhamnetin, myricetin, herbacetin, kaemferol, epicatechin, chrysin, amentoflavone, rutin, orientin, epiafzelechin, quercetin-3- rhamnoside, formononetin, isoliquiritigenin, vitexin, catechine, and isoquercitrin. Moreover, His- 197 was found to be the most important amino acid involved in the ligand binding for the enzyme. Conclusion: The results of the current study could be used in the prevention and therapeutic procedures of a number of disorders such as cancer progression and invasion, oral diseases, and acute/chronic inflammation. Although, in vitro and in vivo tests are inevitable in the future.

Background: Protein Tyrosine Phosphatase 1B (PTP1B) is an attractive target for antidiabetic drug discovery owing to its pivotal role as a negative regulator of insulin and leptin signaling. Objective: The objective of this research is to design, synthesize, and evaluate some acetamidobenzoic acid derivatives as a novel class of protein tyrosine phosphatase 1B inhibitors with therapeutic potential for Type II diabetes. Methods: 3-(2-(Benzo[d]thiazol-2-ylthio)acetamido)benzoic acid derivatives 4(a-j) were synthesized and characterized by employing spectral studies. All the synthesized compounds were screened for in vitro PTP1B inhibitory activity and the most potent compound in the series was also evaluated for in vivo anti-hyperglycemic activity using STZ induced diabetic Wistar rat model. Molecular docking studies were also performed with the most potent analog using FlexX docking algorithm to delineate its binding mode to the active site of the PTP1B. Results: Among all the synthesized compounds, 3-(2-(benzo[d]thiazol-2-ylthio)acetamido)-4- methylbenzoic acid (4f) displayed good PTP1B inhibitory activity with an IC50 value of 11.17 μM. The compound also exhibited good anti hyperglycemic efficacy in streptozotocin induced diabetic Wistar rats. Docking studies with 4f revealed that the compound bound in the catalytic and second aryl binding site of the PTP1B. Conclusion: Overall, compound 4f with good in vitro PTP1B inhibitory potency and in vivo antihyperglycemic efficacy would be a valuable lead molecule for the development of acetamidobenzoic acid based PTP1B inhibitors with antidiabetic potential.

Background: Biscoumarin scaffolds are known for their promising pharmacological properties. These compounds have not been studied for their activity against tuberculosis strains. Objective: Unveil the antitubercular properties of biscoumarin scaffolds. Methods: Biscoumarin derivatives (3a-3l) were synthesized using lemon juice as a catalyst and were investigated for their in-vitro anti-tubercular activity against the H37Rv strain of Mycobacterium tuberculosis using Microplate Alamar Blue Assay Method (MABA). Their binding interaction was investigated by Molecular Docking Studies using InhA with PDB-ID: 2NSD as target receptors in the H37Rv strain of Mycobacterium tuberculosis. These derivatives (3a-3l) were subjected to the neutrophil function test. Results: The results revealed that compounds 3b, 3c, 3d, 3f, 3i, 3j showed excellent activity with MIC 1.6μg/mL. Molecular docking interactions for their antitubercular activity proved that the derivatives (3a-3l) can easily bind into the pockets of the enzyme. Neutrophil function test signified that they exhibit moderate neutrophil functions assuring that they do not harm the functioning of Neutrophils. Conclusion: These studies have awakened the property of Biscoumarins as promising antitubercular scaffolds.

Background: Recently, novel coronavirus disease, COVID-19 caused the outbreak situation of global public health. In this pandemic situation, all the people's lives of 212 Countries and Territories have been affected due to partial or complete lockdown and also as a result of mandatory isolations or quarantines. This is due to the non-availability of any secure vaccine. Objective: The present study helps us to identify and screen the best phytochemicals as potent inhibitors against COVID-19. Methods: In this paper, we choose two standard drugs namely hamamelitannin and rosmarinic acid as a probable inhibitor of pandemic COVID-19 receptor as compared to antimalarial drugs hydroxychloroquine, anti-viral drug remdesivir, and also baricitinib. This study was done by taking into consideration of molecular docking study, performed with Auto Dock 4.0 (AD4.0). All chemical structures were optimized with the Avogadro suite by applying the MMFF94 force field and also hamamelitannin, rosmarinic acid was optimized using the Gaussian G16 suite of UB3LYP/6- 311++G(d,p) basis set. Protein-ligand interaction was visualized by PyMOL software. Results: This work has provided an insightful understanding of protein-ligand interaction of hamamelitannin and rosmarinic acid showing comparable binding energies than that of clinically applying probable COVID-19 inhibitors hydroxychloroquine (an anti-malarial drug) and remdesivir (an anti-viral drug). Conclusion: We will expect that if its anti-SARS-CoV-2 activity is validated in human clinical trials, these two drugs may be developed as an effective antiviral therapeutics towards infected patients in this outbreak and pandemic situation of COVID-19.

Background: The appearance of antibiotic resistance caused by metallo-β-lactamases (MβLs) is a global public health threat. Developing MβLs inhibitor is an effective way to overcome antibiotic resistance. Recently, azolylthioacetamides were reported to be promising MβLs inhibitors. Methods: Triazolylthioacetamides were synthesized and tested for inhibition activity against the purified MβL IMP-1. Antimicrobial activities of these inhibitors in combination with cefazolin were evaluated. Isothermal Titration Calorimetry (ITC) was employed to characterize the binding of the inhibitor to IMP-1, and their action mechanism was studied by molecular docking. Results: Twenty compounds exhibited specific inhibitory activity against IMP-1 with an IC50 value in the range of 3.1-62.5 μM. Eight of the compounds can restore the antibacterial efficacy of cefazolin against E. coli BL21 strain producing IMP-1 by 2-4 fold. ITC monitoring showed that 1c exhibited dose-dependent inhibition on IMP-1. Docking studies revealed that the triazole group in 1c and 2d played an essential role in the inhibition activity. Cytotoxicity assay showed that 1c and 2d have low toxicity in L929 mouse fibroblastic cells. Conclusion: The triazolylthioacetamides are efficient inhibitors of IMP-1 in vitro and in vivo.

Background: Sphingolipids, even in extremely low doses, regulate various physiological functions. Particularly, immune and cancer cells might be controlled by changes in the sphingosine- 1-phosphate (S1P) levels, and S1P has been studied for a long time as a major target for new drug development. Sphingosine kinase (SK) phosphorylates sphingosine to produce S1P. An increase in the S1P levels promotes the growth of cancer cells. SK has 2 isoforms, SK1 and SK2, both of which are involved in the growth of cancer cells. Objective: PF-543 has been developed as an SK1 inhibitor and has a non-lipid structure that differs from those of general SK inhibitors. While PF-543 has a potent SK1 inhibitory effect, and has low anticancer activity in some types of cancer cells. Therefore, the development of other PF-543 derivatives is needed. Methods: We designed a structurally simplified derivative of PF-543. To primarily demonstrate that the designed structure was biologically active, 8 derivatives were synthesized by a 2-step method using the commercial starting material, and their biological activities were evaluated. Results: The SK1-inhibitory effects of the synthesized derivatives were not higher than that of PF- 543. However, the anticancer activity and apoptotic effect of the derivatives were similar to those of PF-543, despite their fabrication from a simple modification of the PF-543 structure. In a docking study, the derivatives were found to bind SK1 in a form similar to PF-543. Conclusion: Our analogs, which are similar to PF-543, showed comparable anticancer activity, indicating that the synthesized derivatives are structurally more efficient for anticancer activity than PF-543. Therefore, our study provides important information that may be useful for developing new anticancer substances that target SK1.

Background and Objective: The development of pharmacologically active molecules for the treatment of hypertension and other cardiovascular diseases are important nowadays. In the present investigation, computational techniques have been implemented on Angiotensin II Type 1 (AT1) antagonists to develop better predictive models. Methods: Quantitative Structure Activity Relationship (QSAR) and structural patterns/fragments analyses were performed using physicochemical descriptors and MACCS Fingerprints calculaced from AT1 inhibitors collected from the literature. Results: The significant models developed have been validated by Leave One Out (LOO) and test set methods, which exhibit considerable Q2 values (>0.65 for the training set and >0.5 for the test set) and the R²pred values for the models are also >0.5. The applicability of the contributed descriptors in these models revealed that the chlorine atom, dipole moment, hydrogen bond donor atoms and electrostatic potential are negatively contributing, and the presence of bond between heavy atoms and the carbon atom connected with small side chain and topological polar vdW surface area are favorable for the AT1 antagonistic activity. The MACCS Fingerprints showed that the presence of atoms (kind of heavy atoms), such as N, O, and S, connected with other heteroatoms or carbon or any other atoms, through single or double bonds are predominantly present in highly active molecules. The presence of halogens, long chain alkanes, halogenated alkanes, and sulfur atoms attached with nitrogen through any atoms are responsible for decreased AT1 antagonistic activity. Conclusion: The results have provided additional information on the structural patterns of the compounds based on its MACCS Fingerprints, which may be used for further characterization and design of novel AT1 inhibitors.

Background: The combination of two or more therapeutic drugs is an attractive approach to improve the treatment of experimental tumors. Leveraging nanocarriers for combinational drug delivery can allow control over drug biological fate and promote co-localization in the same area of the body. However, there are certain concerns regarding the biodegradability and potential longterm toxicity arising from these synthetic nanoscale carriers. Objective: Our aim was to develop a combinational nanodrug delivery system formed by selfassembling of amphiphilic drug molecules minimizing potential toxicities associated with using additional synthetic nanocarriers. Methods: A novel prodrug chlorambucil gemcitabine conjugate was synthesized, this prodrug was used for the encapsulation of an additional hydrophobic anticancer drug paclitaxel, taking the form of combinational nanodrugs. Particle size and zeta potential were evaluated, cytotoxicity assay and apoptosis/cell cycle analysis were also performed to validate the anticancer efficacy of the combinational nanodrugs. Results: The combinational nanodrugs were acquired by means of nanoprecipitation. In A549 lung adenocarcinoma cell line, cellular assays revealed that co-delivery of low dosage paclitaxel with chlorambucil gemcitabine conjugate can act synergistically to inhibit cell growth and induce accumulation of cells in the G2/M phase with a concomitant decrease in G0/G1 compartment. Conclusion: Chlorambucil gemcitabine conjugate and paclitaxel can co-assemble into composite nanoparticles by a nanoprecipitation process and the resulting combinational nanodrugs showed a synergistic anticancer effect. This synthetic nanocarrier-free approach might broaden the nanodrug concept and have potential in cancer therapy.