Department of Pharmacy
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Item Design, synthesis, and biological evaluation of novel quinoxaline aryl ethers as anticancer agents(Wiley, 2024-03) Murugesan, SankaranarayananWe designed and synthesized thirty novel quinoxaline aryl ethers as anticancer agents, and the structures of final compounds were confirmed with various analytical techniques like Mass, 1H NMR, 13C NMR, FTIR, and elemental analyses. The compounds were tested against three cancer cell lines: colon cancer (HCT-116), breast cancer (MDA-MB-231), prostate cancer (DU-145), and one normal cell line: human embryonic kidney cell line (HEK-293). The obtained results indicate that two compounds, FQ and MQ, with IC50 values < 16 μM, were the most active compounds. Molecular docking studies revealed the binding of FQ and MQ molecules in the active site of the c-Met kinase (PDB ID: 3F66, 1.40 Å). Furthermore, QikProp ADME prediction and the MDS analysis preserved those critical docking data of both compounds, FQ and MQ. Western blotting was used to confirm the impact of the compounds FQ and MQ on the inhibition of the c-Met kinase receptor. The apoptosis assays were performed to investigate the mechanism of cell death for the most active compounds, FQ and MQ. The Annexin V/7-AAD assay indicated apoptosis in MDA-MB-231 cells treated with FQ and MQ, with FQ (21.4%) showing a higher efficacy in killing MDA-MB-231 cells than MQ (14.25%). The Caspase 3/7 7-AAD assay further supported these findings, revealing higher percentages of apoptotic cells for FQ-treated MDA-MB-231 cells (41.8%). The results obtained from the apoptosis assay conclude that FQ exhibits better anticancer activity against MDA-MB-231 cells than MQ.Item Design, synthesis and biological evaluation of 1,2,3-triazole based 2-aminobenzimidazoles as novel inhibitors of LasR dependent quorum sensing in Pseudomonas aeruginosa(RSC, 2019) Murugesan, SankaranarayananBacteria regulate their phenotype, growth and population via a signalling pathway known as quorum sensing. In this process, bacteria produce signalling molecules (autoinducers) to recognize their population density. Inhibiting this quorum sensing signalling pathway is one of the potential methods to treat bacterial infection. 2-Aminobenimdazoles are reported to be the strongest inhibitors of quorum sensing against wild-type P. aeruginosa. 1,2,3-Triazole based acyl homoserine lactones are found to be good inhibitors of the quorum sensing LasR receptor. Hence, in our current study, forty 1,2,3-triazole based 2-aminobenzimdazoles were synthesized and characterized using IR, NMR, MS and elemental analysis. A single crystal was developed for N-(1H-benzo[d]imidazol-2-yl)-2-(4-nonyl-1H-1,2,3-triazol-1-yl)acetamide (6d). All final compounds were screened for in vitro quorum sensing inhibitory activity against Pseudomonas aeruginosa. The quorum sensing inhibitory activity was determined in the LasR expressing P. aeruginosa MH602 reporter strain by measuring green fluorescent protein production. Among the title compounds, N-(1H-benzo[d]imidazol-2-yl)-2-(4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)acetamide (6i) exhibited good quorum sensing inhibitory activity of 64.99% at 250 μM. N-(1H-Benzo[d]imidazol-2-yl)-2-(4-(4-nitrophenyl)-1H-1,2,3-triazol-1-yl)acetamide (6p) exhibited the most promising quorum sensing inhibitory activity with 68.23, 67.10 and 63.67% inhibition at 250, 125 and 62.5 μM, respectively. N-(1H-Benzo[d]imidazol-2-yl)-2-(4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)acetamide (6o) and N-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)-2-(4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)acetamide (7l) also exhibited 64.25% and 65.80% quorum sensing inhibition at 250 μM. Compound 6p, the most active quorum sensing inhibitor, also displayed low cytotoxicity at the tested concentrations (25, 50 and 100 μM) against normal human embryonic kidney cell lines. Finally, a docking study using Schrodinger Glide elucidated the possible putative binding mode of the significantly active compound 6p at the active site of the target LasR receptor (PDB ID: 2UV0).Item Design, synthesis, α-amylase inhibition and in silico docking study of novel quinoline bearing proline derivatives(Elsevier, 2020-05) Murugesan, Sankaranarayananα-amylase enzyme hydrolyses carbohydrate into glucose is known to be an important molecular target for type 2 Diabetes mellitus. In the course of developing α-amylase enzyme inhibitors, we designed, synthesized seventeen novel quinoline bearing proline analogs, subsequently physico-chemical properties of designed analogs were also in silico predicted for their drug likeness evaluation. Synthesized compounds were characterized by spectral analysis such as Mass, IR, 1H NMR, 13C NMR and further screened in vitro for α-amylase inhibitory activity using acarbose as standard drug. Seven analogs, 6a, 6b, 6c, 6d, 6g, 10b and 10c showed significant α-amylase inhibitory activity. Eight analogs, 5, 6e, 6f, 6h, 6j, 10a, 10d and 10e showed good to moderate activity while other two analogs, 6i and 9 showed least activity. The molecular docking study of significantly active and weakly active compounds was performed in order to study their putative binding mode of the most and least active compounds (6c and 6i).Item Coumarin-Oxadiazole Derivatives: Synthesis and Pharmacological Properties(Bentham Science, 2020) Murugesan, SankaranarayananCoumarin and oxadiazole moieties ubiquitously occur in a wide range of natural products and are valued for their varied and beneficial pharmacological activities. Herein, this review focuses on various documented techniques used by researchers to synthesize an assortment of biologically active coumarin-oxadiazole scaffolds. Also, the common techniques discussed are used to establish the wide-range of biological activities of the synthesized coumarin and oxadiozole derivatives, including; antioxidant, anthelmintic, antimicrobial, anti-tuberculosis, analgesic, anti-inflammatory, cytotoxicity and anticonvulsant. Additionally, the current, well-established drugs synthesized using coumarin-oxadiazole scaffolds are typically dispensed in regular clinical practice are also highlighted in this review paper.Item Synthesis, biological evaluation, molecular docking, molecular dynamics and DFT studies of quinoline-fluoroproline amide hybrids(Elsevier, 2020-10) Murugesan, SankaranarayananThree analogs of quinoline hybrid 4-cis-fluoro-proline amides (QHCFPAs) were synthesized and characterized using spectroscopic techniques like 1H NMR, 13C NMR, DEPT 135, FT-IR and ESI-MS. The in vitro antidiabetic activity of the titled compounds was performed by reported spectrophotometric method and the percentage inhibition of α-amylase was found comparable to that of standard drug acarbose. In silico ADMET properties of the titled compounds were predicted and discussed. Further, molecular docking studies of QHCFPAs were performed against the target α-amylase enzyme to identify the plausible binding interactions between enzyme and the QHCFPAs. Among QHCFPAs, (2R,4R)-1-((2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)methyl)-4-fluoro-N-phenylpyrrolidine-2-carboxamide (QPAA) exhibited good docking score andbinding energy of −4.5 and −40.12 kcal/mol, respectively and (2R,4R)-1-((2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)methyl)-N-(2,4-dimethylphenyl)-4-fluoropyrrolidine-2-carboxamide(QPDMAA) exhibited docking score and binding energy of −4.7 and −42.90 kcal/mol, respectively. Further, frontier molecular orbitals and molecular electrostatic potential studies were also performed to support the in silico and in vitro biological screening results. Finally, molecular dynamics study was also explored for QPAA in order to correlate the findings of in silico and in vitro studies.Item 1,2,3,4-Tetrahydroisoquinoline (THIQ) as privileged scaffold for anticancer de novo drug design(Taylor & Francis, 2021-04) Murugesan, SankaranarayananCancer is a dreadful disorder that is emerging as one of the leading causes of mortality across the globe. The complex tumor environment, supplemented with drawbacks of the existing drugs, has made it a global health concern. The Tetrahydroisoquinoline (THIQ) ring holds an important position in medicinal chemistry due to its wide range of pharmacological properties. Several THIQ based natural products have been previously explored for their antitumor properties, making it a vital scaffold for anticancer drug design.Item Design, synthesis and anti-mycobacterial evaluation of imidazo[1,2-a]pyridine analogues(RSC, 2022) Murugesan, SankaranarayananBased on the molecular hybridization strategy, thirty-four imidazo[1,2-a]pyridine amides (IPAs) and imidazo[1,2-a]pyridine sulfonamides (IPSs) were designed and synthesized. The structures of the target compounds were characterized using 1H NMR, 13C NMR, LCMS, and elemental analyses. The synthesized compounds were evaluated in vitro for anti-tubercular activity using the microplate Alamar Blue assay against Mycobacterium tuberculosis H37Rv strain and the MIC was determined. The evaluated compounds exhibited MIC in the range 0.05–≤100 μg mL−1. Among these derivatives, IPA-6 (MIC 0.05 μg mL−1), IPA-9 (MIC 0.4 μg mL−1), and IPS-1 (MIC 0.4 μg mL−1) displayed excellent anti-TB activity, whereas compounds IPA-5, IPA-7 and IPS-16 showed good anti-TB activity (MIC 0.8–3.12 μg mL−1). The most active compounds with MIC of <3.125 μg mL−1 were screened against human embryonic kidney cells to check their cytotoxicity to normal cells. It was observed that these compounds were nontoxic (SI value ≥66). The ADMET characteristics of the final compounds were also predicted in silico. Further, using the Glide module of Schrodinger software, a molecular docking study of IPA-6 was carried out to estimate the binding pattern at the active site of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis (PDB 4TZK). Finally, molecular dynamics simulations were performed for 100 ns to elucidate the stability, conformation, and intermolecular interactions of the co-crystal ligand and significantly active compound IPA-6 on the selected target protein. IPA-6, the most active compound, was found to be 125 times more potent than the standard drug ethambutol (MIC 6.25 μg mL−1).Item Recent Progress in Synthesis, POM Analyses and SAR of Coumarin-Hybrids as Potential Anti-HIV Agents—A Mini Review(MDPI, 2023) Murugesan, SankaranarayananThe human immunodeficiency virus (HIV) is the primary cause of acquired immune deficiency syndrome (AIDS), one of the deadliest pandemic diseases. Various mechanisms and procedures have been pursued to synthesise several anti-HIV agents, but due to the severe side effects and multidrug resistance spawning from the treatment of HIV/AIDS using highly active retroviral therapy (HAART), it has become imperative to design and synthesise novel anti-HIV agents. Literature has shown that natural sources, particularly the plant kingdom, can release important metabolites that have several biological, mechanistic and structural representations similar to chemically synthesised compounds. Certainly, compounds from natural and ethnomedicinal sources have proven to be effective in the management of HIV/AIDS with low toxicity, fewer side effects and affordability. From plants, fungi and bacteria, coumarin can be obtained, which is a secondary metabolite and is well known for its actions in different stages of the HIV replication cycle: protease, integrase and reverse transcriptase (RT) inhibition, cell membrane fusion and viral host attachment. These, among other reasons, are why coumarin moieties will be the basis of a good building block for the development of potent anti-HIV agents. This review aims to outline the synthetic pathways, structure–activity relationship (SAR) and POM analyses of coumarin hybrids with anti-HIV activity, detailing articles published between 2000 and 2023.