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Item Exploration of quinoxaline triazoles as antimycobacterial agents: design, synthesis and biological evaluation(Elsevier, 2025-06) Murugesan, SankaranarayananIn this work, novel 2-substituted-3-((1-substituted-1H-1,2,3-triazol-4-yl) methoxy) quinoxaline analogues were designed, synthesized, and various analytical techniques, viz., 1H NMR, 13C NMR, and Mass spectrometry, were deployed in the structure confirmation of the final compounds. Synthesized derivatives were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis (Mtb) H37Rv. Target molecules mainly consist of methyl substituent in the second position of quinoxaline moiety (QM series) or phenyl substituent in the second position (QP series). Among the forty-two compounds synthesized and evaluated for anti-mycobacterial activity, the MIC values ranged between 5.58 μg/mL to >100 μg/mL. Among QM series compounds, QM7, with MIC 5.58 μg /mL, was the most active compound. Among the QP series derivatives, the intermediate QP-Acy with MIC 23.39 μg /mL was the most promising. Most of the analogues tested in the QP series are less potent than the QM series. All the synthesized molecules showed good drug-likeness when evaluated using the SWISS ADME tool. QM7 was evaluated for docking studies using the crystal structure of enoyl-acyl carrier (INH-A) enzyme PDB: 4TZK, and it showed significant docking scores and interactions. MD simulations were carried out to assess the stability of the protein QM7 complex. Single crystals were grown for QM1, QM6, and QPb from these forty-two compounds, and their structures were solved using OLEX. The corresponding CCDC numbers for these compounds are 2,388,310, 2,388,309, and 2,388,291, respectively.Item Design, synthesis, and biological evaluation of (E)-3-amino-N′-substituted benzylidene-6-chloropyrazine-2-carbohydrazide derivatives as anti-mycobacterial agents(Elsevier, 2025-12) Murugesan, SankaranarayananPyrazinamide is a powerful sterilizing agent that reduces the treatment duration required to cure tuberculosis and works synergistically with both new and existing anti-tuberculosis drugs. Thirty-one derivatives of (E)-3-amino-N′-substituted benzylidene-6-chloropyrazine-2-carbohydrazide (20a-20ae) were designed and synthesized. The structures of these compounds were confirmed through various analytical methods, such as 1H NMR, 13C NMR, and mass spectrometry. To better understand the arrangement of atoms and confirm the structures, single crystals of 20 m and 20aa were grown and analyzed. The final derivatives, 20a-20ae, were evaluated for their anti-mycobacterial activity against the Mycobacterium tuberculosis (M.tb) H37Ra strain using the Microplate Alamar Blue Assay (MABA). Among all the synthesized compounds tested, 20 m and 20s showed potent activity with a minimum inhibitory concentration (MIC) of 3.13 μg/mL (8.66 μM and 11.37 μM, respectively). 20q and 20r also displayed significant anti-TB activity with an MIC of 6.25 μg/mL (23.66 μM and 21.47 μM, respectively). The MIC values of the remaining compounds ranged from 12.5 to >50 μg/mL (34.62 μM to 172.96 μM). To further evaluate the binding interaction within the active site of the enzyme aspartate decarboxylase (PanD) from M. tb (PDB: 6P02), a molecular docking analysis of compound 20s was performed. Finally, 100 ns molecular dynamics simulations were carried out to comprehend the stability, conformation, and intermolecular interactions of the co-crystal ligand and the highly active compound 20s with the selected target protein. Further, in order to better understand bacterial resistance and pathogenesis and to create efficient treatments against significant drug-resistant pathogens, in vitro anti-mycobacterial activity of the compounds with MIC ≤12.5 μg/mL (43.24 μM) was assessed for their effectiveness against the ESKAPE group of pathogens using the MABA method. Results indicate that 20e exhibited the most promising activity with an MIC of 50 μg/mL (172.9 μM) against Staphylococcus aureus among the ESKAPE group of pathogens.Item Discovery of novel chromone and acrylate-based pancreatic lipase inhibitors: Molecular modelling, synthesis, and in vitro evaluation for the treatment of obesity(Wiley, 2024-01) Paul, Atish TulshiramBy the optimization of previously established pancreatic lipase (PL) inhibitory lead, we have developed novel chromone-containing analogues with embedded acrylate fragment as potential PL inhibitors. The analogues were designed by considering the structural features required for binding at the active site of PL enzyme with the utilization of molecular docking study. An optimized synthetic scheme was utilized for the synthesis of designed analogues of prototypes 1&2. Through in vitro PL inhibitory screening, three analogues namely, 5fj, 5gj and 9a were identified as potent PL inhibitory leads with IC50 values of 4.92, 4.23 and 3.32 μM, respectively. The protein binding of analogue 9a was analysed by fluorescence quenching study and it was found to bind at one binding site with a binding constant of 1.93 × 105 L mol−1. Analogue 9a also exhibited a competitive inhibitory mechanism with Ki value of 1.601 μM. In future, the potent lead 9a can be optimized to get a comparable or more potential PL inhibitory activity than marketed drugs.Item Computational insights into human UCP1 activators through molecular docking, MM-GBSA, and molecular dynamics simulation studies(Elsevier, 2024-12) Paul, Atish TulshiramThe prevalence of obesity is rapidly increasing worldwide. Brown adipose tissue activates uncoupling protein 1 (UCP1) to generate heat through bypassing ATP synthesis, offering a potential target for obesity treatment. Targeting UCP1 activation to induce thermogenesis through small molecules presents a promising approach for obesity management. In this study, molecular docking of UCP1 activators, using 2,4-dinitrophenol (DNP) as a reference ligand (PDB ID: 8J1N, docking score: −5.343 kcal/mol), identified seven top-scoring compounds: naringin (-7.284 kcal/mol), quercetin (-6.661 kcal/mol), salsalate (-6.017 kcal/mol), rhein (-5.798 kcal/mol), mirabegron (-5.535 kcal/mol), curcumin (-5.479 kcal/mol), and formoterol (-5.451 kcal/mol). Prime MM-GBSA calculation of the top-scored molecule (i.e., naringin) in the docking study showed ΔGBind of −70.48 kcal/mol. Key interactions of these top 7 activators with UCP1 binding pocket residues Trp280, Arg276, Glu190, Arg83, and Arg91 were observed. Molecular dynamics simulations performed for 100 ns confirmed complex stability, with RMSD values below 6 Å. Additionally, most activators showed favorable intestinal absorption (>90 %) and lipophilicity (LogP 2–4), with pKa values supporting their pharmacological potential as UCP1-targeting therapeutics for obesity. These findings provide a foundation for designing potent UCP1 activators by integrating docking scores, interaction profiles, statistical profiles from MD simulations, and physicochemical assessments to develop effective anti-obesity therapies.Item Synthesis, molecular modelling and biological evaluation of novel benzyloxy substituted indolyl oxoacetamides as potent pancreatic lipase inhibitors(Springer, 2025-08) Paul, Atish TulshiramA series of 21 indolyl oxoacetamide analogues with benzyloxy-substituents were designed, synthesized and characterized using 1H NMR (Nuclear Magnetic Resonance), 13C NMR, and HRMS (High Resolution Mass Spectrometry) analysis. All the analogues were tested for inhibitory activity against pancreatic lipase. Two analogues, 9f and 10f, exhibited significant activity (IC50 of 2.89 and 2.50 µM, respectively), comparable to the standard drug, orlistat (IC50 = 0.99 µM). The potent analogues 10f and 9f exhibited significant binding affinity for pancreatic lipase (-170.222 kcal mol− 1 and − 153.547 kcal mol− 1). Additionally, both the potent analogues exhibited crucial interaction with Ser 152 and His 263 residues in the PL active site via hydrogen bonding. Molecular dynamics (MD) simulation was performed on the ligand-receptor complex of potent analogue (10f) for 200 ns. The molecule was stabilized by extending the π-π interactions with Phe 77 and Phe 215 of the active site lid domain due to benzyloxy substitution. Toxicity profile prediction indicated that all the analogues were non-hepatotoxic, unlike orlistat.Item Copper-mediated cyclization of thiosemicarbazones leading to 1,3,4-thiadiazoles: Structural elucidation, DFT calculations, in vitro biological evaluation and in silico evaluation studies(Elsevier, 2024-05) Garg, MohitCancer's global impact necessitates innovative and less toxic treatments. Thiosemicarbazones (TSCs), adaptable metal chelators, offer such potential. In this study, we have synthesized N (4)-substituted heterocyclic TSCs from syringaldehyde (TSL1, TSL2), and also report the unexpected copper-mediated cyclization of the TSCs to form thiadiazoles (TSL3, TSL4), expanding research avenues. This work includes extensive characterization and studies such as DNA/protein binding, molecular docking, and theoretical analyses to demonstrate the potential of the as-prepared TSCs and thiadiazoles against different cancer cells. The DFT results depict that the thiadiazoles exhibit greater structural stability and reduced reactivity compared to the corresponding TSCs. The docking results suggest superior EGFR inhibition for TSL3 with a binding constant value of − 6.99 Kcal/mol. According to molecular dynamics studies, the TSL3-EGFR complex exhibits a lower average RMSD (1.39 nm) as compared to the TSL1-EGFR complex (3.29 nm) suggesting that both the thiadiazole and thiosemicarbazone examined here can be good inhibitors of EGFR protein, also that TSL3 can inhibit EGFR better than TSL1. ADME analysis indicates drug-likeness and oral availability of the thiadiazole-based drugs. The DNA binding experiment through absorption and emission spectroscopy discovered that TSL3 is more active towards DNA which is quantitatively calculated with a Kb value of 4.74 × 106 M−1, Kq value of 4.04 × 104 M−1and Kapp value of 5 × 106 M−1. Furthermore, the BSA binding studies carried out with fluorescence spectroscopy showed that TSL3 shows better binding capacity (1.64 × 105 M−1) with BSA protein. All the compounds show significant cytotoxicity against A459-lung, MCF-7-breast, and HepG2-liver cancer cell lines; TSL3 exhibits the best cytotoxicity, albeit less effective than cisplatin. Thiadiazoles demonstrate greater cytotoxicity than the TSCs. Overall, the promise of TSCs and thiadiazoles in cancer research is highlighted by this study. Furthermore, it unveils unexpected copper-mediated cyclization of the TSCs to thiadiazoles.Item In silico evaluation of bisphosphonates identifies leading candidates for SARS-CoV-2 RdRp inhibition(Elsevier, 2025-05) Garg, Mohit; Murugesan, SankaranarayananThe novel coronavirus disease (COVID-19) pandemic has resulted in 777 million confirmed cases and over 7 million deaths worldwide, with insufficient treatment options. Innumerable efforts are being made around the world for faster identification of therapeutic agents to treat the deadly disease. Post Acute Sequelae of SARS-CoV-2 infection or COVID-19 (PASC), also called Long COVID, is still being understood and lacks treatment options as well. A growing list of drugs are being suggested by various in silico, in vitro and ex vivo models, however currently only two treatment options are widely used: the RNA-dependent RNA polymerase (RdRp) inhibitor remdesivir, and the main protease inhibitor nirmatrelvir in combination with ritonavir. Computational drug development tools and in silico studies involving molecular docking, molecular dynamics, entropy calculations and pharmacokinetics can be useful to identify new targets to treat COVID-19 and PASC, as shown in this work and our recent paper that identified alendronate as a promising candidate. In this study, we have investigated all bisphosphonates (BPs) on the ChEMBL database which can bind competitively to nidovirus RdRp-associated nucleotidyl (NiRAN) transferase domain, and systematically down selected seven candidates (CHEMBL608526, CHEMBL196676, CHEMBL164344, CHEMBL4291724, CHEMBL4569308, CHEMBL387132, CHEMBL98211), two of which closely resemble the approved drugs minodronate and zoledronate. This work and our recent paper together provide an in silico mechanistic explanation for alendronate and zoledronate users having dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations, and indicate that similar observational studies in Japan with minodronate could be valuable.Item Comprehensive analysis of hydrazone Schiff bases: synthesis, structural characterization, DFT studies, molecular docking insights and bioactivity assessment(Elsevier, 2025-07) Garg, MohitThe four new hydrazone Schiff bases have been synthesized in absolute ethanol at the reflux of 78 °C. These hydrazones are named as: (E)-1-(2,4-dinitrophenyl)-2-(2-ethoxy benzylidene) hydrazine(2-EDNPH) (L1), (E)-1-(2,4-dinitrophenyl)-2-(4-ethoxy benzylidene) hydrazine(4-EDNPH) (L2), (E)-3-chloro-2-((2-(2,4-dinitrophenyl) hydrazinylidene) methyl) phenol(3-Cl-2-OH-DNPH) (L3) and (E)-1-(2,4-dinitrophenyl)-2-(thiophen-3-ylmethylene) hydrazine (3-Thiophene Carbaldehyde-DNPH) (L4). Spectroscopic and physicochemical techniques were employed to validate these compound's structure, including 1H NMR, 13C NMR spectra, UV–Vis, IR, and melting point. A solubility test is also carried out on all the Schiff bases, indicating that all four ligands are soluble in THF and DMF. The thermal breakdown behavior of all ligands is being examined by thermogravimetric analysis (TGA/DTG) at a heating rate of 10 °C min−1 under a nitrogen environment. The crystalline structure of L1 was also investigated in an XtaLAB AFC12 (RINC): Kappa single diffractometer, which included unit cell computation and data collecting. The radioactive photon was created with MoKα (λ = 0.7107Å). In addition, density functional theory (DFT) is utilized to compute the optimized molecular structures, stability, reactivity, and numerous chemical characteristics of the synthesized ligands. The in-silico prediction of ADME features revealed that synthesized compounds gain notable drug-like characteristics. Also, molecular docking was enforced to predict the inhibitory action of the β-ketoacyl acyl carrier (KAS1) protein of E. Coli (PDB Id: 6TZF) on the examined hydrazones. Finally, all ligands were to assess the anti-bacterial properties against gram-positive (B. subtilis and MRSA) and gram-negative (P. mirabilis and E. coli) infections; only L1 and L2 showed activity against these pathogens.Item Identification of synthetically tractable MERS-CoV main protease inhibitors using structure-based virtual screening and molecular dynamics potential of mean force (PMF) calculations(Taylor & Francis, 2023-11) Sundriyal, SandeepThe Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a potentially lethal infection that presents a substantial threat to health, especially in Middle East nations. Given that no FDA-approved specific therapy for MERS infection exists, designing and discovering a potent antiviral therapy for MERS-CoV is crucial. One pivotal strategy for inhibiting MERS replication is to focus on the viral main protease (Mpro). In this study, we identify potential novel Mpro inhibitors employing structure-based virtual screening of our recently reported Ugi reaction-derived library (URDL) consisting of cherry-picked molecules from the literature. The key features of the URDL library include synthetic tractability (1–2 pot synthesis) of the molecules scaffold and unexplored chemical space. The hits were ranked based on the docking score, MM-GBSA free energy of binding, and the interaction pattern with the active site residues. A molecular dynamics (MD) simulation study was performed for the first two top-ranked compounds to analyze the stability and free binding energy based on the molecular mechanics Poisson-Boltzmann surface area. The potential mean force calculated from the steered molecular dynamics (SMD) simulations of the hits indicates improved H-bond potential, enhanced conformational stability, and binding affinity toward the target, compared to the cocrystallized ligand. The discovered hits represent novel synthetically tractable scaffolds as potential MERS-CoV Mpro inhibitors.Item Computational search for potential covid-19 drugs from ayurvedic medicinal plants to identify potential inhibitors against sars-cov-2 targets(Bentham Science, 2023-02) Murugesan, SankaranarayananTo date, very few small drug molecules are used for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has been discovered since the epidemic commenced in November 2019. SARS-CoV-2 RdRp and spike protein are essential targets for drug development amidst whole variants of coronaviruses. Objective: This study aims to discover and recognize the most effective and promising small molecules against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and spike protein targets through molecular docking screening of 39 phytochemicals from five different Ayurveda medicinal plants. Methods: The phytochemicals were downloaded from PubChem, and SARS-CoV-2 RdRp and spike protein were taken from the protein data bank. The molecular interactions, binding energy, and ADMET properties were analyzed. Results: Molecular docking analysis identified some phytochemicals, oleanolic acid, friedelin, serratagenic acid, uncinatone, clemaphenol A, sennosides B, trilobine and isotrilobine from ayurvedic medicinal plants possessing greater affinity against SARS-CoV-2-RdRp and spike protein targets. Two molecules, namely oleanolic acid and sennosides B, with low binding energies, were the most promising. Furthermore, based on the docking score, we carried out MD simulations for the oleanolic acid and sennosides B-protein complexes. Conclusion: Molecular ADMET profile estimation showed that the docked phytochemicals were safe. The present study suggested that active phytochemicals from medicinal plants could inhibit RdRp and spike protein of SARS-CoV-2.