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Item Greener alternatives for synthesis of isoquinoline and its derivatives: a comparative review of eco-compatible synthetic routes(RSC, 2025) Deepa, P.R.; Murugesan, SankaranarayananIsoquinoline derivatives, a prominent class of nitrogen-containing heterocycles, serve a pivotal role in medicinal chemistry due to their broad spectrum of bioactivities. While traditional synthetic routes for these scaffolds are well-established, conventional methods often rely on transition-metal catalysts, harsh conditions, expensive reagents, and toxic solvents, raising environmental and economic concerns. In response to the pressing demand for sustainable practices, this review underscores the integration of green chemistry principles into modern synthetic design, offering environmentally acceptable methods for accessing isoquinoline frameworks. Despite extensive research on isoquinoline synthesis and its therapeutic relevance, a dedicated analysis of sustainable methodologies remains absent. This work bridges that gap by critically evaluating recent innovations in green synthesis, including the use of benign solvents, recyclable catalytic systems, atom-economical reactions, and energy-efficient processes.Item Targeting stearoyl-coa desaturase-1 (SCD1) by the drug–nutraceutical combination of montelukast and bixin in ameliorating steatotic NAFLD(ACS, 2025-10) Sharma, Pankaj Kumar; Murugesan, Sankaranarayanan; Deepa, P.RNonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome, which progresses from simple fat accumulation (steatosis) to nonalcoholic steatohepatitis (NASH), fibrosis, and eventually liver cancer. Stearoyl-CoA desaturase 1 (SCD1), a key lipogenic enzyme, plays a significant role in the progression of NAFLD by promoting the accumulation of fat in the liver. This study investigated the drug-nutraceutical combination of Montelukast (a synthetic anti-inflammatory drug) and Bixin (an apo-carotenoid) as SCD1 inhibitors for treating fatty liver disease. Bixin was identified through virtual screening of a curated carotenoid database (carotenoid DB) targeting lipogenic enzyme SCD1. In the in vitro model of steatotic HepG2 cells, the combination treatment of Montelukast and Bixin showed a marked reduction (P < 0.05) in SCD1 gene expression (41%), protein expression (61%), and SCD1 enzyme activity (56.22%). The combination treatment showed a significant reduction of 21.64% (P < 0.05) in lipid accumulation relative to individual treatment with Bixin or Montelukast and was comparable with the reference drug Aramchol (21.83%). The markers of oxidative stress were also significantly reduced (P < 0.05), evidenced by decreased MDA (42.25%), RNS levels (32.59%), and ROS levels (30.72%) in the combination group. These findings suggest that Bixin and Montelukast in combination hold potential for managing the multiple aspects in the pathophysiology of NAFLD development and progression.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 Insight into antiacetylcholinesterase potential of modified chalcones: synthesis, characterization, in vitro, and computational investigation(Wiley, 2025-01) Murugesan, SankaranarayananNeurological disorders remain a major challenge in modern medicine due to the brain’s complexity and the limited efficacy of genetic therapies. Acetylcholinesterase (AChE) is a key target in the treatment of Alzheimer’s disease. In this study, a series of modified 4-benzyloxychalcone derivatives (9a–j) were synthesized and structurally characterized using various spectroscopic techniques, including IR, 1H NMR, 13C NMR, and HRMS. Quantum chemical calculations, along with MM/GBSA and MM/PBSA analyses, were performed to evaluate the electronic properties and binding free energies of the compounds. All compounds met Lipinski’s criteria. Molecular docking and dynamics simulations revealed that compound 9c exhibited the most stable interaction with AChE (PDB ID: 4EYZ), supported by a strong binding profile. Additionally, the small HOMO–LUMO energy gap indicates the compounds' potent anticholinesterase capabilities via the POM/DFT approach. Furthermore, high hyperpolarizability and polarizability values suggest additional potential as pharmacophores. The derivatives demonstrated favorable binding with active site residues of the enzyme, suggesting their potential as effective AChE inhibitors. Overall, the findings indicate that benzyloxychalcones (9a–j) bind key amino acids in the 4EYZ binding pocket, highlighting their potential as candidates for Alzheimer’s disease treatment.Item Folic acid-conjugated ferulic acid-entangled single-walled carbon nanotubes: a targeted therapeutic approach for effective breast cancer treatment(Elsevier, 2025-09) Murugesan, SankaranarayananBreast cancer remains one of the major causes of cancer-related deaths in the world for women, which emphasizes the need for better treatment approaches. Conventional therapies target both cancerous as well as normal cells, which can lead to serious adverse effects. This research aimed to develop a targeted therapy employing a new folic acid-conjugated Ferulic Acid-Entangled Single-Walled Carbon Nanotubes (FA-FeA-SWCNTs) formulation to maximize treatment specificity and reduce off-target effects. The efficiency of the FA-FeA-SWCNTs formulation against breast cancer is assessed in this study. Molecular modelling studies were performed to predict the mechanism of action of ferulic acid. FA-FeA-SWCNTs particle size analysis, FTIR, XRD, and SEM were assessed to confirm the formulation tethered to single-walled carbon nanotubes (SWCNTs). MTT assay against MCF-7 cells and CAM assays in chicken eggs were executed to measure cytotoxicity and evaluate anti-angiogenesis efficacy. Sub-acute oral toxicity by OECD 407 guidelines and DMBA-induced breast cancer models in female Wistar rats were used to examine the in vivo anticancer efficacy. The potential therapeutic mechanism was suggested by the study's finding that the Ferulic Acid strongly interacted with mitogen-activated protein kinase (MAPK). The formulation showed excellent-, stability, and suitable particle size. Through in vitro tests, substantial anti-angiogenic effects (71.2 % inhibition) and significant cytotoxicity (IC50 of 19.60 μg/mL) were identified. Subacute toxicity tests verified a favorable safety profile, and in vivo, the formulation successfully decreased tumor growth and improved overall wellness, making it a viable option for more clinical investigation.Item In silico and in vitro investigations reveal pan-PPAR agonist activity and anti-NAFLD efficacy of polydatin by modulating hepatic lipid-energy metabolism(Springer Nature, 2025) Sharma, Pankaj Kumar; Murugesan, Sankaranarayanan; Deepa, P.R.Polydatin (PD), a stilbenoid resveratrol-derivative in Vitaceae, Liliaceae, and Leguminosae, exhibits pharmacological protection in metabolic disorders. This study investigated Polydatin, as a potential pan-PPAR agonist for treating non-alcoholic fatty liver disease (NAFLD). High-throughput-virtual-screening (HTVS) was performed to identify potential pan-PPAR agonists, followed by in vitro testing of Polydatin in HepG2 steatosis model. Effects on lipid metabolism and oxidative stress, PPAR signaling gene expression analysis, and GC-MS profiling were compared with the hepatoprotectant Silymarin. Pan-PPAR targeted HTVS of PhytoHub natural products database, followed by molecular docking/dynamics simulations, revealed lead-candidate, Polydatin, which was tested in steatotic cells for gene and protein deregulations by qRT-PCR and western blot, followed by GC-MS analysis of biochemical metabolites. HTVS revealed 53 potential pan-PPAR agonists. Molecular docking and dynamics simulations suggested that PD, a stable ligand for PPARs (α,β/δ,γ), exhibited strong binding. Polydatin treatment decreased ALT, triglycerides, and oxidative stress, wherein ROS and malondialdehyde levels decreased by 60.94% and 28%, respectively. PD upregulated PPARs, AMPK, GLUT2, and CPT1α, while downregulating lipogenic enzymes (ACC1, FASN, SCD1). GC-MS analysis revealed Polydatin mediated impact on saturated FFAs-palmitic acid, stearic acid, and unsaturated fatty acid product of SCD1, oleic acid. HTVS identified PD as a promising pan-PPAR agonist, which favorably ameliorated changes in lipid, glucose, and overall energy metabolism in steatotic NAFLD, by modulating PPAR(α,β/δ,γ) expressions and associated downstream lipogenic and lipid-utilization mechanisms, supporting anti-steatotic efficacy of Polydatin.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 Unraveling PPARβ/δ nuclear receptor agonists via a drug-repurposing approach: HTVS-based ligand identification, molecular dynamics, pharmacokinetics, and in vitro anti-steatotic validation(RSC, 2025-04) Sharma, Pankaj Kumar; Murugesan, Sankaranarayanan; Deepa, P.R.Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors with a crucial regulatory role in carbohydrate and lipid metabolism and are emerging druggable targets in “metabolic syndrome” (MetS) and cancers. However, there is a need to identify ligands that can activate specific PPAR subtypes, particularly PPARβ/δ, which is less studied compared with other PPAR isoforms (α and γ). Herein, using the drug-repurposing approach, the ZINC database of clinically approved drugs was screened to target the PPARβ/δ receptor through high-throughput-virtual-screening, followed by molecular docking and molecular dynamics (MD) simulation. The top-scoring ligands were subjected to drug-likeness analysis. The hit molecule was tested in an in vitro model of NAFLD (non-alcoholic fatty liver disease). The top five ligands with strong binding affinity towards PPARβ/δ were canagliflozin > empagliflozin > lumacaftor > eprosartan > dapagliflozin. RMSD/RMSF analysis demonstrated stable protein–ligand complexation (PLC) by the top-scoring ligands with PPARβ/δ. In silico ADMET prediction analysis revealed favorable pharmacokinetic profiles of these top five ligands. Canagliflozin showed significant (P < 0.001) dose-dependent decrease in lipid accumulation and the associated oxidative stress-inflammatory response, suggesting its promising anti-steatotic potential. These outcomes pave the way for further validation and development of PPAR activity-modulating therapeuticsItem 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 Metal-free, visible-light-mediated synthesis of tetracyclic benzimidazole: regioselective c–h functionalization with in vitro and computational study of anti-breast cancer compounds(ACS, 2025-02) Murugesan, Sankaranarayanan; Mukherjee, SudeshnaGlobally, breast cancer is the leading cause of mortality. Within the field of antibreast cancer drug design by several compound docking studies, eight new N-containing nonsteroid tetracyclic derivatives have been synthesized via regioselective intramolecular C–H functionalization by visible light. The adopted methodology is highly efficient, green, and sustainable to unload a new pathway with excellent yield. It offers a rapid, low-cost, catalyst-free method for creating physiologically active molecules from easily accessible substrates. The synthesized substances were described using spectroscopic methods like HRMS, 1HNMR, 13CNMR, and XRD analysis. This study explores the cytotoxic potential of novel compounds against human MCF-7 breast cancer cells. This study includes in vitro experiments to assess the effect of our compounds on cells. These experiments include cytotoxicity assessment by cell cycle, apoptosis, MTT test analysis by flow cytometry, reactive oxygen species (ROS) production assessment, etc. Among the novel compounds, compound 2e exhibited the most potent cytotoxic activity, with an inhibitory concentration (IC50) of 40 nM, surpassing the efficacy of established drugs such as exemestane (IC50 24.97 micromolar) and tamoxifen (IC50 5.45 μM). Compound 2e also significantly induced apoptosis and cell cycle arrest in the G1 phase, increasing the apoptotic cell population to 65.97%. Additionally, the compound led to a marked rise in the level of ROS generation, implicating oxidative stress in its mechanism of action. Molecular docking and dynamic simulation further supported the vigorous anticancer activity of compound 2e, demonstrating its promise as an effective breast cancer treatment.