Department of Pharmacy
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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 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 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.Item Design, synthesis, and antimycobacterial evaluation of novel tetrahydroisoquinoline hydrazide analogs(Wiley, 2023-01) Murugesan, SankaranarayananA series of novel 2-substituted-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carbohydrazide were designed, synthesized and structures were confirmed by analytical methods, viz., 1H-NMR, 13C-NMR and Mass spectrometry. Synthesized derivatives were evaluated for their anti-mycobacterial activity against Mycobacterium tuberculosis (Mtb) H37Ra. Among all the evaluated compounds, 10A25 containing biphenyl moiety exhibited significant inhibition with IC50 4.7 μM. 10A19, with an electron-withdrawing Iodo group in the ortho position of the phenyl exhibited significant anti-tubercular activity with IC50 8.8 μM. IC50 values of the remaining compounds ranged from 9.2 to 73.6 μM. Molecular docking study of the significantly active compound 10A25 was performed to determine the putative binding position of the test ligand at the active site of the selected target proteins Mycobacterium tuberculosis enoyl reductase (InhA) PDB – 4TZK and peptide deformylase PDB – 3E3U. A suitable single crystal for one of the active compounds, 10A12, was generated and analysed to further confirm the structure of the compounds.Item Spotlight on 4-substituted quinolines as potential anti-infective agents: Journey beyond chloroquine(Wiley, 2022-12) Murugesan, SankaranarayananContinued emerging resistance of pathogens against the clinically approved candidates and their associated limitations continuously demand newer agents having better potency with a more suited safety profile. Quinoline nuclei containing scaffolds of natural and synthetic origin have been documented for diverse types of pharmacological activities, and a number of drugs are clinically approved. In the present review, we unprecedentedly covered the biological potential of 4-substituted quinoline and elaborated a rationale for its special privilege to afford the significant number of approved clinical drugs, particularly against infectious pathogens. Compounds with 4-substituted quinoline are well documented for antimalarial activity, but in the last two decades, they have been extensively explored for activity against cancer, tuberculosis, and several other pathogens including viruses, bacteria, fungi, and other infectious pathogens. In the present study, the anti-infective spectrum of this scaffold is discussed against viruses, mycobacteria, malarial parasites, and fungal and bacterial strains, along with recent updates in this area, with special emphasis on the structure–activity relationship.Item Inspection of in-house designed novel thiochromone amino-acid conjugate derivatives as Lm-NMT inhibitor – An in-silico analysis(Elsevier, 2023-03) Murugesan, SankaranarayananLeishmaniasis is a complex neglected tropical disease caused by various leishmanial parasites that primarily affect the world's poorest people. A limited number of standard medications are available for this disease that has been used for several decades, which have drawbacks such as resistance, higher cost, and patient compliance, making it difficult to reach the poor. The search for novel chemical entities to treat leishmaniasis has led to target-based scaffold research. Thiochromone moieties in conjugation with aromatic amino acids have been considered for the study, along with possible substitutions of the electron-withdrawing and electron-donating groups. N-myristoyl transferase (NMT) has been selected as the molecular target for the study responsible for protein-protein interaction and ribosylation of proteins necessary for the growth inside the human body of the parasite. The designed novel thiochromone analogs were docked against the selected leishmanial NMT using the in-silico methods, physicochemical and toxicity properties were predicted, and Structure-Activity Relationship was also established in-silico. Finally, a molecular dynamics simulation study for 100 ns gave an idea about the stability of the protein-ligand complex. A time frame analysis of each 10 ns confirmation was also studied to understand better the putative binding pattern designed analogs.Item Retrospective review of chromane analogues as anti-protozoal leads: a decade's worth of evolution(Bentham Science, 2023-04) Murugesan, SankaranarayananTropical, vector-borne, and neglected diseases with a limited number of medication therapies include Leishmaniasis, Malaria, Chagas and Human African Trypanosomiasis (HAT). Chromones are a large class of heterocyclic compounds with significant applications. This heterocycle has long aroused the interest of scientists and the general public from biosynthetic and synthetic points of view owing to its interesting pharmacological activities. Chromones and their hybrids and isomeric forms proved to be an exciting scaffold to investigate these diseases. The in vitro activities of Chromone, Chromane, and a panel of other related benzopyran class compounds against Trypanosoma brucei rhodesiense, Trypanosoma brucei gambiense, Trypanosoma cruzi, and numerous Leishmanial and Malarial species were investigated in our previous studies. The current article briefly describes the neglected diseases and the current treatment. This review aims to attempt to find better alternatives by scrutinizing natural and synthetic derivatives for which chromones and their analogues were discovered to be a new and highly effective scaffold for the treatment of neglected diseases, including compounds with dual activity or activity against multiple parasites. Additionally, the efficacy of other new scaffolds was also thoroughly examined. This article also discusses prospects for identifying more unique targets for the disease, focusing on flavonoids as drug molecules that are less cytotoxic and high antiprotozoal potential. It also emphasizes the changes that can be made while searching for potential therapies-comparing existing treatments against protozoal diseases and the advantages of the newer chromone analogues over them. Finally, the structure- activity relationship at each atom of the chromone has also been highlighted.