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 Coumarin analogues as promising anti-obesity agents: in silico design, synthesis, and in vitro pancreatic lipase inhibitory activity(Wiley, 2025-01) Paul, Atish TulshiramA set of coumarin-3-carboxamide analogues were designed, synthesized, and evaluated for their ability to impede pancreatic lipase (PL) activity. Out of all the analogues, 5dh and 5de demonstrated promising inhibitory activity against PL, as indicated by their respective IC50 values of 9.20 and 11.4 μM, as compared to Orlistat (IC50 = 0.97 μM). It was found that analogue 5dh inhibited PL in a competitive manner with an inhibition constant (Ki) of 4.504 μM. Additionally, the docking analysis validated the interactions between the analogue 5dh (MolDock score of −140.251 kcal/mol) and key amino acids in the active site, including Leu 153, Gly 76, Arg 256, His 151, Phe 77, and His 263. The inhibitory activity of these analogues was significantly correlated with their MolDock scores (Pearson's r = 0.6586). Finally, molecular dynamics simulation was also performed for 100 ns in order to elucidate the stability, confirmation and intermolecular interactions of the active analogue 5dh. The results of this investigation suggested that the complex maintained its stability despite the dynamic conditions exhibiting interactions with important amino acids. In summary, the outcomes indicated that the synthesized analogues exhibited the potential to inhibit PL activity.Item A multifaceted scaffold for building bioactive compounds: phenothiazine(Bentham Science, 2023-07) Jain, AnkitIn the growing field of heterocyclic compounds, phenothiazine and the associated nucleus are among the most significant potential scaffolds with excellent pharmacological activities. The knowledge of chemistry, synthetic routes, and various physicochemical parameters of these compounds draws particular attention to create a chemical library. Related compounds synthesized by various routes have diverse pharmacological functions. The exhaustive search of phenothiazine literature helps the medicinal chemists who develop the molecules for designing new drugs. A broad view of the synthetic routes has been outlined in this study. This paper includes the chemistry, physiochemical properties, and various biological activities of phenothiazine and related compounds.Item Discovery of small molecule inhibitors of Mycobacterium tuberculosis ClpC1: SAR studies and antimycobacterial evaluation(Elsevier, 2023-01) Sundriyal, SandeepThe emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) in humans, is a primary reason for treatment failure. Currently, only limited options are available for the management of multi-drug resistant TB, warranting the design of novel anti-TB drugs by exploiting newer targets. One of the caseinolytic protease (Clp) machinery components, an unfoldase known as ClpC1, has emerged as a distinct anti-TB drug target owing to its essential role in the pathogen's survival. The naturally occurring cyclic peptides targeting the Mtb ClpC1, exhibit potent antimycobacterial activity. However, the large, complex, and poor synthetic tractability of these peptides limit their clinical application. Identification of small molecule inhibitors of Mtb ClpC1 will be useful for future drug development. Here, we report the discovery of a bisquinoline chemotype from the screening of a small molecule chemical library against Mtb ClpC1. The hit molecule binds with ClpC1 and exhibits dose-dependent inhibition of its enzymatic activity by direct binding. The in vitro growth of Mtb is inhibited by the hit molecule at a minimum inhibitory concentration of 12.5 µM. Investigation of the structure–activity relationship by chemical synthesis underlines the requirement of the two quinoline rings, 9/10 carbon linker, and the importance of basic ring nitrogen for its inhibitory activity. To our knowledge, this is the first report on the systematic analysis of small molecule inhibitors of Mtb ClpC1.Item New Antimicrobial Hexapeptides: Synthesis, Antimicrobial Activities, Cytotoxicity, and Mechanistic Studies(Wiley, 2009-12) Sundriyal, SandeepThe lead optimization of an antimicrobial hexapeptide Orn-D-Trp-D-Phe-Ile-D-Phe-His(1-Bzl)-NH2 depending on the hydrophobic or positive-charge character of amino acids at various positions along its sequence was performed, followed by biological evaluation and mechanistic studies. This led to the identification of a new class of antimicrobial hexapeptides that interact preferentially with the negatively charged phospholipids of a model bacterial membrane.Item Synthesis of modified bile acids via palladium-catalyzed C(sp3)–H (hetero)arylation(RSC, 2023-07) Chitkara, Deepak; Sakhuja, RajeevA Pd(II)-catalyzed strategy for the diastereo- and regioselective (hetero)arylation of unactivated C(sp3)–H bonds in bile acids is accomplished with aryl and heteroaryl iodides under solvent-free conditions using the 8-aminoquinoline auxiliary as a directing group. This methodology demonstrated excellent functional group tolerance with respect to aryl/heteroaryl iodides on O-protected N-(quinolin-8-yl)cholyl/deoxycholyl amides to afford β-C(sp3)–H (hetero)arylated products in good-to-excellent yields. Moreover, the 8-aminoquinoline (AQ) auxiliary can easily be removed to obtain modified bile acids.Item Design, Synthesis, Molecular Modelling and in Vitro Evaluation of Indolyl Ketohydrazide-Hydrazone Analogs as Potential Pancreatic Lipase Inhibitors(Wiley, 2023-08) Paul, Atish TulshiramInhibition of Pancreatic lipase (PL) is considered to be a promising target for the management of obesity, owing to its crucial role in the digestion of dietary triglycerides. A series of 31 indolyl ketohydrazide-hydrazone analogs (5 aa–cm) were designed, synthesized and evaluated for their PL inhibitory potential. The analogs were designed using molecular modelling studies. The designed analogs were then synthesized by condensation of indolyl oxoacetohydrazide with various substituted benzaldehydes. All the synthesized analogs showed PL inhibitory activity in the range of 4.13–48.35 μM, as compared with orlistat (0.86±0.09 μM). The most potent analog 5 bi (IC50=4.13±0.95 μM) was found to show a competitive type of inhibition with Ki value of 0.725 μM. Additionally, the molecular docking study proved the binding of analog 5 bi at the active site of PL (PDB ID: 1LPB) with MolDock score of −141.279 kcal/mol. It also exhibited various interactions with the key amino acids namely Phe77, Phe215, Tyr114, Ser152, Arg256, His263, etc. Furthermore, the protein-ligand complex of analog 5 bi was found to be stable in molecular dynamics simulation for 100 ns with RMSD of less than 3.2 and 4 Å for the protein and ligand, respectively. The current work hereby provides a basis for the potential role of indolyl ketohydrazide-hydrazone analogs in PL inhibition and further optimization could result in the generation of new leads as anti-obesity agents.Item Synthesis of amide warhead containing coumarin derivatives as potential pancreatic lipase inhibitors: in silico and in vitro evaluation for obesity treatment(Springer, 2023-07) Paul, Atish TulshiramA series of coumarin-3-carboxamide analogues has been designed, synthesized and assessed for their ability to inhibit pancreatic lipase (PL). Amongst all the synthesized analogues 5q, 5k and 5c exhibited potential PL inhibition activity with IC50 values of 19.41, 21.30 and 24.90 µM, respectively when compared to orlistat (IC50 = 0.97 µM). Analogue 5q was found to inhibit PL with IC50 value of 19.41 µM and in a competitive manner with an inhibition constant (Ki) of 10.386 µM. Further, the docking study confirmed the interaction of analogue 5q (MolDock score of −113.845 kcal mol−1) with important active site amino acids, namely Phe 77, Arg 256, His 263, etc. The MolDock scores displayed a substantial association with their inhibitory activity (Pearson’s r = 0.5139), which was consistent with the in vitro results for these analogues. In order to comprehend the stability of the protein-ligand complex (5q) in a dynamic environment, a molecular dynamics study (100 ns) was conducted, and the findings indicated that this complex was stable under dynamic conditions. Overall, our findings demonstrated that the synthesized coumarin-3-carboxamide analogues had the ability to inhibit PL.Item Design, synthesis, evaluation, and molecular modeling studies of indolyl oxoacetamides as potential pancreatic lipase inhibitors(Wiley, 2020-06) Paul, Atish TulshiramA series of indolyl oxoacetamide analogs was synthesized, characterized, and evaluated for their pancreatic lipase inhibitory activity using porcine pancreatic lipase (type II) and 4-nitrophenyl butyrate. Compound 8d exhibited a potent inhibition, with an IC50 value of 4.53 µM, followed by 8c (IC50 = 5.12 µM), compared with the standard drug, orlistat (IC50 = 0.99 µM). Furthermore, analogs 8c and 8d exhibited a reversible competitive inhibition, similar to orlistat. Molecular docking studies of the compounds 7a–f and 8a–f were in agreement with the in vitro results, wherein 8d exhibited a potential MolDock score of −163.052 kcal/mol. A 10-ns molecular dynamics simulation of 8d complexed with pancreatic lipase confirmed the role of π–π stacking and π–cation interactions with the lid domain and Arg 256, respectively, in stabilizing the ligand at the active site (maximum observed root mean square deviation ≈ 2 Å). The present study led to the identification of novel indolyl oxoacetamides (8a–d) as potential pancreatic lipase inhibitory leads that might further result in enhanced potency through lead optimization.Item Design, synthesis, biological evaluation and molecular modelling studies of oxoacetamide warhead containing indole-quinazolinone based novel hybrid analogues as potential pancreatic lipase inhibitors(RSC, 2022-05) Paul, Atish TulshiramA novel series of indolyl oxoacetamide-quinazolinone hybrid analogues (9aa–9df) were designed, synthesized, and evaluated for their in vitro pancreatic lipase (PL) inhibitory potential which may lead to efficient anti-obesity agents. All the synthesized hybrid analogues exhibited moderate to potent PL inhibitory activity (IC50 = 32.51 to 4.86 μM). Among all the analogues, 9ak, 9af, 9aj, and 9ah were found to have the most potent PL inhibitory activity (IC50 = 4.86, 5.73, 5.83, and 5.94 μM respectively), as compared to orlistat (IC50 = 0.86 μM). The most potent analogues 9af and 9ak were found to inhibit PL competitively with an inhibition constant (Ki) of 2.136, 1.648 μM. Furthermore, the docking study confirmed the binding of analogues 9ak and 9af (MolDock score of −161.25, −133.67 kcal mol−1) that exhibited docking interactions with important active site amino acids, namely Phe 77, Tyr 114, Ser 152, Arg 256, His 263, etc. Also, the analysis of analogue 9ak and 9af in SeeSAR revealed the covalent inhibition of PL. In molecular dynamics simulations of 100 ns, the complex between each analogue (9ak & 9af) and PL was found to be stable (RMSD < 1.5 Å). The present work highlights the importance of a hybrid drug design approach for the development of indole and quinazolinone containing hybrids as potential PL inhibitors.
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