Department of Pharmacy
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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 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.Item Design, synthesis, biological evaluation and molecular modelling studies of conophylline inspired novel indolyl oxoacetamides as potent pancreatic lipase inhibitors(RSC, 2020-06) Paul, Atish TulshiramA novel series of 21 indolyl oxoacetamide analogues was designed based on the natural product lead conophylline, and evaluated for their pancreatic lipase inhibitory activity using porcine pancreatic lipase (Type II). Analogues 12c and 12b exhibited comparatively greater potential (IC50 values of 2.95 and 3.26 μM) than conophylline (IC50 – 3.31 μM), while the standard drug, orlistat, exhibited a potent IC50 value of 0.99 μM. Further, analogues 12b and 12c exhibited reversible competitive inhibition similar to orlistat and conophylline, and possessed Ki values of 1.89 and 1.69 μM, respectively. Molecular docking of these analogues was in agreement with the in vitro results, wherein the MolDock scores exhibited significant correlation with their inhibitory activity. A 10 ns molecular dynamics simulation of 12c complexed with pancreatic lipase confirmed the role of extended alkyl interactions, along with π–π stacking and π–cation interactions, in stabilising the ligand in the active site (maximum observed RMSD ≈ 3.5 Å). ADMET prediction indicated the GI absorption of these analogues to be high; however, they did not possess carcinogenicity and hepatotoxicity in contrast to orlistat and conophylline.Item Design, synthesis and biological evaluation of N-substituted indole-thiazolidinedione analogues as potential pancreatic lipase inhibitors(Wiley, 2021-04) Paul, Atish TulshiramPancreatic Lipase (PL) is a key enzyme responsible for the digestion of 50%–70% of dietary triglycerides, hence its inhibition is considered as a viable approach for the management of obesity. A series of indole-TZD hybrid analogues were synthesized, characterized and evaluated for their PL inhibitory activity. Knoevenagel condensation of various substituted indole-3-carboxaldehyde with substituted thiazolidinediones resulted in the formation of titled analogues. Analogues 6d and 6e exerted potent PL inhibitory activity (IC50-6.19 and 8.96 µM, respectively). Further, these analogues exerted a competitive mode of PL inhibition. Moreover, molecular modelling studies were in agreement with the in vitro results (Pearson's r = .8682, p < .05). The fluorescence spectroscopic analysis further supported the strong binding affinity of these analogues with PL. A molecular dynamics study (20 ns) indicated that these analogues were stable in a dynamic environment. Thus, the present study highlighted the potential role of indole-thiazolidinedione hybrid analogues as potential PL inhibitors and further optimization might result in the development of new PL inhibitory lead candidates.Item Design, synthesis, in silico molecular modelling studies and biological evaluation of novel indole-thiazolidinedione hybrid analogues as potential pancreatic lipase inhibitors(RSC, 2021) Paul, Atish TulshiramPancreatic lipase (PL) is a key enzyme responsible for the digestion of dietary triglycerides; hence its inhibition is considered as a promising target for the management and/or treatment of obesity. A new series of indole-thiazolidinedione (TZD) hybrid analogues were synthesized using a molecular hybridisation approach and evaluated for their anti-obesity effects via PL inhibition. The targeted analogues were synthesized via the condensation reaction between various substituted isatin with TZD in the presence of aqueous KOH in methanol. Amongst the synthesized analogues, 7k and 7m exhibited a potential PL inhibitory activity (IC50 – 7.30 and 9.51 μM, respectively). Kinetic study of these potent analogues revealed their competitive mode of enzyme inhibition. This fact was confirmed via fluorescence spectroscopy which further suggested the presence of one binding site for the synthesized analogues. Molecular docking of the synthesized analogues was performed using human PL (PDB ID: 1LPB). The obtained MolDock scores were aligned with the in vitro PL inhibitory activity (Pearson's r = 0.9108, p < 0.05). Moreover, a stable conformation of the 1LPB-ligands suggested the stability of these complexes in the dynamic environment. These studies provided a basis for the potential role of the indole-TZD hybrids in PL inhibition and further optimization might result in the development of new lead candidates for obesity treatment.