Department of Pharmacy
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Item Unveiling the potential of naturally occurring rosmarinic acid inspired analogues as pancreatic lipase inhibitors: In silico, in vitro and in vivo evaluation as anti-obesity agents(Elsevier, 2025-12) Paul, Atish TulshiramPancreatic Lipase (PL) is a prime enzyme responsible for the digestion of dietary fat and is considered a safer and more efficient target for managing obesity. Orlistat is the only approved drug for the long-term management of obesity. In this study, using a molecular docking study, various inhibitors were designed via structural optimization of one of the moderately active natural products, namely, rosmarinic acid. A total of 17 acrylate-linked chromone analogues were synthesized, followed by structure elucidation via NMR spectroscopy and HR-MS. To confirm the stereochemistry of the analogues, a single-crystal XRD spectroscopy was performed for analogue 5ab. Among all the synthesized analogues, six analogues were found to exhibit IC50 values in the range of 1.24–2.76 µM. The analogue 5gb was the most potent among the series with IC50 of 1.24 ± 0.296 µM. The enzyme kinetics study revealed a competitive inhibitory mechanism, with Ki values of 0.554 and 0.488 for 5gb and orlistat, respectively. The number of binding sites (n) and binding constant values were obtained through a fluorescence quenching study and found to be 0.57 and 2.97 × 105 L mol−1, respectively, confirming the single binding site of analogue 5gb in the PL enzyme. Through in vivo screening, 5gb was found to exhibit significant weight reduction and normalization of the serum parameters (triglycerides, total cholesterol, HDL, and LDL cholesterol) at a dose of 20 mg/kg. Through a faecal triglyceride quantification study, the PL inhibitory mechanism was confirmed. Further, the histopathological changes (that occurred in obese animals) in liver and adipose tissue were normalized in the case of 5gb treatment groups. Thus, 5gb possessed a comparable anti-obesity activity to that of orlistat.Item Discovery of thiazolidinedione-based pancreatic lipase inhibitors as anti-obesity agents: synthesis, in silico studies and pharmacological investigations(Taylor & Francis, 2024-02) Paul, Atish TulshiramA series of new 2,5-disubstituted arylidene derivatives of thiazolidinedione (16a-e, 17a-d, 18a-c) designed using molecular hybridization approach were synthesized, structurally characterized, and explored for their anti-obesity potential via inhibition of Pancreatic Lipase (PL). Compound 18a presented the most potent PL inhibitory activity with IC50 = 2.71 ± 0.31 µM, as compared to the standard drug, Orlistat (IC50 = 0.99 µM). Kinetic study revealed reversible competitive mode of enzyme inhibition by compound 18a with an inhibitory constant value of 1.19 µM. The most promising compound 18a revealed satisfactory binding mode within the active site of the target protein (human PL, PDB ID: 1LPB). Also, MM/PBSA binding free energy and molecular dynamics (MD) simulation analysis were performed for the most promising compound 18a, which showed potent inhibition according to the results of in vitro studies. Furthermore, a stable conformation of the 1LPB-ligand suggested the stability of this compound in the dynamic environment. The ADME and toxicity analysis of the compounds were examined using web-based online platforms. Results of in vivo studies confirmed the anti-obesity efficacy of compound 18a, wherein oral treatment with compound 18a (30 mg/kg) resulted in a significant reduction in the body weight, BMI, Lee index, feed intake (in Kcal), body fat depots and serum triglycerides. Compound 18a significantly decreased the levels of serum total cholesterol (TC) to 128.6 ± 0.59 mg/dl and serum total triglycerides (TG) to 95.73 ± 0.67 mg/dl as compared to the HFD control group. The present study identified disubstituted TZD derivatives as a new promising class of anti-obesity agents.Item Design and Synthesis of Echitamine-inspired Hybrid Analogues Containing Thiazolidinediones as Potential Pancreatic Lipase Inhibitors(Bentham Science, 2022-11) Paul, Atish TulshiramObesity is a multifactorial metabolic disease characterised by excessive accumulation of triglycerides. The prevalence and morbidity rates associated with obesity are increasing tremendously, posing a significant risk to society. Pancreatic lipase (PL) is a key enzyme responsible for the digestion of dietary triglycerides; hence its inhibition is considered an attractive target in obesity.Item Synthesis, molecular modelling and pharmacological evaluation of novel indole-thiazolidinedione based hybrid analogues as potential pancreatic lipase inhibitors(Taylor & Francis, 2023-12) Paul, Atish TulshiramA series of novel indole-thiazolidinedione hybrid analogues (7a to 7 u) were synthesised, characterised and evaluated for their potential Pancreatic Lipase (PL) inhibition. Amongst the screened analogues, 7r was found to be the most active PL inhibitor with an IC50 of 2.67 µM. Furthermore, enzyme inhibition kinetics study revealed a competitive mode of inhibition by the analogues. This fact was confirmed via fluorescence spectroscopy which further suggested the presence of one binding site for the synthesized analogues. Molecular docking was performed using human PL (PDB ID: 1LPB) and were in agreement with the in vitro results (Pearson’s r = 0.8355, p < 0.05). A molecular dynamics study (100 ns) indicated that 7r was stable in a dynamic environment. The analogue 7r exhibited potential antioxidant activity and was devoid of cytotoxic effect on RAW 264.7 cells. Based on the in-vitro profiles, 7r was selected for the in-vivo pharmacological evaluation. Oral triglyceride tolerance test highlighted effect of 7r on the inhibition of triglyceride absorption. A four-week treatment of 7r in the HFD feed mice provided information regarding its anti-obesity effect with respect to parameters such as body weight, triglycerides, total cholesterol and high-density lipids. Quantification of the faecal triglyceride contents inveterates the potential role of 7r in the PL inhibition. Overall, the synthesized analogue 7r exerted an anti-obesity effect comparable to orlistat. All these results demonstrated the potential role of the newly synthesised indole-thiazolidinedione hybrid analogues in PL inhibition and may be studied further to find potential drug candidates for treating obesity.Item Pancreatic lipase and its related proteins: where are we now?(Elsevier, 2024-01) Paul, Atish TulshiramObesity is a disease of epidemic proportions, with a worrisome upward trend. The high consumption of lipids, a major energy source, leads to obesity because of their high calorific value. Pancreatic lipase (PTL), produced by pancreatic acinar cells, hydrolyzes 50–70% of triacylglycerol (TAG) from food. PTL-related protein 1 (PLRP1) and 2 (PLRP2) are also produced by these cells. In vertebrates, PLRP1 has relatively less lipolytic activity, whereas PLRP2 has an essential role in lipid digestion, especially in infants. In this review, we summarize the structure and function of PTL, PLRP1, and PLRP2, and the metabolic fate of PTL inhibitors. We also discuss the current status of clinical trials on orlistat and its combinations for obesity treatment.Item Investigating the role of indole and quinazolinone-based hybrid analogues with ketoamide fragment and alkyl extension for potential PL inhibition(Elsevier, 2024-04) Paul, Atish TulshiramPancreatic lipase (PL) is a key enzyme responsible for the digestion of dietary fat. Hence the inhibition of PL is an effective strategy for mitigating obesity. In this study, a novel series of 18 indolyl oxoacetamide–quinazolinone hybrid analogues (9a-h, 13aa-13fd) were designed, synthesized, and evaluated for PL inhibition activity. An approach of molecular hybridization was utilized by considering the PL inhibitory potential of indole, α-ketoamide, and quinazolinone scaffolds. A Propyl linker was attached for better binding at the PL active site, leading to enhanced PL inhibitory potential. Among all the synthesized analogues, 13be exhibited the highest PL inhibitory activity (IC50 = 4.71 ± 0.851 μM) with a docking score of -147.06 kcal/mol. The activities of all the synthesized analogues were compared with the orlistat (IC50 = 0.86 ± 0.090 µM). The most potent analogue, 13be revealed the competitive mode of enzyme inhibition with the Ki value of 1.826 µM. The molecular docking and dynamics simulation analysis also revealed the strong binding of 13be at the active site of PL. Interestingly, the potent analogue 13be when tested on RAW 264.7 cell line using MTT assay, was found to be nontoxic at a concentration range of 1-20 µM. Therefore, the current work validates the effectiveness of the molecular hybridization approach for designing indolyl oxoacetamide–quinazolinone hybrids for inhibiting PL.Item Chromone-3-acrylic acid ester analogues: Design, synthesis and biological evaluation as potential pancreatic lipase inhibitors(Elsevier, 2023-12) Paul, Atish TulshiramA novel series of 21 chromone-3-acrylic acid ester analogues (5aa-5cm) were designed, synthesized and evaluated for PL inhibitory activity. The molecular docking study indicate that all the designed chromone analogues have the good binding ability (MolDock score: -115.86 to -160.07 kcal/mol) in the active site of PL enzyme (PDB ID: 1LPB), showing interactions with essential amino acid residues (Phe77, Tyr114, Ser152, Phe215, Arg256). Also, all the analogues were checked for in silico drug likeness property and all were found to have drug like properties, obeying Lipinski rule of 5, with no PAINS alerts. Analogue 5am, with the best docking score, was stable in molecular dynamics simulation for 100 ns (maximum RMSD of 6.4 Å), showing crucial amino acid interactions for more than 60% of the simulation time. The structure of the synthesized analogues were then confirmed by NMR, HRMS and IR spectroscopy. Among the synthesized analogues, 5am and 5ad exhibited potent PL inhibition with IC50 of 5.16 ± 0.287 & 5.82 ± 0.933 µM, respectively, as compared with orlistat (IC50 = 0.86 ± 0.09 µM). The inhibition kinetics and in silico studies confirmed competitive type of inhibition of analogue 5am. The current work highlights the importance of chromone analogues as potential PL inhibitors. Further, the lead optimization may lead to much more potential PL inhibitors.Item Molecular modelling, synthesis and in vitro evaluation of quinazolinone hybrid analogues as potential pancreatic lipase inhibitors(Taylor & Francis, 2022-11) Paul, Atish TulshiramObesity is a multifactorial metabolic disorder, growing in an alarming rate across the world. Amongst the numerous targets explored for obesity management, inhibition of pancreatic lipase (PL) is considered as one of the promising approaches. Orlistat is the only PL inhibitory drug approved for long term treatment of obesity. However, it is reported to possess hepatotoxicity and nephrotoxicity. Thus, novel drug candidates that act through PL inhibition are considered the hour’s need. Based on this aim, a series of quinazolinone hybrid analogues have been synthesized, characterized and evaluated for their PL inhibitory potential. The physicochemical properties and toxicity parameters suggested that these parameters are in an acceptable range for the screened analogues. Amongst the synthesised analogues, QH-25 exerted potential PL inhibition (IC50 = 16.99 ± 0.54 µM). Further, enzyme inhibition studies suggested a reversible competitive inhibition. Molecular docking of these analogues was in line with in vitro results, wherein the obtained MolDock scores exhibited a significant correlation with their inhibitory activity (Pearson’s r = 0.6629). To further confirm the stability of the QH-25-PL complex in a dynamic environment, a molecular dynamics study (100 ns) was carried out and the results suggested that this complex is stable at dynamic conditions. Overall, these results shed light on the quinazolinone hybrids as potential PL inhibitors. Further structural modification may result in the development of potent anti-obesity agents which acts through PL inhibition.Item Optimisation of an extraction conditions for Rumex nepalensis anthraquinones and its correlation with pancreatic lipase inhibitory activity(Elsevier, 2020-09) Paul, Atish TulshiramRumex nepalensis Spreng. (Polygonaceae) is an edible plant rich in anthraquinones, that significantly inhibits Pancreatic Lipase (PL), a key enzyme in the dietary fat digestion. The effectiveness of Ultrasonic Assisted Extraction (UAE) of R.nepalensis was investigated using ethyl acetate as a solvent. Further, optimization of extraction conditions required for maximizing the PL inhibitory activity was determined using response surface methodology with Box-Behnken Design (BBD with three factor, 17 experimental runs). Extraction time (A, min), solid: solvent ratio (B, g/mL) and temperature (C, °C) were selected as the variables. The optimum conditions were established as extraction time (37 min), solid: solvent ratio (1:10.5) and extraction temperature 33 °C. However, till date, no HPTLC reports are available for the simultaneous quantification of chrysophanol and physcion from R. nepalensis. Thus, chrysophanol and physcion were quantified in various extractives of R. nepalensis via. a validated HPTLC method and a positive correlation were obtained with PL inhibition activity (Pearson’s r = 0.801 and 0.755 for chrysophanol and physcion respectively), that justified the PL inhibition potential of R. nepalensis derived anthraquinones.Item Development and validation of a new HPTLC method for quantification of conophylline in Tabernaemontana divaricata samples obtained from different seasons and extraction techniques: Insights into variation of pancreatic lipase inhibitory activity(Elsevier, 2018-01) Paul, Atish TulshiramTabernaemontana divaricata (L.) R. Br. Ex Roem. & Schult Apocynaceae) is an important indole alkaloid rich Indian medicinal plant with conophylline being a potential lead in the treatment of diabetes mellitus and obesity. Seasonal variations and extraction techniques are two major variables that play a crucial role in the extractive yield of phytochemical constituents. Till date, there are no reports on quantification of conophylline from the leaves of T. divaricata of Indian origin, and its variation due to season and extraction techniques. The present study reports for the first time, development and validation of a new HPTLC method for the quantification of conophylline. A resolved peak of conophylline was achieved in the chromatogram with mobile phase of chloroform: methanol (90:10% v/v), when developed on a 15 cm length TLC plate. Further, the leaf samples of T. divaricata were collected during the months of August, November, February and May, and subjected individually to different extraction techniques viz., ultrasonic extraction, hot percolation and cold maceration. A total of 12 alkaloid rich fractions were obtained, and the extractive value of conophylline was found to be highest in August sample, when subjected to ultrasonic extraction (35.57 mg per 1 g of alkaloid rich fraction). Pancreatic lipase inhibitory activity of the alkaloid rich fractions was in correlation to their respective conophylline content (Pearson’s r = −0.7152) with potent activity exhibited by August sample, that was obtained by ultrasonic extraction (IC50 = 7.86 μg/mL).