Design, synthesis, biological evaluation, and molecular modeling studies of rhodanine derivatives as pancreatic lipase inhibitors

Abstract

A series of rhodanine‐3‐acetic acid derivatives were synthesized via Knoevenagel condensation of rhodanine‐3‐acetic acid with various substituted aromatic aldehydes. The synthesized derivatives were screened in vitro for understanding the inhibitory potential towards pancreatic lipase (PL), a key enzyme responsible for the digestion of dietary fats. Derivative 8f exhibited a potential inhibitory activity towards PL (IC50 = 5.16 µM), comparable to that of the standard drug, orlistat (0.99 µM). An increase in the density of the aromatic ring resulted in potential PL inhibition. The enzyme kinetics of 8f exhibited a reversible competitive‐type inhibition, similar to that of orlistat. Derivative 8f exhibited a MolDock score of ‐125.19 kcal/mol in docking studies, and the results were in accordance with their PL inhibitory potential. Furthermore, the reactive carbonyl group of 8f existed at a distance adjacent to Ser152 (≈3 Å) similar to that of orlistat. Molecular dynamics simulation (10 ns) of the 8f‐PL complex revealed a stable binding conformation of 8f in the active site of PL (maximum root mean square displacement of ≈2.25 Å). The present study identified novel rhodanine‐3‐acetic acid derivatives with promising PL inhibitory potential, and further lead optimization might result in potent PL inhibitors.

Exploring Aurone Derivatives as Potential Human Pancreatic Lipase Inhibitors through Molecular Docking and Molecular Dynamics Simulations

“…Natural plant-derived compounds (alkaloids, saponins, carotenoids, glycosides, polyphenols, polysaccharides, and terpenoids) and microorganism-derived compounds (lipstatin, valilactone, and panclicins) have been isolated and reported to inhibit in vitro and in vivo pancreatic lipase [ 16 , 17 , 18 ]. Synthetic compounds with diverse structures have been prepared and screened for pancreatic lipase inhibitory activity [ 19 , 20 , 21 , 22 ]. Along with the conventional approaches, in silico models such as 3D QSAR, 2D pharmacophore, molecular docking, and molecular dynamics simulations are utilized to identify potential bioactive compounds for obesity treatment [ 23 , 24 , 25 , 26 ].…”

Design, Synthesis, and Structure‐Activity Relationship Study of Pyrazolones as Potent Inhibitors of Pancreatic Lipase

“…At present, orlistat remains the only PL inhibitor approved by FDA for obesity management in conjunction with a reduced caloric diet. However, orlistat can cause non‐negligible adverse effects, including stomach pain, steatorrhea and incontinence, abdominal cramping and fat‐soluble vitamin deficiencies, hepatotoxicity, and acute pancreatitis [16,17] . Thus, it is highly desirable to find more safe and effective PL inhibitors for the prevention and treatment of obesity.…”

Design, synthesis and biological evaluation of N‐substituted indole‐thiazolidinedione analogues as potential pancreatic lipase inhibitors

“…Past research has demonstrated the importance of five‐membered nitrogen heterocycles on PL inhibitory profiles. For instance, oxadiazole (Point et al., 2012), 1,2,4‐triazole (Bekircan et al., 2014; Kahveci et al., 2017), triaza‐phospholinoalkanes (Hamzaoui et al., 2015), rhodanine (Chauhan et al., 2019), thiazolidinedione (Sridhar, Bhurta, et al., 2017) etc. have explored for PL inhibition.…”

“…Some of the five‐membered heterocycles possessed these active warheads for the PL inhibition. For instance, thiazolidinedione and rhodanine analogues with a nitrogen centred diamide linkage exerted a potential PL inhibitory activity (Chauhan et al., 2019; George et al., 2020; Sridhar, Bhurta, et al., 2017). The structural diversity at two positions of thiazolidinedione and rhodanine offers an additional advantage for the further incorporation of essential pharmacophoric features coverts these as attractive structural scaffolds in the area of PL inhibitors.…”

“…Numerous chemical entities consisting of these individual scaffolds have been reported previously. For instance, indole glyoxamide analogues, tryptophan‐containing amino acids derivatives (Sridhar et al., 2020; Stefanucci, Dimmito, et al., 2019; Stefanucci, Luisi, et al., 2019), diaryl substituted pyrazolyl thiazolidinediones and rhodanine acetic acid containing analogues (Chauhan et al., 2019; Sridhar, Bhurta, et al., 2017) have been explored for their PL inhibition (Figure 2).…”