Publication Type : Journal Article
Publisher : Bioorg Med Chem
Source : Bioorg Med Chem, Volume 25, Issue 2, p.609-620 (2017)
Url : https://pubmed.ncbi.nlm.nih.gov/27908755/
Keywords : Acetamides, Dose-Response Relationship, Drug, Enzyme Inhibitors, Humans, Lipase, Models, Molecular, Molecular Structure, pancreas, Structure-Activity Relationship
Campus : Kochi
School : School of Pharmacy
Center : Analytical Chemistry
Department : Chemistry
Year : 2017
Abstract : A series of twenty four 2-(carbazol-3-yl)-2-oxoacetamide analogues were synthesized, characterized and evaluated for their pancreatic lipase (PL) inhibitory activity. Porcine PL was used against 4-nitrophenyl butyrate (method A) and tributyrin (methods B and C) as substrates during the PL inhibition assay. Compounds 7e, 7f and 7p exhibited potential PL inhibitory activity (IC values of 6.31, 8.72 and 9.58μM, respectively in method A; and X of 21.85, 21.94 and 26.2, respectively in method B). Further, inhibition kinetics of 7e, 7f and 7p against PL, using method A, revealed their competitive nature of inhibition. A comparison of the inhibition profiles of the top three compounds in methods B and C, provided a preliminary idea of covalent bonding of the compounds with Ser 152 of PL. Molecular docking studies of the compounds 7a-x into the active site of human PL (PDB ID: 1LPB) was in agreement with the in vitro results, and highlighted probable covalent bond formation with Ser 152 apart from hydrophobic interactions with the lid domain. Molecular dynamics simulation of 7e complexed with PL, further confirmed the role of aromatic groups in stabilising the ligand (RMSD ⩽4Å). The present study led to the identification of 2-(carbazol-3-yl)-2-oxoacetamide analogues 7a-x as a new class of potential PL inhibitors.
Cite this Research Publication : Sridhar S. N. C., Ginson George, Venkataramana Reddy P. O., Tantak, M. P., Kumar, D., and Atish T. Paul, “Synthesis, evaluation and molecular modelling studies of 2-(carbazol-3-yl)-2-oxoacetamide analogues as a new class of potential pancreatic lipase inhibitors.”, Bioorg Med Chem, vol. 25, no. 2, pp. 609-620, 2017.