title: Synthesis, evaluation and molecular modelling studies of 2-(carbazol-3-yl)-2-oxoacetamide analogues as a new class of potential pancreatic lipase inhibitors.
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 (IC50values of 6.31, 8.72 and 9.58μM, respectively in method A; and Xi50of 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.
authors.affiliation: Laboratory of Natural Drugs, Department of Pharmacy, Birla Institute of Technology and Science Pilani (Pilani Campus), Pilani 333 031, Rajasthan, India.
authors.forename: S N C
authors.initials: SN
authors.lastname: Sridhar
authors.affiliation: Laboratory of Natural Drugs, Department of Pharmacy, Birla Institute of Technology and Science Pilani (Pilani Campus), Pilani 333 031, Rajasthan, India.
authors.forename: George
authors.initials: G
authors.lastname: Ginson
authors.affiliation: Department of Chemistry, Birla Institute of Technology and Science Pilani (Pilani Campus), Pilani 333 031, Rajasthan, India.
authors.forename: P O
authors.initials: PO
authors.lastname: Venkataramana Reddy
authors.affiliation: Department of Chemistry, Birla Institute of Technology and Science Pilani (Pilani Campus), Pilani 333 031, Rajasthan, India.
authors.forename: Mukund P
authors.initials: MP
authors.lastname: Tantak
authors.affiliation: Department of Chemistry, Birla Institute of Technology and Science Pilani (Pilani Campus), Pilani 333 031, Rajasthan, India. Electronic address: dalipk@pilani.bits-pilani.ac.in.
authors.forename: Dalip
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Laboratory of Natural Drugs, Department of Pharmacy, Birla Institute of Technology and Science Pilani (Pilani Campus), Pilani 333 031, Rajasthan, India. Electronic address: atish.paul@pilani.bits-pilani.ac.in.
authors.forename: Atish T
authors.initials: AT
authors.lastname: Paul
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008049:Lipase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010179:Pancreas / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D004791:Enzyme Inhibitors; C030686:acetamide; D008049:Lipase
keywords: Carbazolyl oxoacetamides; Inhibition kinetics; Molecular dynamics; Orlistat; Pancreatic lipase