title: Synthesis, evaluation and molecular docking of prolyl-fluoropyrrolidine derivatives as dipeptidyl peptidase IV inhibitors.
abstract: A series of prolyl-fluoropyrrolidine derivatives were designed, synthesized and screened for in vitro inhibition of dipeptidyl peptidase IV. The SAR study revealed the influence of substituted chemical modifications on dipeptidyl peptidase IV inhibitory activity. Among all the compounds screened, compound 9 (IC50  = 0.83 μm) and 10 (IC50  = 0.43 μm) possessing aryl substituted piperazine with acetamide linker resulted as most potent dipeptidyl peptidase IV inhibitors. Both the compounds 9 and 10 resulted significant reduction in glucose excursion during oral glucose tolerance test in streptozotocin-induced diabetic rat model at single dose of 10 mg/kg. Molecular docking studies were performed to illustrate the probable binding mode and interactions of prolyl-fluoropyrrolidine nucleus and its derivatives at binding site of receptor. The fluoropyrrolidine moiety of prolyl-fluoropyrrolidine derivatives occupied S1 pocket as observed in the crystal structure (PDB id: 2FJP). The compounds 9 and 10 were observed to occupy S2 binding pocket and were observed to have interaction with Arg125, Tyr547 and Ser630 acquired through hydrogen bond. The aryl moiety at piperazine ring was found to extend into the cavity and interacted with Arg358. The observed interactions signalled that occupancy of the highly hydrophobic S2 pocket is very crucial for dipeptidyl peptidase IV inhibitory activity.
authors.affiliation: Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research, Pushp Vihar, Sector-3, M B Road, New Delhi, 110017, India. mani120484@gmail.com
authors.forename: Mani
authors.initials: M
authors.lastname: Sharma
authors.forename: Monica
authors.initials: M
authors.lastname: Gupta
authors.forename: Divya
authors.initials: D
authors.lastname: Singh
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.forename: Punit
authors.initials: P
authors.lastname: Kaur
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D054879:Halogenation; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D008297:Male; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011759:Pyrrolidines; D018819:Dipeptidyl Peptidase 4; C032519:pyrrolidine
keywords: diabetes; dipeptidyl peptidase IV; molecular docking; prolyl-fluoropyrrolidine