Synthesis, biological evaluation, molecular docking, molecular dynamics and DFT studies of quinoline-fluoroproline amide hybrids

Abstract

Three analogs of quinoline hybrid 4-cis-fluoro-proline amides (QHCFPAs) were synthesized and characterized using spectroscopic techniques like 1H NMR, 13C NMR, DEPT 135, FT-IR and ESI-MS. The in vitro antidiabetic activity of the titled compounds was performed by reported spectrophotometric method and the percentage inhibition of α-amylase was found comparable to that of standard drug acarbose. In silico ADMET properties of the titled compounds were predicted and discussed. Further, molecular docking studies of QHCFPAs were performed against the target α-amylase enzyme to identify the plausible binding interactions between enzyme and the QHCFPAs. Among QHCFPAs, (2R,4R)-1-((2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)methyl)-4-fluoro-N-phenylpyrrolidine-2-carboxamide (QPAA) exhibited good docking score andbinding energy of −4.5 and −40.12 kcal/mol, respectively and (2R,4R)-1-((2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)methyl)-N-(2,4-dimethylphenyl)-4-fluoropyrrolidine-2-carboxamide(QPDMAA) exhibited docking score and binding energy of −4.7 and −42.90 kcal/mol, respectively. Further, frontier molecular orbitals and molecular electrostatic potential studies were also performed to support the in silico and in vitro biological screening results. Finally, molecular dynamics study was also explored for QPAA in order to correlate the findings of in silico and in vitro studies.