MOLECULAR DOCKING, SYNTHESIS, CHARACTERIZATION AND ADME STUDIES OF SOME NEW FIVE-MEMBER RING HETEROCYCLIC COMPOUNDS WITH IN VITRO ANTIPROLIFERATIVE EVALUATION.
Kanar M. Alawad
1Department of Pharmacy, AL-Rasheed University College, Baghdad-Iraq, kanar.muthana93@gmail.com
Monther F. Mahdi
Department of Pharmaceutical Chemistry, College of Pharmacy, Mustansiriyah university, Baghdad-Iraq.
Ayad M.R. Raauf
Department of Pharmaceutical Chemistry, College of Pharmacy, Mustansiriyah university, Baghdad-Iraq.
Abstract
A series of pyrazoline, Isoxazoline, and amide derivatives bearing nabumetone moiety were designed, synthesized, and primarily evaluated (In Vitro) for their cytotoxic activity against lung (A549). Nabumetone is a nonsteroidal anti-inflammatory (NSAID) prodrug. Chalcone derivative of nabumetone; compound (1) synthesized by Claisen-Schmidt condensation reaction, and then, the intermediate compounds (1a-e) were synthesized by incorporating pyrazoline, and Isoxazoline pharmacophore into compound (1). Amide derivatives synthesized to develop the final compounds (2a-e). Melting point, and FT-IR spectra used to characterize all the synthesized compounds, and confirmed by 1H-NMR, and 13C-NMR spectroscopy. Molecular docking software (GOLD suite v. 5.7.1) were used before synthesis to check the selectivity for EGFR. Precisely compounds (1e & 2e) with EGFR receptor showed the highest PLP fitness value of (92.07 & 97.11) as compared to erlotinib reference drug that give PLP fitness of (94.84). IC50 values for the synthesized compounds showed that compound (2e) give 21.62 µM against A549 cancer cell line as compared to erlotinib that give IC50 value of (24.6) µM. Finally, in silico studies including ADME studies, were The pharmacokinetics of the designed compounds were predicted using the SwissADME service. The results show that all the compounds expected passively and highly absorbed from the GIT except (1e& 2e) which are poorly absorbed from the GIT. Further, all designed compounds satisfied the Lipinski rule of five.
Keywords:
Nabumetone, Pyrazoline, Isoxazoline, Docking Study, ADME.Full Text:
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