Effects of anti-cyclooxygenases (COX-1 and COX-2), structure activity relationship, molecular docking and in silico ADMET of some synthesized chalcones

Abstract

Purpose: To develop effective cancer chemopreventive and anti-inflammatory agents, a series of chalcones were prepared by reacting suitable aromatic aldehyde with appropriate acetophenones. Methods: Twenty-four synthesized chalcones (namely, 1 - 24) were assessed for their in vitro anti-cyclooxygenase-1 (COX-1) and anti-cyclooxygenase-2 (COX-2) activity in a COX catalyzed prostaglandin synthesis bioassay. Molecular docking was done to investigate the ligand-protein interactions, and selectivity on both enzymes. ADMET (absorption, distribution, metabolism, excretion, toxicity) modeling and software were also used. Results: The compounds inhibited both COX-1 and COX-2. Two compounds (3 and 19) demonstrated more marked COX-2 inhibition than compound 1. Indomethacin as a standard anti-cyclooxygenase shows unselective inhibition of 81.44 ± 6.5 and 91 ± 9.5, respectively. The in silico data revealed that a chalcone skeleton with C=O at 4-position, C2–C3 double bond and OH at 5-position are necessary properties for anti-cyclooxygenase effects. It was also revealed that the propenone moiety comprises of an appropriate scaffold which proposes a new acyclic 1,3-diphenylprop-2-en-1-ones with selective anti-COX effects. A molecular modeling investigations where these chalcones 1, 3 and 19 were docked in the active site of COX-2 depicted that the p-CH3 substituent on the C-4- phenyl ring A are oriented in the vicinity of the COX-2 secondary pocket Phe381, Gly526, Tyr385 and Val349. Conclusion: Based on the screening for oral bioavailability, in silico ADMET, and toxicity risk assessment, this study shows that these compounds could be a cornerstone for the development of new pharmaceuticals in the battle against COX-associated inflammatory disorders.