Aspirin vs. ibuprofen: unveiling the distinct cyclooxygenase-1/2 behaviour and dual efficacy of their synthesized analogues via molecular modeling and in vitro biological assessment.

Dual inhibition of cyclooxygenase isozymes along with the platelet aggregation activities via the arachidonic acid pathway may offer a better anti-inflammatory agent with enhanced cardiac safety. Although the literature is more focused on COX-2 selectivity, sufficient or improved COX-1/COX-2 selectivity has garnered significant attention recently since it can ensure cardiovascular safety. Herein, in this regard, novel derivatives of non-steroidal anti-inflammatory drugs containing amide, thiourea, thiosemicarbazide, and triazole functionalities were synthesized and characterized. Calculations on the in silico drug-likeness and toxicological properties demonstrated the suitability of the compounds for oral administration. Meanwhile, the molecular docking results suggested two different mechanistic pathways for the anti-inflammatory and anti-platelet effects via COX-2 and COX-1 inhibition. Compounds 3 and 12 were shown to be the most efficient based on their excellent docking scores and favorable interactions, particularly with the selective side-pocket residues of COX-2 and main catalytic residues of COX-1. Furthermore, molecular dynamics simulation confirmed that compounds 3 and 12 exhibited good interactions at the active sites, having stable binding throughout 100 ns. Overall, two major findings were made in the current study. (i) Compound 12 bearing the triazole moiety proved to be the most effective cyclooxygenase inhibitor with IC(50) values of 95.11 and 98.73 μM against COX-1 and COX-2 isozymes, respectively. It also maintained its anti-platelet activity (IC(50) = 277.67 μM), confirming the dual functioning of compound 12. (ii) Compound 3 purely behaved as an anti-platelet agent (IC(50) = 261.0 μM) in contrast to aspirin with fare inhibitory effects against COX-2.