Dual inhibition of cyclooxygenase isozymes along with platelet aggregation activities via the arachidonic acid pathway may provide 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 drawn much attention these days since it ensures cardiovascular safety. In this respect, novel derivatives of non-steroidal anti-inflammatory drugs containing amide, thiourea, thiosemicarbazide, and triazole functionalities were synthesized and characterized. Calculation of in-silico drug-likeness and toxicological properties demonstrated the suitability of compounds for oral administration. Meanwhile, the molecular docking results suggested the 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 score, and favorable interactions, particularly with the selective side pocket residues in COX-2 and main catalytic residues in COX-1. Further, molecular dynamics simulation confirmed that compounds 3 and 12 exhibited good interactions at the active site having stable binding throughout 100 ns. Overall, two major findings have been made in the current study. With an IC50 of 95.11 and 98.73 μM against COX-1 and COX-2 isozymes, respectively, compound 12 bearing the triazole moiety proved to be the most effective cyclooxygenase inhibitor while also maintaining the anti-platelet activity (IC50 = 277.67 μM) and this, in turn, confirmed the dual functioning of compound 12 whereas compound 3 purely behaved as an anti-platelet agent (IC50 =261.0 μM) in contrast to aspirin with fare inhibitory effects against COX-2.
Aspirin Vs Ibuprofen: Unveiling Distinct Cyclooxygenase-1/2 Behaviour and Dual Efficacy of Their Synthesized Analogues via Molecular Modeling and In-Vitro Biological Assessment
