In silico and In vivo approach to Discovery and Development Vanillin Derivatives as Anti-Thrombotic Agent

One of the deadliest diseases in worldwide was coronary heart disease caused 9.1 million deaths in 2021, which can be brought on by plaque accumulation on the artery walls. This plaque causes the arteries to narrow and restrict blood flow, which might result in blood clots (thrombosis). Aspirin treatment may induce adverse consequences on gastrointestinal health. Vanillin was reported to show anti-platelet aggregation activity in vitro induced by arachidonic acid, but it was lower than aspirin. So, it needs to be modified to increase its activity as anti-thrombotic and support good health and well being. The study aims to modify the structure of vanillin, in order to enhance their activity as anti-thrombotic agents. This research modified vanillin structures based on their lipophilic and electronic properties, and carried out molecular docking using the AutoDock 1.5.7 program for inhibitory activity against P2Y12 receptor. Three selected compounds were obtained to be synthesized using a microwave method with a triethylamine catalyst. The synthesized compounds were characterized by FTIR and UV-Vis spectrophotometer, 1H-NMR and 13C-NMR spectrometers, melting point apparatus, and in vivo studies to evaluate their anti-thrombotic activity by clotting time and bleeding time methods in three separate doses. According to the calculation of ∆G and Ki values, it was observed that all vanillin analogs had the potential for more effective anti-thrombotic activity than aspirin and clopidogrel. In addition, the results of in vivo studies indicated that three synthesized compounds showed better anti-thrombotic activity compared to the aspirin. The administration of 4-formyl-2-methoxyphenyl 4-methylbenzoate (V2) at 160 mg demonstrated the highest activity. These results suggested that V2 is the most promising compound for prospective use as an anti-thrombotic drug.