Exploring New Tetrahydrothienopyridine Derivatives as Platelet Agglutination Inhibitors: Synthesis, Biological Evaluation and In Silico Study

The P2Y12 receptor is the major target for antithrombic drugs which plays a key role in platelet activation. New derivatives of 4,5,6,7‐tetrahydrothieno[3,2‐c]pyridine (THP) were designed targeting P2Y12 receptor. An efficient route was developed for synthesis of THP derivatives and subsequently evaluated for their antiplatelet agglutination activity. Amongst the synthesized THP derivatives ( 4 a – 4 g ), the compounds 4 a and 4 g displayed significant activity (with 88.25 and 70.17 % inhibition) as compared to other analogs and comparable with that of the reference drugs, aspirin and prasugrel. Data extracted from computational chemistry techniques such as molecular docking, provided the structural rationale for the observed platelet agglutination inhibition by the newly synthesized tetrahydrothienopyridine analogs. We proposed the involvement of residues such as Cys‐194 in the formation of the covalent adduct with the active metabolite of tetrahydrothienopyridine derivatives. This study also put forward the possibility of the existence of an alternate pathway for metabolizing the tetrahydrothienopyridine compounds. The structural data presented in this study is expected to accelerate the research on developing a tetrahydrothienopyridine scaffold as an effective antithrombotic therapeutic modality.