Novel furo[2,3-d]pyrimidinones as direct thrombin inhibitors: Design, synthesis and biological evaluation

Thrombin, a versatile protease is a promising target in coagulation cascade for thrombosis related conditions. We designed and synthesized thirty novel furo[2,3-d]pyrimidinone analogs and evaluated them for their antithrombotic potential. Initial in vitro screening revealed that most of the compounds displayed good to moderate level of antithrombin properties. Compounds (7b, IC₅₀ = 0.96 μM and 7g, IC₅₀ = 1.36 μM) displayed the most potent direct thrombin inhibition activity. The results from the ex vivo anticoagulant activity demonstrated compound (7b) having prolonged PT and aPTT in rats relative to the control. Interestingly, compound (7b, BT = 91 s.) exhibited better safety profile than the standard drug dabigatran (BT = 102 s.) in terms of bleeding risk. Molecular docking and dynamics simulation studies identified and validated the binding interactions of potent derivatives with the target protein thrombin.