Identification of new pyrazolyl piperidine molecules as factor Xa inhibitors: Design, synthesis, in silico, and biological evaluation

•A series of Pyrazolyl piperidine derivatives were designed and synthesized.•Compound 4a-h bind to factor-Xa protein active site similar to rivaroxaban ligand.•The lead molecule, 4a displayed an IC50 of 13.4 nM against F-Xa.•4a also showed prolonged aPPT and PT on a par with that of Heparin.•ADMET and DFT studies for the designed analogs 4a-h were carried out. Coagulation factor Xa (FXa), a serine endopeptidase is a common coagulation factor activated as a result of the initiation of both intrinsic and extrinsic blood coagulation pathways. Hence, FXa has been regarded as an important pharmaceutical target for the treatment of thrombotic disorders. In this study, we reported the design and synthesis of pyrazolyl piperidine analogs 4(a–h) as a new class of anticoagulant drug candidates. Among the synthesized analogs 4(a–h), compound 4a consisting of the 4-chlorophenyl substitution displayed the highest in vitro FXa inhibition activity with an IC50 value of 13.4 nM. The PT and aPTT assay indicated that compound 4a showed good anticoagulation activity compared to Heparin. Furthermore, docking studies suggested that the synthesized analogs displayed binding modes similar to the cocrystallized Rivaroxaban ligand. In addition, in-silico ADMET and DFT studies were carried out for all the designed compounds. Together, our study suggests that the compound (4a) displayed anti-coagulant activity through the inhibition of FXa.