2‐Aminobenzamide‐Based Factor Xa Inhibitors with Novel Mono‐ and Bi‐Aryls as S4 Binding Elements

Abstract

Factor Xa, a key serine protease in the coagulation cascade, has attracted a great deal of attention as a target for developing new antithrombotic agents. A series of novel alkyl, benzyl, biphenyl and substituted piperazine derivatives as S4 binding elements have been synthesized as potential human factor Xa (FXa) inhibitors with 2‐amino‐5‐chloropyridine as the S1 binding moiety. All the synthesized compounds were tested in vitro for FXa inhibitory activity by chromogenic substrate hydrolysis assay. The active compounds were selected to assess their ex vivo prothrombin time prolonging activity. Keeping in mind the promising in vitro and ex vivo profile of N‐(5‐chloropyridin‐2‐yl)‐2‐(4‐(2‐cyanophenyl)benzylamino)benzamide (16 f), it was selected for further in vivo evaluation of its antithrombotic potential. Structure‐activity relationship and molecular interaction analysis by the docking and dynamics studies within the series are discussed.

Novel Multitarget Directed Triazinoindole Derivatives as Anti-Alzheimer Agents

“…Maestro–Desmond (based on the OPLS-2005 force field) was used to perform the molecular dynamics simulation study of the molecule 23e . − To begin, the system was solvated with the TIP3P water model in an orthorhombic box of 10 Å 3 and neutralized by Na + ions for AChE and by Cl – ions for BuChE. The long-range electrostatic interactions were studied by smooth particle-mesh Ewald (PME) approximation, and the nonbonded interactions were analyzed by using a MSHAKE algorithm with a cutoff of 9 Å.…”