Molecular design, synthesis, and biological evaluation of bisamide derivatives as cyclophilin A inhibitors for HCV treatment.

Molecular design, synthesis, and biological evaluation of bisamide derivatives as cyclophilin A inhibitors for HCV treatment. Eur J Med Chem. 2020 Jan 02;188:112031 Authors: Han J, Lee HW, Jin Y, Khadka DB, Yang S, Li X, Kim M, Cho WJ Abstract Hepatitis C virus (HCV) is a major cause of end-stage liver diseases. Direct-acting antivirals (DAAs), including inhibitors of nonstructural proteins (NS3/4A protease, NS5A, and NS5B polymerase), represent key components of anti-HCV treatment. However, some DAAs are associated with increased drug resistance and undesired side effects. Previous reports have shown that bisamides could be a novel class of cyclophilin A (CypA) inhibitors for treating HCV as a member of combinational therapies. To fully elucidate structure-activity relationships of bisamide derivatives and find a better hit compound with diverse binding modes, 16 biamides were designed with the help of docking program. They were then synthesized using one-pot four-component Ugi reaction. 7e with selectivity index of more than 18.9 (50% effective concentration of 5.3 μM, but no cytotoxicity at 100 μM) and unique binding mode that could be dived into gatekeeper pocket was selected as a new hit compound. Surface plasmon resonance experiments revealed that 7e is able to bind to CypA with a KD of 3.66 μM. Taken together, these results suggest that 7e as a CypA inhibitor could be used as an alternative anti-HCV agent in combinationa...
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Tags: Eur J Med Chem Source Type: research