Discovery and SAR studies of methionine-proline anilides as dengue virus NS2B-NS3 protease inhibitors

Abstract

A series of methionine-proline dipeptide derivatives and their analogues were designed, synthesized and assayed against the serotype 2 dengue virus NS2B-NS3 protease, and methionine-proline anilides 1 and 2 were found to be the most active DENV 2 NS2B-NS3 competitive inhibitors with Ki values of 4.9 and 10.5 μM. The structure and activity relationship and the molecular docking revealed that L-proline, L-methionine and p-nitroaniline in 1 and 2 are the important characters in blocking the active site of NS2B-NS3 protease. Our current results suggest that the title dipeptidic scaffold represents a promising structural core to discover a new class of active NS2B-NS3 competitive inhibitors.

Keywords: 4-(N,N′-dimethyl)-aminopyridine; 4-Nitroaniline; DCC; DCM; DENV; DMAP; Dengue virus NS2B-NS3 protease; EtOAc; EtOH; HQRJJHXKCFABSI-UONOGXRCSA-N; K(i); Methionine; Methionine–proline anilides; NS2B-NS3; Proline; SAR; TFA; dengue virus; dichloromethylene; dicyclohexylcarbodiimide; ethyl acetate; ethyl alcohol; inhibition constant; nonstructural protein 2B and 3; structure and activity relationship; trifluoroacetic acid.