Synthesis and biological evaluation of 12-benzyl matrinic amide derivatives as a novel family of anti-HCV agents

A new series of 12-benzyl matrinic amide/ethanamide derivatives were synthesized from matrinine (1) and evaluated for their anti-HCV activity, taking compound 2 as the lead. SAR revealed that the introduction of a suitable substituent at the N′-end of matrinic amide might greatly enhance the potency. Among them, matrinic acid 17 and N′-substituted matrinic amides 18a–d exhibited promising potency with low micromolar EC50 values ranging from 1.03 μmol/L to 7.54 μmol/L, and better therapeutic window with SI from 66 to 132. Moreover, compound 17 displayed an excellent PK and safety profile in vivo, demonstrating good drug-like characteristics. Thus, it has been selected for further investigation, with an advantage of decreased chances of inducing drug-resistance mutations.

Graphical abstractA new series of 12-benzyl matrinic amide/ethanamide derivatives were synthesized. Compounds 17 and 18a–d exhibited promising anti-HCV potency with EC50 values ranging from 1.03 μmol/L to 7.54 μmol/L and SI from 66 to 132. Compound 17 displayed an excellent PK and safety profile in vivo, demonstrating good drug-like characteristics.Figure optionsDownload full-size imageDownload as PowerPoint slide