Synthesis and Biological Evaluation of N-Substituted Sophocarpinic Acid Derivatives as CoxsackievirusB3 Inhibitors

A series of novel N-substituted sophocarpinic acid derivatives was designed, synthesized, and evaluated for their anti-enteroviral activities against coxsackievirus typeB3 (CVB3) and coxsackievirus typeB6 (CVB6) in Vero cells. Structure-activity relationship analysis revealed that the introduction of a benzenesulfonyl moiety on the 12-nitrogen atom in (E) beta-,gamma-sophocarpinic acid might significantly enhance anti-CVB3 activity. Among the derivatives, (E)-12-N-(m-cyanobenzenesulfonyl)-beta,gamma-sophocarpinic acid (11m), possessing a meta-cyanobenzenesulfonyl group, exhibited potent activity against CVB3 with a selectivity index (SI) of 107. Furthermore, compound 11m also showed a good oral pharmacokinetic profile, with an AUC value of 7.29 mu M h(-1) in rats, and good safety through the oral route in mice, with an LD50 value of >1000 mg kg(-1); these values suggest a druggable characteristic. Therefore, compound 11m was selected for further investigation as a promising CVB3 inhibitor. We consider (E)-beta,gamma-N-(benzenesulfonyl)sophocarpinic acids to be a novel class of anti-CVB3 agents.