title: Synthesis and biological evaluation of N-substituted sophocarpinic acid derivatives as coxsackievirus B3 inhibitors.
abstract: A series of novel N-substituted sophocarpinic acid derivatives was designed, synthesized, and evaluated for their anti-enteroviral activities against coxsackievirus type B3 (CVB3) and coxsackievirus type B6 (CVB6) in Vero cells. Structure-activity relationship analysis revealed that the introduction of a benzenesulfonyl moiety on the 12-nitrogen atom in (E)-β,γ-sophocarpinic acid might significantly enhance anti-CVB3 activity. Among the derivatives, (E)-12-N-(m-cyanobenzenesulfonyl)-β,γ-sophocarpinic acid (11 m), possessing a meta-cyanobenzenesulfonyl group, exhibited potent activity against CVB3 with a selectivity index (SI) of 107. Furthermore, compound 11 m also showed a good oral pharmacokinetic profile, with an AUC value of 7.29 μM 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 11 m was selected for further investigation as a promising CVB3 inhibitor. We consider (E)-β,γ-N-(benzenesulfonyl)sophocarpinic acids to be a novel class of anti-CVB3 agents.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Tiantan Xili No. 1, Beijing 100050, PR China.
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Gao
authors.forename: Sheng
authors.initials: S
authors.lastname: Tang
authors.forename: Yan-Xiang
authors.initials: YX
authors.lastname: Wang
authors.forename: Rong-Mei
authors.initials: RM
authors.lastname: Gao
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Zong-Gen
authors.initials: ZG
authors.lastname: Peng
authors.forename: Jian-Rui
authors.initials: JR
authors.lastname: Li
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Jiang
authors.forename: Yu-Huan
authors.initials: YH
authors.lastname: Li
authors.forename: Dan-Qing
authors.initials: DQ
authors.lastname: Song
mesh_terms: D000284:Administration, Oral; D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019540:Area Under Curve; D001557:Benzenesulfonates / Q000737:chemistry; D002522:Chlorocebus aethiops; D029822:Enterovirus B, Human / Q000187:drug effects*; D005260:Female; D006207:Half-Life; D008297:Male; D051379:Mice; D012372:ROC Curve; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014709:Vero Cells; D000093842:Matrines
chemical_list: D000470:Alkaloids; D000998:Antiviral Agents; D001557:Benzenesulfonates; C586998:12-N-(m-cyanobenzenesulfonyl)-delta(betagamma)-sophocarpinic acid; C035933:sophocarpine; D000093842:Matrines; C032365:benzenesulfonic acid
keywords: antiviral agents; druggability; enteroviruses; sophocarpinic acids; structure-activity relationships