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.

Structure–activity relationship of N-benzenesulfonyl matrinic acid derivatives as a novel class of coxsackievirus B3 inhibitors

“…1) analogues as a novel class of antienterovirus agents against CVB3. 11,12 This discovery is due to our successive modification from 1 and sophocarpinic acid (3, Fig. 1).…”

“…All of them have an improved ability against CVB3 and also an increased selectivity index (SI) between 5.2 and 24.6, which are much better than 1. 12 These results offered us promising lead compounds and useful information for our further chemical modification and optimization of this kind of compounds. In the present study, taking 4-6 as the leads, SAR studies were further conducted with the variations of the carboxyl group at the 4 0 -position and substituents located on the phenyl ring.…”

“…As we anticipated, matrinic esters (18,22) and matrinol (19) exhibited reasonable activities higher than the matrinic acids (20a-b), consistent with our previous SAR analysis. 11,12 While, matrinic ester 23 and matrinol 24 completely lost the potency against CVB3, owing to decreasing electron-withdrawing ability of substituents on the phenyl ring. Together, these compounds indicate that the ester or hydroxyl group is a better choice as a 4 0 substituent than a carboxyl group, but the anti-CVB3 activity is sensitive to the substituent on the phenyl ring.…”

“…11,12 The required matrinic amides (21a-j) were gained by amidation reaction of 20 with various amino compounds in DMSO/CH 2 Cl 2 with yields of 44-48%, 18 using EDCI and DIPEA as the activating agents to ensure the successful transformation of carboxylic acid into amide. The product 23 was synthesized via the condensation between 22 and hydroxylamine using CH 3 COOH as a catalyst in an alkaline condition with an 80% yield.…”

“…Chemical structure and anti-CVB3 activity of the lead compounds matrinic acid (4), matrinic ester (5) as reported previously. [11][12][13] The key intermediate (11) was prepared by the selective oxidization of 10 using oxalyl chloride as an oxidizing agent at À80°C in CH 2 Cl 2 /DMSO with a 35% yield. 14,15 The desired matrinic amines (14a-j) were acquired through aldehyde-amine condensation, reduction with NaBH 3 CN, 16,17 de-protection of Boc and 12-N-benzenesulfonyl substitution from compound 11 with overall yields of 50-54%.…”