Novel N-Benzenesulfonyl Sophocarpinol Derivatives as Coxsackie B Virus Inhibitors

Abstract

Novel N-benzenesulfonyl sophocarpinic acid/ ester and sophocarpinol derivatives were synthesized and evaluated for their antienteroviral activities against coxsackievirus type B3 (CVB3) from sophocarpine (1), a natural medicine isolated from Chinese herb. Structure−activity relationship (SAR) analysis revealed that the double bond and its geometrical configuration and position at the C-11 attachment did not greatly affect the potency. Among these derivatives, sophocarpinol 24d exerted the promising activities against not only CVB3 but also CVB1, CVB2, CVB5, and CVB6 with IC 50 ranging from 0.62 to 3.63 μM (SI from 46 to 275), indicating a broad-spectrum antienteroviral characteristic. The SAR results provided the powerful information for further strategic optimization and development of a novel scaffold of broad-spectrum antiviral candidates against enteroviruses. KEYWORDS: Sophocarpine, sophocarpinol, structure−activity relationship, enteroviruse, coxsakievirus type B3 E nteroviruses are a genus of single-stranded (+) RNA viruses associated with many human diseases. 1,2 Among the enteroviruses, coxsackie B viruses (CVB) are important human pathogens causing pleurodynia, myocarditis, hepatitis, and so on. 3,4 Coxsackievirus type B3 (CVB3) is an important pathogen that induces acute and chronic viral myocarditis in children and young adults, and eventually leads to cardiomyopathy. 5,6 Besides heart infections, CVB3 causes chronic inflammatory diseases of the pancreas and central nervous system as well. 7,8 In recent years, the sudden epidemic infections of enteroviruses have caused great concerns of society. 9−11 However, there has been no special efficient drug approved for the treatment of the infections caused by CVB3 until now. 12 Therefore, there is an urgent need to develop broad-spectrum antiviral candidates against enteroviruses to meet an emergency of sudden infectious diseases. (1); E-β,γ-sophocarpinic acid (2); E-β,γ-12-N-m-cyanobenzene-sulfonyl sophocarpinic acid (3); E-β,γ-12-N-p-trifluoromethy-benzenesulfonyl sophocarpinic acid (4); and Z-α,β-sophocarpinic acid (14).Scheme 1 a a Reagents and conditions: (a) 5 N NaOH, reflux, 9 h, 2 N HCl, pH = 5−6; (b) diphenyldiazomethane, MeOH, r.t., 12 h; (c) RPhSO 2 Cl, K 2 CO 3 , CH 2 Cl 2 , r.t., overnight; (d) flash column chromatography; (e) m-cresol, reflux, 8−9 h; (f) 2 N HCl/MeOH, reflux, 2 h.

Evolution and Biological Evaluation of Matrinic Derivatives with Amantadine Fragments As New Anti-Influenza Virus Agents

“…The key intermediates, methyl trifluoromethyl benzenesulfonyl matrinic butyrates ( 4a – c ) were obtained by a three-step procedure, including hydrolysis, esterification, and 12 N -sulfonylation from MT , with high yields of 70–75% [ 18 ]. Then, the reduction of the ester bond in the compounds 4a – c by LiAlH 4 achieved the intermediates 12 N -trifluoromethyl benzenesulfonyl matrinic butanols ( 5a – c ) respectively [ 19 ]. The target compounds 12 N -trifluoromethyl benzenesulfonyl matrinic butanes ( 7a – c ) were gained from 5a – c by a two-step sequence reaction, including hydroxyl sulfonylation, and the reductive elimination of tosyloxy (OTs) by LiAlH 4 at yields of 65–70% [ 20 ].…”

Synthesis and biological evaluation of tricyclic matrinic derivatives as a class of novel anti-HCV agents

“…The targeted ( Z )-Δ βγ -matrinic crotonol derivatives ( 14a – b ) were gained from a LiAlH 4 reduction of 13a – b in 70–80% yields. Another nitro substituted crotonol derivative 20 was obtained from compound 12 via a six-step procedure, including 12 N -tert-butoxycarbonyl (Boc) protection, ester reduction by LiAlH 4 , de-protection of Boc, silicane protection, 12 N -substitution and deprotection with an overall yield of 30% [ 14 , 15 ].…”

Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway

“…The method of the HPLC analysis was as follows: column, Inertsustain C18, 250 mm × 4.6 mm, id; flow rate, 1.0 mL/min; mobile phase, acetonitrile/water (0.01 mol·L −1 KH 2 PO 4 in water, pH = 4.0) = 5:95; Flash column chromatography was performed on Combiflash Rf 200 (Teledyne, Lincoln, NE, USA), particle size 0.038 mm. The target compounds 1 and 5a – d were reported previously [ 9 , 15 , 23 ], but 1 and 5b – d were obtained in this manuscript by a new method with improved yields.…”