The Design, Synthesis And SAR Research For Inhibiting CVB3 Of New Matrinic Derivatives

Coxsackie virus is a wild-spread and highly pathogenic virus among the human Enteroviruses family which is a leading cause of many intestinal and heart disease, with morbidities such as viral myocarditis, pericarditis, epidemic chest pain, pancreatitis, meningitis. In contrast to other coxsackie virus, coxsackie virus B3 has the most great potential to induce extreme disease, especially the viral myocarditis.Infections of CVB3 virus can lead to the apoptosis of cardiomyocytes, which in turn cause the onset of viral myocarditis. Statistics reveals that about 50%of viral myocarditis is induced by the infection of CVB3.Sophocarpine is a natural medicine extracted from the old Chinese herb matrinic, has been used for treating vial myocarditis caused by CVB3 in china for many years. However, the low value and SI index for inhibiting CVB3 virus limited the potential of this traditional medicine growing to be a global therapeutic drug for treating these fatal heart diseases, and which really arise our interests to optimize its ability against CVB3 by modifying the structures.In our previously work,12-N-benzenesulfonyl matrinic acid derivatives have been identified as a quality family for inhibiting CVB3, which can dramatically enhance the inhibiting value and regulate the SI index. And a brief SAR has also been summarized by the former co-worker in our team.In this work, SAR study was further convert on to the variations of the carboxyl group and substituents with electron-withdrawing feature located on the phenyl ring.Combine this strategy and a Computer-Aided Drug Design technology which can be used to calculate and regulate the chemical character of compound, such as Clop, tPSA. A series of novel N-benzenesulfonyl matrinic amine/amide, and matrinic methyl ester derivatives were designed and synthesized and evaluated for their anti-enterovirus activity against CVB3 in African green monkey kidney cells (Vero cells) with ribavirin (RBV) as a conference drug using viral cytopathogenic effect (CPE) assay.Overall, Thirty-four aimed derivatives were prepared respectively with commercially available matrine as the starting material via ring-opening reaction, 12-Nprotection via N-tert-butoxycarbonyl (Boc), ester reduction by LiAlH4,selective oxidization, aldehyde-amine condensation, reduction with NaBH3CN, etherization and some other chemical reactions.The final products were purified by flash column chromatography on silica gel with dichloromethane and methanol as the eluents. The antiviral activity of each compound was evaluated with its IC50 as well as selectivity index (SI) value.The new SAR analysis had been proposed from the results of IC50 and selectivity index (SI) value. It revalidates that the strong electron-withdrawing feature located on the phenyl ring is pretty important for the potency against CVB3, and discovered that the PKa value of C11-side chain can also affect the inhibitor potency against CVB3. matrinic amide derivatives 21c-d and 21j and matriane derivatives ks-dw-1,ks-dw-3 exerted the promising effect against CVB3 and then they have been chosen for the next investigation. The SAR results provided the useful information for further strategical optimization and development into a novel of class of anti-enterovirus candidates against CVB3.