Benzimidazole Derivatives as Novel Zika Virus Inhibitors
Bùi Thị Bửu Huê, Phuong Hong Nguyen, Quang De Tran, Van-Hieu Mai, Eunji Jo, Nguyễn Văn Tuấn, Than Thi Thoa, Lê Đức Anh, Nguyễn Hoàng Sơn, Danh La Duc Thanh, Myrielle Dupont‐Rouzeyrol, Régis Grailhe, Marc P. Windisch
Abstract
Abstract We have synthesized 50 benzimidazole (BMZ) derivatives with 1,2‐phenylenediamines and aromatic aldehydes under mild oxidation conditions by using inexpensive, nontoxic inorganic salt sodium metabisulfite in a one‐pot condensation reaction and screened their ability to interfere with Zika virus (ZIKV) infection utilizing a cell‐based phenotypic assay. Seven BMZs inhibited an African ZIKV strain with a selectivity index (SI=CC 50 /EC 50 ) of 9–37. Structure‐activity relationship analysis demonstrated that substitution at the C‐2, N‐1, and C‐5 positions of the BMZ ring were important for anti‐ZIKV activity. The hybrid structure of BMZ and naphthalene rings was a structural feature responsible for the high anti‐ZIKV activity. Importantly, BMZs inhibited ZIKV in human neural stem cells, a physiologically relevant system considering the severe congenital anomalies, like microcephaly, caused by ZIKV infection. Compound 39 displayed the highest antiviral efficacy against the African ZIKV strain in Huh‐7 (SI>37) and neural stem cells (SI=12). Compound 35 possessed the highest activity in Vero cells (SI=115). Together, our data indicate that BMZs derivatives have to be considered for the development of ZIKV therapeutic interventions.