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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., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Histone deacetylases (HDACs) have proven to be promising targets for the development of anticancer drugs. In this work, we report the design and synthesis of a series of 19 novel hydroxamic acid-based histone deacetylase inhibitors conjugated to benzimidazole and benzoxazole core structures. Five compounds showed anti-proliferative activity with an IC50 value of 2.9–70.9 μM. Compound 7 displayed the highest efficacy against MCF-7 cells and exhibited antiproliferative effects against a panel of cancer cell lines. Compound 7 was the most potent selective inhibitor of HDAC6 and had an IC50 value 8- to >111.1-fold those of HDAC3, HDAC4, HDAC8, and HDAC11, and was a superior HDAC6 inhibitor to belinostat. Its interaction with and inhibitory activity on HDAC enzymes were then explored in a molecular docking study. The obtained data revealed the highest binding affinity (−8.46 kcal mol−1) of compound 7 toward HDAC6, as it formed interactions with the key residues Cys584 and Asp612 within the active site. Furthermore, the HDAC inhibitory activity of compound 7 was demonstrated from the dose-dependent increase in the tubulin acetylation level. Together, our results indicated that compound 7 with a cap of benzimidazole and four carbon-chain-containing thioether linker is a potent anticancer agent for selective HDAC6 inhibition and deserves further investigation. [ABSTRACT FROM AUTHOR]