Zika virus (ZIKV) infection can lead to severe neurological complications such as microcephaly in newborns, yet no specific antiviral drugs are currently available in clinical practice. In this study, screening of an in-house compound library led to the identification of hit compound 5a, featuring a tetrahydrobenzo[b]thiophene scaffold, which exhibited >50% inhibition of ZIKV-induced cytopathic effect (CPE) in Vero cells at 10 μM. Based on 5a, a series of novel derivatives were designed, synthesized, and evaluated for their anti-ZIKV. Four compounds showed >80% inhibition at 10 μM, with EC50 values were 6–20 times lower than that of the positive control ribavirin (RBV). The optimized compound 5v demonstrated potent antiviral activity across multiple cell models (Vero, A549, U251) and against ZIKV strains of different genetic lineages (MR766 and HPF2013). Mechanistic studies revealed that 5v acted as a novel ZIKV entry inhibitor, primarily by blocking the early attachment of viral particles to the cell surface. This work not only establishes tetrahydrobenzo[b]thiophene as a promising anti-ZIKV scaffold but also provides a valuable lead compound for the development of antiviral agents.
PMID: 41997002
