Coumarin-imidazopyridine hybrids and their first-in-class ZnII metal complexes as potent dual entry and replication inhibitors of Zika viral infection

[Display omitted] •Discovery of first-in-class ZnII metal complexes as potent inhibitors of Zika viral infection.•Dual entry and replication inhibition Mode of Action.•High potency and selectivity in Vero cells. In this study, we synthesized and characterized a series of coumarin-imidazopyridine hybrid ligands (HL1-HL4) and their corresponding Zn(II) complexes (C1-C4). The ligands were synthesized via a two-step process in 56–90 % yields. The resulting ligands, were utilized to form Zn(II) complexes, characterized by conductivity measurements, HRMS, IR, 1H NMR spectroscopy and X-ray diffractions. Biological evaluations revealed that these compounds exhibited potent antiviral activity against Zika virus (ZIKV), with EC50 values ranging from 0.55 to 4.8 µM and SI of up to 1490. Notably, the complexes (the first-in-class Zn(II) anti-ZIKV complexes) generally displayed enhanced activity compared to their respective ligands, with some compounds outperforming the reference antiviral, ribavirin. The Time of Addition assay suggested that while some compounds interfere with both viral entry (with a virucidal component) and replication phases, other only acted in replication phases. These results together with molecular modeling studies on ZIKV Envelope protein and ZIKV NS2B-NS3 offered insights for their mode of actions and further optimizations.