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

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, ¹ H NMR spectroscopy and X-ray diffractions. Biological evaluations revealed that these compounds exhibited potent antiviral activity against Zika virus (ZIKV), with EC ₅₀ 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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Arthur Kummerle reports financial support was provided by Carlos Chagas Filho Foundation for Research Support of Rio de Janeiro State. Henrique Jefferson de Arruda and Larissa Almeida Ferreira reports financial support was provided by Coordination of Higher Education Personnel Improvement. Arthur Kummerle reports financial support was provided by National Council for Scientific and Technological Development. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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