Design, synthesis and evaluation of arylpurine-based sinefungin mimetics as zika virus methyltransferase inhibitors

Arylpurine derivatives were designed and synthesized to mimic sinefungin by targeting the SAM/SAH binding site of zika virus (ZIKV) methyltransferase (MTase). These compounds incorporate adenine or 6-methyl-7-deazapurine bases, while the ribose of sinefungin has been replaced by an aniline, linked to its amino acid chain via a CO or a CH₂ unit. Compounds 18, 29 and 31 inhibited ZIKV 2'-O-MTase activity. Docking studies showed that compounds 18 and 29 interact with both the purine and amino acid binding sites, effectively mimicking sinefungin. In contrast, compound 31 has its amino acid chain positioned above the ribose binding site. Notably, compound 18 exhibited modest antiviral activity against ZIKV.