A previously identified Pictet-Spengler reaction product ZFD-10, derived from indole-2-carbophenylhydrazide scaffold, was shown to inhibit ZIKV replication and infection with anti-NS5 RdRp function. Building on this finding, we conducted systematic structural optimization of the indole-2-carbophenylhydrazide framework. In addition to expanding the library of ZFD-10 analogues bearing 2 '-N-linked six-membered pyridazinone rings, we also synthesized a series of 1 '-N-linked five-membered pyrrolidinone derivatives. Several compounds from both series exhibited potent anti-ZIKV activity and inhibited NS5 enzymatic function, as confirmed across multiple experimental assays. These compounds also markedly reduced expression of the viral E protein. Similar to ZFD10, time-of-addition and time-of-withdrawal assays showed that 16 ab primarily blocks ZIKV infection during the late entry stage and RNA synthesis stage. Collectively, these Pictet-Spengler products as antiviral leads provide a strong foundation for advancing anti-zika drug R&D efforts.