Design, Synthesis, and Antiviral Activity of 8‑Aza Fluoroneplanocin Derivatives Targeting SAH Hydrolase and Viral RdRp.

RNA viruses such as SARS-CoV-2 and dengue virus pose global health threats, highlighting the urgent need for broad-spectrum antivirals with improved safety. We synthesized 8-aza Fluoroneplanocin derivatives designed to reduce cytotoxicity while maintaining antiviral potency. Among them, compound 3a, bearing an 8-aza adenine base, exhibited its potential broad-spectrum activity against SARS-CoV-2 (EC50 = 12.2 μM) and dengue virus (E50 = 37.4 μM), with no detectable cytotoxicity (CC50 > 100 μM). Mechanistic studies showed that 3a moderately inhibited S-adenosylhomocysteine (SAH) hydrolase (IC50 = 1.51 μM), in contrast to the potent inhibition by Fluoroneplanocin A (1, IC50 = 0.15 μM), indicating that weaker SAH hydrolase inhibition contributes to reduced toxicity. Docking against SARS-CoV-2 RdRp revealed that 3a formed an additional hydrogen bond with Arg555, supporting RdRp binding as a complementary mechanism. Collectively, these results demonstrate the dual-targeting potential of 8-aza Fluoroneplanocins, offering a promising scaffold for the development of safe and effective broad-spectrum nucleoside antivirals.