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 <b>3a</b>, 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 <b>3a</b> moderately inhibited S-adenosylhomocysteine (SAH) hydrolase (IC₅₀ = 1.51 μM), in contrast to the potent inhibition by Fluoroneplanocin A (<b>1</b>, IC₅₀ = 0.15 μM), indicating that weaker SAH hydrolase inhibition contributes to reduced toxicity. Docking against SARS-CoV-2 RdRp revealed that <b>3a</b> 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.