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

Year: 2025

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide 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 (EC 50 = 12.2 μM) and dengue virus (E 50 = 37.4 μM), with no detectable cytotoxicity (CC 50 > 100 μM). Mechanistic studies showed that 3a moderately inhibited S-adenosylhomocysteine (SAH) hydrolase (IC 50 = 1.51 μM), in contrast to the potent inhibition by Fluoroneplanocin A ( 1, IC 50 = 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.

Source: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.5c00463