Antiviral profile of 4-Amino-1H-1,2,3-Triazole-1,2-naphthoquinones as SARS-CoV-2 inhibitors: Synthesis, in vitro and in silico evaluation

• New method to afford 14 novel 4-amino-1 H -1,2,3-triazole-1,2-naphthoquinones. • A docking simulation showed 6a, 6e and 6l as target of the SARS-CoV-2 exonuclease. • Compound 6a as the most potent antiviral (EC 50 = 0.9 μM, CC 50 ≈ 102.8 μM). • Hybrids Amino-triazole-naphthoquinones as a new class of SARS-CoV-2 inhibitors. A series of fourteen compounds, 4-(((1-aryl-1 H -1,2,3-triazol-4-yl)methyl)amino)naphthalene-1,2-dione derivatives ( 6a-n ), were synthesized through a microwave-assisted Huisgen 1,3-dipolar cycloaddition, affording moderate to good yields (34-66%). The molecular structures of the obtained hybrids were designed to combine amino, triazole, and naphthoquinone pharmacophores and were evaluated for their in vitro activity against SARS-CoV-2. Compounds 6a, 6e, and 6l exhibited potent in vitro inhibition of SARS-CoV-2 replication (approximately 80%). Compound 6a showed high antiviral potency (EC 50 = 0.9 μM) and low cytotoxicity (CC 50 = 102.8 μM) relative to Remdesivir. These findings highlight 6a as a promising antiviral candidate for COVID-19 and that hybrid amino-triazole-naphthoquinones represent a novel scaffold for SARS-CoV-2 inhibition, offering a molecular basis for the rational design of a new coronavirus inhibitor.