Triazenes as inhibitors of HIV-1 and HCoV-OC43: A structure-activity relationship study

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Triazenes, or amino-substituted diazenes, are organic compounds containing three contiguous nitrogen atoms, that have potent biological activities. We previously demonstrated that triazenes, particularly those substituted with a phenyl or 3-pyridyl ring at the 1-position and a 2-pyridyl ring at the 3-position, exhibit anti-DENV properties. Here, we evaluated the antiviral activity against a betacoronavirus (HCoV-OC43) and a lentivirus (HIV-1). 1-(4-trifluoromethylphenyl)-2-imidazol-1-yldiazene ( 21 ) exhibited broad-spectrum activity (EC 50 = 6.6–6.8 μM) but was cytotoxic to THP-1 cells. Pyridyl triazenes ( 14, 15 ) were the most potent against HCoV-OC43, while 1-(4-methoxyphenyl)-2-morpholin-4-yldiazene ( 6 ) and 1-(4-methoxyphenyl)3-(-6-methylpyridin-2-yl)triazene ( 10 ) inhibited HIV-1 the most. Structure–activity relationship analysis, supported by molecular docking, indicated that para -methoxy groups favored interactions with viral enzyme binding pockets, enhancing antiviral potency, while meta and para -trifluoromethyl groups were associated with reduced activity and increased cytotoxicity. These findings support the further development of triazenes as antiviral scaffolds.

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