1,2-Benzothiazine Derivatives as Anti-HIV and Anti-HCV Agents: Structure–Activity Relationships and Research Perspectives
TL;DR
Despite showing antiviral activity against both HIV and HCV, all tested compounds, including the most active derivatives, were considerably less potent than the corresponding reference drugs.
Abstract
1,2-Benzothiazine derivatives have attracted attention as structurally versatile scaffolds for antiviral drug discovery. Their sulfur-containing heterocyclic core supports diverse substitution patterns, allowing modulation of physicochemical properties and biological activity through medicinal chemistry optimization. This review summarizes published studies on 1,2-benzothiazine-based derivatives as potential inhibitors of human immunodeficiency virus (HIV) and hepatitis C virus (HCV), with particular emphasis on structure–activity relationships (SAR). Comprehensive SAR analyses indicate that substitutions at the N-1 and C-3 positions play a pivotal role in modulating antiviral potency and selectivity. Among the reported compounds, the most selective anti-HIV agent was a pyrazole-substituted 1,2-benzothiazine (9h) bearing a 2-amino-4-methylthiazolehydrazidoacetyl moiety, which exhibited an EC50 value of 3.8 μM against HIV-1 in primary human peripheral blood mononuclear cells. For HCV, the most promising derivative was a pyrazolebenzothiazine (5b) containing a 4-chloro substituent in the N-1 phenyl ring and a p-methanesulfonamidophenyl group at the C-3 position, demonstrating an IC50 value of 7.9 μM in the NS5B polymerase assay. Despite showing antiviral activity against both HIV and HCV, all tested compounds, including the most active derivatives, were considerably less potent than the corresponding reference drugs. Further optimization is therefore needed to improve their antiviral potency.