Design and synthesis of benzothiazole-sulfonate conjugates targeting influenza A (H1N1) and human coronavirus HCoV-229E: in silico and in vitro assessments

Abstract

A novel series of eighteen benzothiazole-sulfonate conjugates, comprising benzothiazolylphenyl-alkanesulfonates (3a-i) and benzothiazolyl acetohydrazide phenyl sulfonates (7a-i), was synthesized and evaluated for dual antiviral efficacy against Influenza A (H1N1) and human coronavirus (HCoV-229E). Biological assessment via dose-response assays identified several leads with potent inhibitory activity and high safety profiles. Against H1N1, compound 3g emerged as the most selective, yielding a Selectivity Index (SI) value of 20.2, whereas the highest viral replication inhibition% was seen in compound 3i. In HCoV-229E assays, derivative 7a demonstrated superior performance with SI value > 20, and compound 7b showed the highest percentage of inhibition of viral replication. In silico absorption, distribution, metabolism, and excretion (ADME) profiling confirmed that the most active conjugates adhere to drug-likeness parameters, exhibiting favorable absorption and distribution properties. Molecular docking simulations within the H1N1 RNA-dependent RNA polymerase (RdRp) subunits and the HCoV-229E main protease (M-pro) elucidated the molecular basis for these activities, showing strong binding affinities and key hydrogen bonding interactions with essential catalytic residues. These findings position the benzothiazole-sulfonate scaffold as a promising template for the development of broad-spectrum antiviral agents.