HIV nucleocapsid proteins as targets for novel 1,2-benzisothiazol-3(2H)-one benzenesulfonamides: Synthesis and antiretroviral activity

Roberta Loddo¹Matteo Incerti²Elda Favari²Valeria Manca¹Marta Cogoni¹Rebecca Piras¹Vanessa Palmas¹Elena Tamburini¹Paolo La Colla¹Giuseppina Sanna^1*

• ¹Department of Biomedical Sciences, Faculty of Medicine and Surgery, University of Cagliari, Cagliari, Italy
• ²Universita degli Studi di Parma Dipartimento di Scienze degli Alimenti e del Farmaco, Parma, Italy

A new class of 1,2-benzisothiazol-3(2H)-one benzenesulfonamides has been synthesised. In cell-based assays, the lead compound 6 inhibits the replication of HIV-1, HIV-2, and HIV-1 variants carrying clinically relevant mutations against non-nucleoside, nucleoside, and protease inhibitors. In enzyme assays, 6 does not inhibit HIV-1 reverse transcriptase and integrase. Genome sequencing of HIV-1 mutants selected for resistance to 6 reveals no mutations in the pol or env genes. Instead, two mutations are mapped in the gag region, which encodes NC proteins involved in early and late key processes of retrovirus replication, suggesting that NC proteins are the target of the title compounds. 6 shows concentration-dependent virucidal activity against cell-free HIV-1 and HIV-2. Benzisothiazol-3(2H)-one benzenesulfonamides are a new class of antiretroviral agents with an intriguing spectrum and mode of action.