Synthesis and anti-retroviral activity of novel 1,2-benzisothiazol-3(2H)-one benzenesulfonamides targeting the HIV nucleocapsid protein 7


The biological activity of new 1,2-benzisothiazol-3(2H)-one benzenesulfonamides is described. In cell-based assays the lead compound 6 inhibits multiplication, but not entry into target cells, of HIV-1, HIV-2 and HIV-1 variants carrying clinically relevant mutations to non-nucleoside, nucleoside and protease inhibitors. In enzyme assays 6 fails to inhibit HIV-1 reverse transcriptase and integrase. Genome sequencing of HIV-1 mutants selected for resistance to 6 shows no mutations in both pol and env genes. On the contrary, two mutations map in the gag region coding for the nucleocapsid (NC) protein p7 (NCp7), which is involved in early and late key processes of retrovirus multiplication. Overall, the above results suggest that NCp7 is the target of title 1,2-benzisothiazol-3(2H)- one benzenesulfonamides. Interestingly, 6 also shows concentration-dependent virucidal activity against cell-free HIV- 1 and HIV-2. Therefore, title compounds represent a new class of antiretroviral agents with intriguing spectrum and mode of action

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This paper was published in UniCA Eprints.

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