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

Ouhtit, Aicha (2012) Synthesis and anti-retroviral activity of novel 1,2-benzisothiazol-3(2H)-one benzenesulfonamides targeting the HIV nucleocapsid protein 7. [Doctoral Thesis]

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Abstract

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.

Item Type:Doctoral Thesis
Date:29 March 2012
Tutor:La Colla, Paolo
PhD classes:Ciclo 24 > Sviluppo e sperimentazione dei farmaci antivirali
Coordinator:Pani, Alessandra
Institution:Universita' degli Studi di Cagliari
Divisions:Dipartimenti (fino a dicembre 2011) > Dipartimento di Scienze biomediche e biotecnologie
Subjects:Area 05 - Scienze biologiche > BIO/19 Microbiologia generale
Uncontrolled Keywords:Virus di HIV, sintesi, benzisothiazolo, HIV virus, synthesis, benzisothiazol
ID Code:762
Deposited On:30 Mar 2012 12:45

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