HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs of highly active antiretroviral therapy (HAART) in the clinical management of AIDS/HIV-1 infection. Our recent studies showed that indolylarylsulfones (IASs) bearing a cyclic moiety at the 2-carboxamide nitrogen linked through a short spacer group were endowed with potent antiretroviral activity. Based on the results previously obtained, we aimed to expand the SAR studies by the introduction of new aryl or heteroaryl portions to the indole nucleus. Interestingly, for the first time IASs endowed with asymmetric centre have shown significant differences in term of antiretroviral potency. In particular, the R-enantiomer proved to be exceptionally potent and uniformly superior to the S-enantiomer against the whole viral panel. Docking studies showed that the methyl group of the R-enantiomer (Figure 1) pointed toward the cleft created by the K103N mutation, differently from the corresponding group of (S) counterpart. By calculating the solvent accessible surface, we observed that the exposed area of the RT in complex with S-enantiomer was larger than the area of the (R) complex.

Masci, D., La Regina, G., Famiglini, V., Coluccia, A., Brancale, A., José A., E., Silvestri, R., Drug design and synthesis of new indolylarylsulfones as HIV-1 non-nucleoside reverse transcriptase inhibitors, Poster, in Programma del XXVI Congresso Nazionale della Società Chimica Italiana, (Paestum, 10-14 September 2017), XXVI Congresso Nazionale della Società Chimica Italiana, Paestum 2017: Comunicazione poster FAR PO12-Comunicazione poster FAR PO12 [http://hdl.handle.net/10807/195413]

Drug design and synthesis of new indolylarylsulfones as HIV-1 non-nucleoside reverse transcriptase inhibitors

Masci, Domiziana
;
La Regina, Giuseppe;
2017

Abstract

HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs of highly active antiretroviral therapy (HAART) in the clinical management of AIDS/HIV-1 infection. Our recent studies showed that indolylarylsulfones (IASs) bearing a cyclic moiety at the 2-carboxamide nitrogen linked through a short spacer group were endowed with potent antiretroviral activity. Based on the results previously obtained, we aimed to expand the SAR studies by the introduction of new aryl or heteroaryl portions to the indole nucleus. Interestingly, for the first time IASs endowed with asymmetric centre have shown significant differences in term of antiretroviral potency. In particular, the R-enantiomer proved to be exceptionally potent and uniformly superior to the S-enantiomer against the whole viral panel. Docking studies showed that the methyl group of the R-enantiomer (Figure 1) pointed toward the cleft created by the K103N mutation, differently from the corresponding group of (S) counterpart. By calculating the solvent accessible surface, we observed that the exposed area of the RT in complex with S-enantiomer was larger than the area of the (R) complex.
Inglese
Programma del XXVI Congresso Nazionale della Società Chimica Italiana
XXVI Congresso Nazionale della Società Chimica Italiana
Paestum
Poster
10-set-2017
14-set-2017
XXVI Congresso Nazionale della Società Chimica Italiana
Masci, D., La Regina, G., Famiglini, V., Coluccia, A., Brancale, A., José A., E., Silvestri, R., Drug design and synthesis of new indolylarylsulfones as HIV-1 non-nucleoside reverse transcriptase inhibitors, Poster, in Programma del XXVI Congresso Nazionale della Società Chimica Italiana, (Paestum, 10-14 September 2017), XXVI Congresso Nazionale della Società Chimica Italiana, Paestum 2017: Comunicazione poster FAR PO12-Comunicazione poster FAR PO12 [http://hdl.handle.net/10807/195413]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/195413
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