We designed and synthesized 21 new indolylarylsulfones (IASs) as new HIV-1 NNRTIs. Among these, IAS 12 exhibited a remarkable antiviral activity against single and double mutants (K103N EC50 = <0.7 nM; Y181C EC50 = <0.7 nM; Y188L EC50 = 21.3 nM; K103N–Y181C EC50 = 6.2 nM), resulting equally or more active than previuosly reported IAS 6 and some approved anti-HIV-1 drugs. Docking and molecular dynamics simulations of compound 12 in complex with WT, Y181C, Y188L, K103N and K103N–Y181C RTs clarified a general binding mode that was consistent with biological results. Kinetic experiments disclosed that derivative 12 preferentially binds WT and K103N–Y181C RTs to binary and ternary complexes, respectively.

New indolylarylsulfone non-nucleoside reverse transcriptase inhibitors show low nanomolar inhibition of single and double HIV-1 mutant strains / Nalli, M.; Armijos Rivera, J. I.; Masci, D.; Coluccia, A.; Badia, R.; Riveira-Muñoz, E.; Brambilla, A.; Cinquina, E.; Turriziani, O.; Falasca, F.; Catalano, M.; Limatola, C.; Esté, J. A.; Maga, G.; Silvestri, R.; Crespan, E.; La Regina, G.. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 208:(2020). [10.1016/j.ejmech.2020.112696]

New indolylarylsulfone non-nucleoside reverse transcriptase inhibitors show low nanomolar inhibition of single and double HIV-1 mutant strains

Nalli, M.;Masci, D.;Coluccia, A.;Cinquina, E.;Turriziani, O.;Falasca, F.;Catalano, M.;Limatola, C.;Silvestri, R.
;
La Regina, G.
2020

Abstract

We designed and synthesized 21 new indolylarylsulfones (IASs) as new HIV-1 NNRTIs. Among these, IAS 12 exhibited a remarkable antiviral activity against single and double mutants (K103N EC50 = <0.7 nM; Y181C EC50 = <0.7 nM; Y188L EC50 = 21.3 nM; K103N–Y181C EC50 = 6.2 nM), resulting equally or more active than previuosly reported IAS 6 and some approved anti-HIV-1 drugs. Docking and molecular dynamics simulations of compound 12 in complex with WT, Y181C, Y188L, K103N and K103N–Y181C RTs clarified a general binding mode that was consistent with biological results. Kinetic experiments disclosed that derivative 12 preferentially binds WT and K103N–Y181C RTs to binary and ternary complexes, respectively.
2020
AIDS; HIV-1; reverse transcriptase; non-nucleoside reverse transcriptase inhibitor; indolylarylsulfone
01 Pubblicazione su rivista::01a Articolo in rivista
New indolylarylsulfone non-nucleoside reverse transcriptase inhibitors show low nanomolar inhibition of single and double HIV-1 mutant strains / Nalli, M.; Armijos Rivera, J. I.; Masci, D.; Coluccia, A.; Badia, R.; Riveira-Muñoz, E.; Brambilla, A.; Cinquina, E.; Turriziani, O.; Falasca, F.; Catalano, M.; Limatola, C.; Esté, J. A.; Maga, G.; Silvestri, R.; Crespan, E.; La Regina, G.. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 208:(2020). [10.1016/j.ejmech.2020.112696]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1436323
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