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

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

Data de publicació online: 15/12/2020 Data de publicació en paper: 15 Desembre 2020 Revista: European Journal of Medicinal Chemistry

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.

Autors: Nalli M, Armijos Rivera JI, Masci D, Coluccia A, Badia R, Riveira-Muñoz E, Brambilla A, Cinquina E, Turriziani O, Falasca F, Catalano M, Limatola C, Esté JA, Maga G, Silvestri R, Crespan E, La Regina G

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