Indolylarylsulfones as HIV-1 non-nucleoside reverse transcriptase inhibitors: new cyclic substituents at indole-2-carboxamide

  • J Med Chem. 2011 Mar 24;54(6):1587-98. doi: 10.1021/jm101614j.
Giuseppe La Regina  1 ,  Antonio Coluccia ,  Andrea Brancale ,  Francesco Piscitelli ,  Valerio Gatti ,  Giovanni Maga ,  Alberta Samuele ,  Christophe Pannecouque ,  Dominique Schols ,  Jan Balzarini ,  Ettore Novellino ,  Romano Silvestri
Affiliations
  • 1. Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
PMID: 21366296 DOI: 10.1021/jm101614j
Abstract

New indolylarylsulfone derivatives bearing cyclic substituents at indole-2-carboxamide linked through a methylene/ethylene spacer were potent inhibitors of the WT HIV-1 replication in CEM and PBMC cells with inhibitory concentrations in the low nanomolar range. Against the mutant L100I and K103N RT HIV-1 strains in MT-4 cells, compounds 20, 24-26, 36, and 40 showed Antiviral potency superior to that of NVP and EFV. Against these mutant strains, derivatives 20, 24-26, and 40 were equipotent to ETV. Molecular docking experiments on this novel series of IAS analogues have also suggested that the H-bond interaction between the nitrogen atom in the carboxamide chain of IAS and Glu138:B is important in the binding of these compounds. These results are in accordance with the experimental data obtained on the WT and on the mutant HIV-1 strains tested.