New indolylarylsulfones as highly potent and broad spectrum HIV-1 non-nucleoside reverse transcriptase inhibitors.
New indolylarylsulfone HIV-1 NNRTIs were synthesized to evaluate unexplored substitutions of the benzyl/phenylethyl group linked at the indole-2-carboxamide. Against the NL4-3 HIV-1 WT strain, 17 out 20 compounds were superior to NVP and EFV. Several compounds inhibited the K103N HIV-1 mutant strain at nanomolar concentration and were superior to EFV. Some derivatives were superior to EFV against the Y181C and L100I HIV-1 mutant strains. Against the NL4-3 HIV-1 strain, the enantiomers 24 and 25 showed small differences of activity. In contrast, 24 turned out significantly more potent than 25 against the whole panel of mutant HIV-1 strains. The docking studies suggested that the difference in the observed inhibitory activities of 24 and 25 against the K03N mutation could be due to a kinetic rather than affinity differences.
Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
Valeria
V
Famiglini
Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy. Electronic address: giuseppe.laregina@uniroma1.it.
Giuseppe
G
La Regina
Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
Antonio
A
Coluccia
Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
Sveva
S
Pelliccia
Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
Andrea
A
Brancale
Institute of Molecular Genetics IGM-CNR, National Research Council, via Abbiategrasso 207, I-27100 Pavia, Italy.
Giovanni
G
Maga
Institute of Molecular Genetics IGM-CNR, National Research Council, via Abbiategrasso 207, I-27100 Pavia, Italy.
Emmanuele
E
Crespan
AIDS Research Institute - IrsiCaixa, Hospitals Germans Trias i Pujol, Universitat Autonóma de Barcelona, 08916 Badalona, Spain.
Roger
R
Badia
AIDS Research Institute - IrsiCaixa, Hospitals Germans Trias i Pujol, Universitat Autonóma de Barcelona, 08916 Badalona, Spain.
Bonaventura
B
Clotet
AIDS Research Institute - IrsiCaixa, Hospitals Germans Trias i Pujol, Universitat Autonóma de Barcelona, 08916 Badalona, Spain.
José A
JA
Esté
Istituto Superiore di Sanità, Dipartimento del Farmaco, Viale Regina Elena 299, I-00161 Roma, Italy.
Roberto
R
Cirilli
Dipartimento di Farmacia, Università di Napoli Federico II, Via Domenico Montesano 49, I-80131, Napoli, Italy.
Ettore
E
Novellino
Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy. Electronic address: romano.silvestri@icloud.com.
Romano
R
Silvestri
D002460:Cell Line; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011487:Protein Conformation; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D007211:Indoles; D018894:Reverse Transcriptase Inhibitors; D013450:Sulfones; C030374:indole; D054303:HIV Reverse Transcriptase
AIDS; HIV-1; Indolylarylsulfone; Nonnucleoside inhibitor; Reverse transcriptase