title: Design, synthesis, biological evaluation, and molecular modeling studies of TIBO-like cyclic sulfones as non-nucleoside HIV-1 reverse transcriptase inhibitors.
abstract: TIBO- and TBO-like sulfone derivatives 1 and 2 were designed, synthesized, and tested for their ability to block the replication cycle of HIV-1 in infected cells. The anti-HIV-1 activities of sulfones 3, which were intermediates in the syntheses of 1 and 2, were also evaluated. Surprisingly, the sulfone analogues of TIBO R82913 (compounds 1) were inactive, whereas interesting results were obtained for truncated derivatives 2. Compound 2 w was the most potent among this series in cell-based assays (EC50=0.07 microM, CC50>200 microM, SI>2857). It was twofold less potent than R82913, but more selective. An X-ray crystallographic analysis was carried out to establish the absolute configuration of 2 w and its enantiomer 2 x, which were obtained by semipreparative HPLC of 2 v, one of the most potent racemates. Compounds 1-3 were proven to target HIV-1 RT. In fact, representative derivatives inhibited recombinant HIV-1 RT in vitro at concentrations similar to those active in cell-based assays. 3D QSAR studies and docking simulations were developed on TIBO- and TBO-like sulfone derivatives to rationalize their anti-HIV-1 potencies and to predict the activity of novel untested sulfone derivatives. Predictive 3D QSAR models were obtained with a receptor-based alignment by docking of TIBO- and TBO-like derivatives into the NNBS of RT.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Università degli Studi di Roma La Sapienza, P. le A. Moro 5, 00185 Roma, Italy. roberto.disanto@uniroma1.it
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Santo
authors.forename: Roberta
authors.initials: R
authors.lastname: Costi
authors.forename: Marino
authors.initials: M
authors.lastname: Artico
authors.forename: Rino
authors.initials: R
authors.lastname: Ragno
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Enrico
authors.initials: E
authors.lastname: Gavuzzo
authors.forename: Francesco
authors.initials: F
authors.lastname: La Torre
authors.forename: Roberto
authors.initials: R
authors.lastname: Cirilli
authors.forename: Reynel
authors.initials: R
authors.lastname: Cancio
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
mesh_terms: D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013450:Sulfones / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D018894:Reverse Transcriptase Inhibitors; D013450:Sulfones; D054303:HIV Reverse Transcriptase