title: Thiocarbamates as non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 1: Parallel synthesis, molecular modelling and structure-activity relationship studies on O-[2-(hetero)arylethyl]-N-phenylthiocarbamates.
abstract: In order to expand the structure-activity relationship (SAR) studies on Thiocarbamates (TCs), a recently discovered class of potent non-nucleoside HIV-1 reverse transcriptase inhibitors, 38 analogues of the lead O-[2-(2-pyridyl)ethyl]-N-phenylthiocarbamate 1 were prepared by parallel solution-phase synthesis. The SAR strategy was focused on the variation (mono- and disubstitution) of the N-phenyl ring and the replacement of the 2-pyridyl with 4-pyridyl, 2-thienyl and phenyl rings. The majority of the new TCs proved to prevent the wild-type HIV-1 multiplication in MT-4 cell culture and the most potent congeners displayed an EC(50) value of 100 nM. Two TCs were active also at micromolar concentrations against the Y181C- and/or K103N/Y181C-resistant mutants. Docking simulations helped to rationalize the SARs.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Genova, Viale Benedetto XV 3, I-16132 Genova, Italy. sara.cesarini@unige.it
authors.forename: Sara
authors.initials: S
authors.lastname: Cesarini
authors.forename: Andrea
authors.initials: A
authors.lastname: Spallarossa
authors.forename: Angelo
authors.initials: A
authors.lastname: Ranise
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.forename: Paolo
authors.initials: P
authors.lastname: La Colla
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Sanna
authors.forename: Gabriella
authors.initials: G
authors.lastname: Collu
authors.forename: Roberta
authors.initials: R
authors.lastname: Loddo
mesh_terms: D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D009705:Nucleosides / Q000737:chemistry; D012194:RNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D013859:Thiocarbamates; D012194:RNA-Directed DNA Polymerase