title: Structure-based design, parallel synthesis, structure-activity relationship, and molecular modeling studies of thiocarbamates, new potent non-nucleoside HIV-1 reverse transcriptase inhibitor isosteres of phenethylthiazolylthiourea derivatives.
abstract: In this paper we describe our structure-based ligand design, synthetic strategy, and structure-activity relationship (SAR) studies that led to the identification of thiocarbamates (TCs), a novel class of non-nucleoside reverse transcriptase inhibitors (NNRTIs), isosteres of phenethylthiazolylthiourea (PETT) derivatives. Assuming as a lead compound O-[2-(phthalimido)ethyl]phenylthiocarbamate 12, one of the precursors of the previously described acylthiocarbamates (Ranise, A.; et al. J. Med. Chem. 2003, 46, 768-781), two targeted solution-phase TC libraries were prepared by parallel synthesis. The lead optimization strategy led to para-substituted TCs 31, 33, 34, 39, 40, 41, 44, 45, and 50, which were active against wild-type HIV-1 in MT-4-based assays at nanomolar concentrations (EC50 range: 0.04-0.01 microM). The most potent congener 50 (EC50 = 0.01 microM) bears a methyl group at position 4 of the phthalimide moiety and a nitro group at the para position of the N-phenyl ring. Most of the TCs showed good selectivity indices, since no cytotoxic effect was detected at concentrations as high as 100 microM. TCs 31, 37, 39, 40, and 44 significantly reduced the multiplication of the Y181C mutant, but they were inactive against K103R and K103N + Y181C mutants. Nevertheless, the fold increase in resistance of 41 was not greater than that of efavirenz against the K103R mutant in enzyme assays. The docking model predictions were consistent with in vitro biological assays of the anti-HIV-1 activity of the TCs and related compounds synthesized.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Genova, Viale Benedetto XV 3, I-16132 Genova, Italy. ranise@unige.it
authors.forename: Angelo
authors.initials: A
authors.lastname: Ranise
authors.forename: Andrea
authors.initials: A
authors.lastname: Spallarossa
authors.forename: Sara
authors.initials: S
authors.lastname: Cesarini
authors.forename: Francesco
authors.initials: F
authors.lastname: Bondavalli
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Olga
authors.initials: O
authors.lastname: Bruno
authors.forename: Giulia
authors.initials: G
authors.lastname: Menozzi
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.forename: Luisa
authors.initials: L
authors.lastname: Mosti
authors.forename: Massimiliano
authors.initials: M
authors.lastname: La Colla
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Sanna
authors.forename: Marta
authors.initials: M
authors.lastname: Murreddu
authors.forename: Gabriella
authors.initials: G
authors.lastname: Collu
authors.forename: Bernardetta
authors.initials: B
authors.lastname: Busonera
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Marongiu
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pani
authors.forename: Paolo
authors.initials: P
authors.lastname: La Colla
authors.forename: Roberta
authors.initials: R
authors.lastname: Loddo
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D010668:Phenylthiazolylthiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; 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: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D013859:Thiocarbamates; D010668:Phenylthiazolylthiourea; D054303:HIV Reverse Transcriptase