title: Design, synthesis, SAR, and molecular modeling studies of acylthiocarbamates: a novel series of potent non-nucleoside HIV-1 reverse transcriptase inhibitors structurally related to phenethylthiazolylthiourea derivatives.
abstract: A novel series of potent, selective HIV-1 N-acylthiocarbamate (ATC) nonnucleoside reverse transcriptase inhibitors (NNRTIs) is described. The title compounds were synthesized through a highly convergent, one-pot procedure. In cell-based assays, the lead compound (17c) prevented the HIV-1 multiplication with an EC(50) of 8 microM. The lead optimization strategy was developed by single or multiple modifications of the three molecular portions, in which 17c was notionally divided. Molecular modeling studies led to the synthesis of O-(2-phthalimidoethyl)-N-(p-substituted phenyl)-N-acylthiocarbamates, which showed in vitro activities against HIV-1 in the low nanomolar range. Nevertheless, the title compounds retained low potency against HIV-1 strains carrying mutations (K103R, Y181C, and K103N/Y181C) responsible for NNRTI resistance. The hypothetical docking model of RT/17c and RT/25c, derived from X-ray crystallographic structure of a PETT derivative in complex with HIV-1 RT, revealed that the model structures of ATCs do not approximate the NNRTI butterfly-like conformation. Analysis of these hypotetical complexes helps to rationalize some SARs and resistance data.
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: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Olga
authors.initials: O
authors.lastname: Bruno
authors.forename: Francesco
authors.initials: F
authors.lastname: Bondavalli
authors.forename: Laura
authors.initials: L
authors.lastname: Vargiu
authors.forename: Tiziana
authors.initials: T
authors.lastname: Marceddu
authors.forename: Massimo
authors.initials: M
authors.lastname: Mura
authors.forename: Paolo
authors.initials: P
authors.lastname: La Colla
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pani
mesh_terms: D002460:Cell Line; D017076:Computer-Aided Design; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D021281:Quantitative Structure-Activity Relationship; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry*; D013859:Thiocarbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013890:Thiourea / Q000737:chemistry*; D014779:Virus Replication
chemical_list: D008024:Ligands; D018894:Reverse Transcriptase Inhibitors; D013844:Thiazoles; D013859:Thiocarbamates; D054303:HIV Reverse Transcriptase; D013890:Thiourea