title: Synthesis, biological evaluation, and binding mode of novel 1-[2-(diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles targeted at the HIV-1 reverse transcriptase.
abstract: A novel series of 1-[2-(diarylmethoxy)ethyl]-2-methyl-5-nitroimidazole (DAMNI) analogues were synthesized and tested in cell-based assays and in enzyme assays against HIV-1 recombinant reverse transcriptase (RT). Preparation of the new derivatives was performed by reacting the appropriate benzhydrols or the corresponding bromides with 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole or the 3-hydroxypropyl homologue. Several compounds showed anti-HIV-1 activity in the submicromolar range. Structure-activity relationship studies suggested that meta substitution at one phenyl ring of the diarylmethane moiety strongly influences the antiviral activity. The 3,5-disubstitution at the same phenyl ring led to less potent derivatives. Molecular modeling and docking studies within the RT non-nucleoside binding site confirmed that DAMNIs, similar to other NNRTIs such as TNK-651 and delavirdine (BHAP U90152), assume a butterfly-like conformation that appears to be halfway between that of classical NNRTIs, such as nevirapine, HEPT, TBZ, TIBO, and DABOs, and the conformation of BHAPs. In particular, the diphenylmethane moiety mimics the wings whereas the 1-(2-methyl-5-nitroimidazolyl)ethane portion resembles the BHAP 5-methanesulfonamidoindole-2-carbonylpiperazine portion.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Università di Roma La Sapienza, BOX 36, Roma 62, P.le Aldo Moro 5, I-00185 Roma, Italy.
authors.forename: Romano
authors.initials: R
authors.lastname: Silvestri
authors.forename: Marino
authors.initials: M
authors.lastname: Artico
authors.forename: Gabriella
authors.initials: G
authors.lastname: De Martino
authors.forename: Rino
authors.initials: R
authors.lastname: Ragno
authors.forename: Silvio
authors.initials: S
authors.lastname: Massa
authors.forename: Roberta
authors.initials: R
authors.lastname: Loddo
authors.forename: Chiara
authors.initials: C
authors.lastname: Murgioni
authors.forename: Anna Giulia
authors.initials: AG
authors.lastname: Loi
authors.forename: Paolo
authors.initials: P
authors.lastname: La Colla
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pani
mesh_terms: D000818:Animals; D002460:Cell Line; D054303:HIV Reverse Transcriptase / Q000737:chemistry*; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014779:Virus Replication
chemical_list: D007093:Imidazoles; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase