Synthesis, biological evaluation, and binding mode of novel 1-[2-(diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles targeted at the HIV-1 reverse transcriptase.
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.
Silvestri
Romano
R
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.
Artico
Marino
M
De Martino
Gabriella
G
Ragno
Rino
R
Massa
Silvio
S
Loddo
Roberta
R
Murgioni
Chiara
C
Loi
Anna Giulia
AG
La Colla
Paolo
P
Pani
Alessandra
A
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
D007093:Imidazoles; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase