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 correspondig 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.