Novel 1-[2-(Diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles as HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors. A Structure−Activity Relationship Investigation
- 27 May 2005
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 48 (13) , 4378-4388
- https://doi.org/10.1021/jm050273a
Abstract
1-[2-(Diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles (DAMNIs) is a novel family of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) active at submicromolar concentration. Replacement of one phenyl ring of 1-[2-(diphenylmethoxy)ethyl]-2-methyl-5-nitroimidazole (4) with heterocyclic rings, such as 2-thienyl or 3-pyridinyl, led to novel DAMNIs with increased activity. In HIV-1 WT cell-based assay the racemic 1-{2-[α-(thiophen-2-yl)phenylmethoxy]ethyl}-2-methyl-5-nitroimidazole (7) (EC50 = 0.03 μM) proved 5 times more active than compound 4. Docking experiments showed that the introduction of a chiral center would not affect the binding of both (R)-7 and (S)-7. The internal scoring function of the Autodock program calculated the same inhibition constant (Ki = 7.9 nM) for the two enantiomers. Compounds 7 (ID50 = 8.25 μM) were found more active than efavirenz (ID50 = 25 μM) against the viral RT carrying the K103N mutation, suggesting for these compounds a potential use in efavirenz based anti-AIDS regimens.Keywords
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