| 1. |
- Rotili, Dante, et al.
(author)
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2-(Alkyl/aryl)amino-6-benzylpyrimidin-4(3H)-ones as inhibitors of wild-type and mutant HIV-1 : enantioselectivity studies.
- 2012
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:7, s. 3558-62
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Journal article (peer-reviewed)abstract
- The single enantiomers of two pyrimidine-based HIV-1 non-nucleoside reverse transcriptase inhibitors, 1 (MC1501) and 2 (MC2082), were tested in both cellular and enzyme assays. In general, the R forms were more potent than their S counterparts and racemates and (R)-2 was more efficient than (R)-1 and the reference compounds, with some exceptions. Interestingly, (R)-2 displayed a faster binding to K103N RT with respect to WT RT, while (R)-1 showed the opposite behavior.
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| 2. |
- Rotili, Dante, et al.
(author)
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Exploring the role of 2-chloro-6-fluoro substitution in 2-alkylthio-6-benzyl-5-alkylpyrimidin-4(3H)-ones : effects in HIV-1-infected cells and in HIV-1 reverse transcriptase enzymes.
- 2014
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 57:12, s. 5212-25
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Journal article (peer-reviewed)abstract
- A comparison of the effects of the 6-(2-chloro-6-fluorobenzyl)-2-(alkylthio)pyrimidin-4(3H)-ones (2-Cl-6-F-S-DABOs) 7-12 and the related 6-(2,6-difluorobenzyl) counterparts 13-15 in HIV-1 infected cells and in the HIV-1 reverse transcriptase (RT) assays is here described. The new 2-Cl-6-F-S-DABOs showed up to picomolar activity against wt HIV-1. Against clinically relevant HIV-1 mutants and in enzyme assays, the simultaneous C5(methyl)/C6(methyl/ethyl) substitution in the 2-Cl-6-F- and 2,6-F2-benzyl series furnished compounds with the highest, wide-spectrum inhibitory activity against HIV-1. Three representative 2-Cl-6-F-S-DABOs carrying two (9c, 10c) or one (10a) stereogenic centers were resolved into their individual stereoisomers and showed a significant diastereo- and enantioselectivity in HIV-1 inhibition, the highest antiviral activity well correlating with the R absolute configuration to the stereogenic center of the C6-benzylic position in both cellular and enzymatic tests. Application of previously reported COMBINEr protocol on 9c and 10c confirmed the influence of the stereogenic centers on their binding modes in the HIV-1 RT.
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