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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.
Dipartimento di Chimica e Tecnologie del Farmaco, Universita ̀ degli Studi di Roma “ La Sapienza ” , P.le A. Moro 5, 00185 Roma, Italy.
Dipartimento di Chimica e Tecnologie del Farmaco, Universita ̀ degli Studi di Roma “ La Sapienza ” , P.le A. Moro 5, 00185 Roma, Italy.
Volgograd State Technical University, pr. Lenina, 28, 400131 Volgograd, Russia.
Volgograd State Technical University, pr. Lenina, 28, 400131 Volgograd, Russia.
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2014 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, no 12, 5212-25 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2014. Vol. 57, no 12, 5212-25 p.
Keyword [en]
HIV-1; DABO; COMBINEr; 3D QSAR; Structure Based Drug Design; in vitro Assays
National Category
Medicinal Chemistry Biological Sciences Chemical Sciences Computer and Information Science
Identifiers
URN: urn:nbn:se:uu:diva-321301DOI: 10.1021/jm500284xPubMedID: 24933420OAI: oai:DiVA.org:uu-321301DiVA: diva2:1095244
Available from: 2017-05-12 Created: 2017-05-12 Last updated: 2017-05-12

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