Scaffold hopping: exploration of acetanilide-containing uracil analogues as potential NNRTIs

Bioorg Med Chem. 2015 Mar 1;23(5):1069-81. doi: 10.1016/j.bmc.2015.01.002.

Denis A Babkov ¹, Vladimir T Valuev-Elliston ², Maria P Paramonova ¹, Alexander A Ozerov ¹, Alexander V Ivanov ², Alexander O Chizhov ³, Anastasia L Khandazhinskaya ², Sergey N Kochetkov ², Jan Balzarini ⁴, Dirk Daelemans ⁴, Christophe Pannecouque ⁴, Katherine L Seley-Radtke ⁵, Mikhail S Novikov ¹

Affiliations

1 Department of Pharmaceutical & Toxicological Chemistry, Volgograd State Medical University, Pavshikh Bortsov Sq., 1, Volgograd 400131, Russia.
2 Engelhardt Institute of Molecular Biology, Russian Academy of Science, Vavilov Str., 32, Moscow 119991, Russia.
3 Zelinsky Institute of Organic Chemistry, Russian Academy of Science, Leninsky pr., 47, Moscow 119991, Russia.
4 Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, Leuven B-3000, Belgium.
5 Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA.

PMID: 25638501 DOI: 10.1016/j.bmc.2015.01.002

Abstract

In order to identify novel nonnucleoside inhibitors of HIV-1 Reverse Transcriptase two series of amide-containing uracil derivatives were designed as hybrids of two scaffolds of previously reported inhibitors. Subsequent biological evaluation confirmed acetamide uracil derivatives 15a-k as selective micromolar NNRTIs with a first generation-like resistance profile. Molecular modeling of the most active compounds 15c and 15i was employed to provide insight on their inhibitory properties and direct future design efforts.

Keywords

Amide; HIV; Inhibitors; NNRTIs; Nonnucleoside reverse transcriptase; Uracil.

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