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.