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  3. Discovery and SAR exploration of novel nanomolar 3,4-dihydroquinazolin-2(1H)-one non-nucleoside reverse transcriptase inhibitors

Discovery and SAR exploration of novel nanomolar 3,4-dihydroquinazolin-2(1H)-one non-nucleoside reverse transcriptase inhibitors

  • Eur J Med Chem. 2025 May 29:296:117818. doi: 10.1016/j.ejmech.2025.117818.
Eline Goffin 1,  Laurynn Torfs 1,  Fanos Tsingis 1,  David Švestka 1,  Kristien Erven 2,  Kris Uyttersprot 2,  Cindy Heens 2,  Simon Wilms 1,  Jef Rozenski 1,  Eveline Lescrinier 1,  Christophe Pannecouque 2,  Peter Verwilst 3
Affiliations

Affiliations

  • 1 KU Leuven, Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Herestraat 49 - box 1041, 3000, Leuven, Belgium.
  • 2 KU Leuven, Rega Institute for Medical Research, Molecular Genetics and Therapeutics in Virology and Oncology Research Group, Herestraat 49 - box 1048, 3000, Leuven, Belgium.
  • 3 KU Leuven, Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Herestraat 49 - box 1041, 3000, Leuven, Belgium. Electronic address: peter.verwilst@kuleuven.be.
PMID: 40554307 DOI: 10.1016/j.ejmech.2025.117818
Abstract

HIV continues to affect people every day and is still considered a global pandemic. Due to the absence of a cure or a vaccine, patients are subjected to a life-long treatment that is often complicated by Antiviral drug resistance, highlighting the need to develop new therapies. One of the key targets for this Antiviral drug development is Reverse Transcriptase. In this paper, we describe the discovery, synthesis and biological evaluation of a novel chemotype of potent 3,4-dihydroquinazolin-2(1H)-one non-nucleoside Reverse Transcriptase inhibitors (NNRTIs). Several compounds exhibit nanomolar Antiviral activity against wild-type (WT) human immunodeficiency virus-1 (HIV-1) and maintain an excellent activity profile against various clinically relevant mutations. These promising first results provide an exciting foundation for further research into this novel NNRTI scaffold.

Keywords

3,4-dihydroquinazolin-2(1H)-ones; AIDS; HIV-1; Molecular hybridization; Non-nucleoside reverse transcriptase inhibitors.

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