Discovery and SAR Exploration of Novel Nanomolar 3,4-dihydroquinazolin-2(1H)-one Non-Nucleoside Reverse Transcriptase Inhibitors

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 NNRTIs. Several compounds exhibit nanomolar antiviral activity against WT 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.