An expansion of the structure–activity relationship study of CXCR4 antagonists led to the synthesis of a series of isoquinolines, bearing a tetrahydroquinoline or a 3-methylpyridinyl moiety as head group. All compounds were investigated for CXCR4 affinity and antagonism in competition binding and calcium mobilization assays, respectively. In addition, the anti-HIV activity of all analogues was determined. All compounds showed excellent activity, with compound 24c being the most promising one, since it displayed consistently low nanomolar activity in the various assays.

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.