Design,Synthesis And Biological Activity Of IPAPYs Hybrids A Reverse Transcriptase Inhibitors

Reverse transcriptase?RT?plays a critical role during the replication cycle of HIV-1,which has been viewed as one of the most successful targets for the development of anti-HIV treatment.Numerous studies have shown that compounds with pyrimidine ring skeleton exhibit extensive and great biological activities,among which many pyrimidine derivatives show potent anti-HIV-1 activity.Based on the structure-activity relationship and their research progress of diarylpyrimidines?DAPYs?and new pyrimidine reverse transcriptase inhibitors,we designed and synthesized a series of novel IPAPYs by hybridizing the molecular structure of diarylether compounds.And the molecular docking studies validated the rationality of the design.The target compounds were prepared through a synthetic route as follows:9a-q were obtained via a nucleophilic substitution reaction of 4 and 8a-q in potassium carbonate/tetrahydrofuran system.9a-q were subjected to a simple deprotection to afford the compounds XT1a-q under the action of trifluoroacetic acid.The intermediate 4 was obtained by a three-step reaction of 1H-Indazole-3-carboxylic acid as a starting material.And the intermediate 7a-q were prepared by2,4-dichloropyrimidine reacted with various phenol and followed by reaction with4-amino-1-tertbutoxycarbonyl-piperidine.Later,7a-q were experienced a deprotection reaction to give 8a-q in the presence of trifluoroacetic acid and dichloromethane.Finally,all target compounds were comfirmed by ¹H NMR,¹³C NMR and HR-MS.In this paper,all target molecules also were docked into the NNIBP of 3NBP based on molecular docking.The results showed that all compounds have good anti-HIV-1 activity,and XT1q owned the highest docking score.This class of compounds have been sent to the Rega Institute of Belgium for testing their biological activity.