Advances in the synthesis of diarylpyrimidine as potent non-nucleoside reverse transcriptase inhibitors: biological activities, molecular docking studies and structure-activity relationship: A critical review

Abstract

Acquired immunodeficiency syndrome (AIDS) is an ailment that is caused primarily by the Human immunodeficiency virus (HIV), which is the main agent responsible for this deadly disease. Of all the different inhibitors employed to curtail the menace caused by this deadly virus, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been cutting edge in the fight against AIDS. Over the past few years, the diaryl pyrimidine family and its derivatives have shown promising NNRTI properties attributed to their characteristic flexibility, targeting of conserved residues of reverse transcriptase, positional adaptability and, importantly, the formation of hydrogen bonds, which altogether led to the generation of second-generation NNRTIs. This breakthrough in the DAPY derivatives led to the development of TMC278 (rilpivirine) and TMC125 (etravirine), the two most recently approved NNRTIs by the FDA because of their low cytotoxicity, superior activities against mutant strains and WT HIV-1, excellent potency and high specificity. However, new challenges loom on the DAPY derivatives: the disappointing pharmaco-kinetic properties and accelerated emergence of resistance (particularly, K1013N and Y181C mutations, which are the two most important HIV-1 mutations that persist in most of the FDA-approved regimens), which implores further research to develop novel HIV-1 NNRTIs. In this review, we detail the reported different synthetic pathways for diaryl pyrimidine modification from published articles from 2010 to 2022, their biological activities, in addition to molecular docking studies and structure-activity relationships to uncover the possible molecular contributions that improved or reduced the NNRTIs properties. In a nutshell, the research findings provide valuable insights into the various modifications of the DAPY derivatives to develop novel NNRTIs.