Recent developments of pyrimidine appended HIV-1 non-nucleoside reverse transcriptase inhibitors

Acquired Immune Deficiency Syndrome (AIDS) is an ailment that progressively weakens the immune system and is responsible for being the sole cause of 630,000 deaths worldwide in 2023. It is a potentially fatal condition that promotes the growth of malignancies and secondary infection. Viruses like Human Immunodeficiency Virus (HIV-1) and Hepatitis B virus (HBV) employ an enzyme, reverse transcriptase (RT), to replicate their genomes and spread across the host genome. RT has proved to be one of the most important therapeutic targets for the treatment of AIDS as well as for the development of new HIV-1 medications. The pyrimidine nucleus has been described as a dynamic cornerstone in developing new anti-HIV-1 medications and represents a familiar motif found in various marketed anti-HIV-1 drugs, such as diaryl pyrimidines (DAPYs). The rapid emergence of drug-resistant viral strains due to mutations in the HIV-1 RT structure along with their unfavourable pharmacokinetics present new challenges. Recent years have witnessed tremendous progress in the design and discovery of new substituted pyrimidines as potent and selective non-nucleoside reverse transcriptase inhibitors (NNRTIs). Further, the current developments in the field of X-ray crystallography and molecular modeling have remarkably augmented the design strategies, with simultaneous improvement in the resistance profiles. This article comprehensively reviews recent trends in the design and development of pyrimidine-based HIV-1 NNRTIs. The study emphasizes their biological activities, structure-activity relationship, and docking studies to guide the rational design of NNRTIs with desired potency, safety, and efficacy.