Pyrimidine-based NNRTIs in HIV therapy: advances in synthesis, potency and structure-activity relationships.

Acquired Immunodeficiency Syndrome (AIDS) caused by human immunodeficiency virus (HIV), as a global health concern, needs to be addressed by the development of new antiretroviral drugs. Pyrimidine is a valued scaffold for the treatment of HIV/AIDS due to its resemblance to the nucleotide base pairs of DNA and RNA. Pyrimidine-based compounds, which have turned out to be the most important compounds with lower cytotoxicity and enhanced antiviral activity, can serve as leads to synthesize new antiretroviral drugs. This review covers the recent advances in the synthesis of pyrimidine-based antiretroviral drugs showing better activity against wild-type and resistant HIV strains, with a key emphasis on their structure-activity relationships. This review aims to assist future research endeavors in designing potent pyrimidine-based non-nucleoside reverse transcriptase inhibitors for resistant HIV strains to overcome the current problems by summarizing compounds reported from 2018 onwards. Based on our analysis, compounds with a pyrimidine core (31, 52c, 56c, 66a, 72b, 82a, 85a, 132b, 185a and 191c) tend to be highly potent against various HIV targets and have the potential to overcome antiviral resistance. This review highlights the significance of this pharmacophoric fragment for developing effective and innovative antiviral drugs.