An amazing 30-year journey around the DABO family. A medicinal chemistry lesson on a versatile class of non-nucleoside HIV-1 reverse transcriptase inhibitors

Since the emergence of AIDS, the non-nucleoside HIV-1 RT inhibitors (NNRTIs) have attracted the attention of scientists and clinicians due to their high potency and specificity combined with low toxicity. 3,4-Dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines (DABOs) are a family of NNRTIs described since 1992, and the best members among S-, NH-, and N,N-DABOs showed high anti-HIV-1 potency in both cellular and enzymatic assays. During 30 years of research, the central 4-(3H)-pyrimidinone nucleus has been decorated with 2,6-dihaloaryl or cyclohexyl groups at the methylene at C6, alkyl- or (arylalkyl/aroylalkyl)thio/amino chains at C2, and hydrogen or a small alkyl group at C5. The further introduction of small (i.e., methoxy) groups at the C6 α-benzylic position furnished potency at the sub-nanomolar level against wild-type HIV-1 and at the nanomolar level against HIV-1 mutant strains. Importantly, some compounds of the DABO family exhibited preventative microbicidal activity, valuable in clinical settings where oral adherence rates are low.