Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors: A Combinatorial Approach

Highly active antiretroviral therapy (HAART) is one of the most effective means for fighting against HIV-infection. HAART primarily targets HIV-1 reverse transcriptase (RT), and 14 of 28 compounds approved by the FDA as anti-HIV drugs act on this enzyme. HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) hold a special place among HIV RT inhibitors owing to their high specificity and unique mode of action. Nonetheless, these drugs show a tendency to decrease their efficacy due to high HIV-1 variability and formation of resistant virus strains tolerant to clinically applied HIV NNRTIs. A combinatorial approach based on varying substituents within various fragments of the parent molecule that results in development of highly potent compounds is one of the approaches aimed at designing novel HIV NNRTIs. Generation of HIV NNRTIs based on pyrimidine derivatives explicitly exemplifies this approach, which is discussed in this review.