Non-peptide inhibitors of HIV-1 protease. Synthesis and structural evaluation of symmetric and non-symmetric naphthalenesulfonic acid analogues

In this study, several representative symmetric and non-symmetric naphthalenesulfonic acid derivatives belonging to various structural classes were evaluated for their potential to inhibit HIV-1 protease. The most active compounds were non-symmetrical and possessed hydrophobic pendant groups. In general, the activity of these derivatives was dependent on the number and position of the sulfonic acid moiety and the nature of the appendages. Remarkably, one of the most active compounds also displayed inhibition of DNA polymerase and RNase H activities of HIV-1 reverse transcriptase. This observation provides an insight into designing singular compounds which could inhibit multiple essential enzymes in the HIV-1 life cycle. Since it is unlikely that these agents will reach targeted cellular enzymes due to their polar nature, the discovery of in vitro protease inhibition rationalizes further modification of sulfonic acid derivatives.