Naphthalenesulphonic Acid Derivatives as Potential anti-HIV-1 Agents. Chemistry, Biology and Molecular Modelling of Their Inhibition of Reverse Transcriptase

Abstract

Activity against human immunodeficiency virus (HIV) in the naphthalenesulphonic acid series is most pronounced in the disulphonic acid series. In this class of compounds, N-acyl derivatives of 4-amino-5-hydroxy-2,7-naphthalenedisulphonic acid demonstrate significant anti-HIV activity at non-toxic doses. The most potent compounds in this group of agents are bis naphthalenedisulphonic acids. A bis derivative containing a decamethylene spacer demonstrated activity against HIV-1, HIV-2 giant cell formation and reverse transcriptase (RT). This compound also demonstrated an in vitro therapeutic index (ratio of 50% cytotoxic concentration to 50% inhibitory antiviral concentration) of 10.6. Molecular modelling analyses of this agent, suramin, and several suramin analogues were undertaken to explain the potent anti-HIV-1 RT activity. These studies were carried out using the molecular decomposition/recomposition strategy, conformational searching, energy minimization and molecular dynamics (MD) simulation. The bis naphthalenedisulphonic acid derivative compound 1, having a flexible decamethylene spacer, was shown to be able to mimic the helical twist of the B-DNA backbone as a low energy conformer state.