The toxicity and efficacy of a series of 13 anti-tubercular sulphone esters has been evaluated using human and rat tissues. The toxicity studies involved comparison of the esters' ability to generate rat microsomally mediated NADPH-dependent methaemoglobin with that of dapsone. All the compounds formed significantly less methaemoglobin in the 1 compartment studies compared with dapsone itself. The ethyl, propyl, 3-methyl-butyl cyclopentyl esters and the carboxy parent derivative all yielded less than 5% of the methaemoglobin generated by dapsone. The 3-nitro benzoic acid ethyl and propyl esters generated 30 and 25% of dapsone's methaemoglobin formation. A similar effect was seen in the 2 compartment system, except for the butyl ester, which yielded similar haemoglobin oxidation to dapsone. The low toxicity ethyl and propyl esters, were also low in toxicity using human liver microsomes, producing less than 30% of the dapsone mediated methaemoglobin. All the compounds except the benzoic acid parent were superior to dapsone in terms of suppression of human neutrophil respiratory burst using a lucigenin-based chemiluminescence assay. The most potent derivatives were the phenyl, propyl and 3-nitro benzoic acid ethyl esters, which were between two- and threefold more potent compared with dapsone in arresting the respiratory burst. Overall, the ethyl ester showed the best combination of low toxicity in the rat and human microsomal systems and its IC50 was approximately 40% lower than that of dapsone in neutrophil respiratory burst inhibition. These compounds indicate some promise for future development in their superior anti-inflammatory capability and lower toxicity compared with the parent sulphone, dapsone. © 2002 Elsevier Science B.V. All rights reserved.
- anti-tubercular sulphone