Evaluation of new thiazolide/thiadiazolide derivatives reveals nitro group-independent efficacy against in vitro development of Cryptosporidium parvum

Abstract

Thirty-nine new thiazolide/thiadiazolide compounds were compared with the nitrothiazole nitazoxanide for activity against Cryptosporidium parvum development in HCT-8 cells. Twenty-seven agents exerted > or =90% inhibition. Agents with a lower 50% inhibitory concentration (IC(50)) than nitazoxanide were either NO(2) or halogen 5 substituted on the thiazole moiety. Other 5 substitutions such as methyl, C(3)H(7), C(6)H(11), H, SO(2)CH(3), and SCH(3) negatively impacted activity. Five-substituted deacetylated analogues exhibited higher IC(50)s than their acetylated counterparts. Halogeno-thiazolide/thiadiazolides may provide valuable nitro-free alternatives to nitazoxanide.

FIG. 1.

Chemical structures of the thiazolides (A) and thiadiazolides (B) used in this study.

FIG. 2.

Inhibition curves of representative active compounds. RM4959 and RM4860 are 5-bromothiazolides; RM4850 (deacetylated metabolite of RM4865) and RM4865 are 5-chlorothiazolides; RM4816 is a thiadiazolide. Data, expressed as percent inhibition compared with untreated infected control cultures, represent the means of triplicate experiments. Error bars indicate standard deviations that were >5%.