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.