Anti-cryptosporidial efficacy of tricyclic carbazole aminoalcohols in vitro and in vivo.

Abstract

Cryptosporidiosis is a major cause of diarrheal disease in humans and animals, yet there are no fully effective drugs, particularly for immunocompromised patients. Carbazole aminoalcohols (CAAs) are a relatively unexplored chemical class with reported broad-spectrum antiparasitic activities. Here, we systematically evaluated 36 CAA derivatives for anti-cryptosporidial efficacy. In vitro screening using a 44-h Cryptosporidium parvum infection assay identified eight compounds with low-micromolar ECvalues (1.53-6.86&#xa0;&#x3bc;M). The three most potent hits (H1402 at 25&#xa0;mg/kg/d, and YFM1 and YFM3 at 15&#xa0;mg/kg/d) were selected for in vivo evaluation in a chronic C. tyzzeri mouse model. Daily oral treatment with these compounds for 7 days reduced fecal oocyst shedding by 55.9-59.1&#xa0;% compared with a 247.5&#xa0;% increase in vehicle controls (P&#xa0;<&#xa0;0.01). Paromomycin at 1000&#xa0;mg/kg/d, used as a positive control, produced an 84.2&#xa0;% reduction. All three CAAs were generally well tolerated, with only minor weight loss observed in H1402-treated mice. Together, these results demonstrate that CAAs possess reproducible in vitro activity and significant in vivo efficacy against cryptosporidial infection, supporting their potential as lead scaffolds for anti-cryptosporidial drug development. Structural optimization to improve potency, selectivity, and pharmacokinetic properties is warranted to advance CAAs toward preclinical development.