Exploration of Structure–Activity Relationships and Gut Restriction in Anti-Cryptosporidium Triazolopyridazine Series
5 affiliations
- 1Department of Chemistry
- 2Saint Louis University
- 3Department of Medicine
- 4University of Vermont Larner College of Medicine
- 5Institute for Drug and Biotherapeutic Innovation
Abstract
Cryptosporidiosis is a major cause of diarrheal disease worldwide, particularly in young children and immunocompromised individuals, yet effective therapeutic options remain limited. Previously, the triazolopyridazine derivative SLU-10482 was identified as a potent anti-Cryptosporidium lead, but it suffers from modest affinity for the hERG ion channel. In the present study, structure–activity relationships (SAR) were investigated through systematic modification of the 3-position of the aryl ring and by designing gutrestricted analogues intended to reduce systemic exposure while maintaining antiparasitic activity. A diverse library of analogues was synthesized using amide coupling, Sonogashira, Suzuki, and Buchwald–Hartwig cross-coupling reactions, followed by hydrogenation and late-stage functional group transformations to access alkynyl, alkyl, tertiary amine, quaternary ammonium, and substituted aryl derivatives. Compounds were evaluated for anti-Cryptosporidium parvum activity in infected HCT-8 cells. SAR studies revealed that smaller, less polar substituents at the 3-position were generally associated with improved potency, whereas increasing substituent size and polarity resulted in diminished activity, although several larger polar analogues retained measurable potency. To develop gut-restricted agents, molecular weight, polarity, and conformational flexibility were intentionally increased to reduce intestinal permeability and systemic exposure. While these modifications were expected to preserve local intestinal activity, the resulting analogues exhibited substantially reduced antiparasitic potency. Because the molecular target of this chemotype remains unknown, the observed loss of activity may arise from reduced target engagement, impaired penetration across the parasite membrane barriers, or a combination of both.
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BibTeX
@misc{giardina2026exploration,
title = {{Exploration of Structure–Activity Relationships and Gut Restriction in Anti-Cryptosporidium Triazolopyridazine Series}},
author = {Antonio Giardina and Caitlin E. Hamill and Gregory M. Giovine and José Teixeira and Edmund Oboh and Soumitra Guin and Christopher D. Huston and Marvin J. Meyers},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15009347/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009347/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Exploration of Structure–Activity Relationships and Gut Restriction in Anti-Cryptosporidium Triazolopyridazine Series
AU - Antonio Giardina
AU - Caitlin E. Hamill
AU - Gregory M. Giovine
AU - José Teixeira
AU - Edmund Oboh
AU - Soumitra Guin
AU - Christopher D. Huston
AU - Marvin J. Meyers
PY - 2026
DA - 2026/09/23
PB - ChemRxiv
DO - 10.26434/chemrxiv.15009347/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009347/v1
AB - Cryptosporidiosis is a major cause of diarrheal disease worldwide, particularly in young children and immunocompromised individuals, yet effective therapeutic options remain limited. Previously, the triazolopyridazine derivative SLU-10482 was identified as a potent anti-Cryptosporidium lead, but it suffers from modest affinity for the hERG ion channel. In the present study, structure–activity relationships (SAR) were investigated through systematic modification of the 3-position of the aryl ring and by designing gutrestricted analogues intended to reduce systemic exposure while maintaining antiparasitic activity. A diverse library of analogues was synthesized using amide coupling, Sonogashira, Suzuki, and Buchwald–Hartwig cross-coupling reactions, followed by hydrogenation and late-stage functional group transformations to access alkynyl, alkyl, tertiary amine, quaternary ammonium, and substituted aryl derivatives. Compounds were evaluated for anti-Cryptosporidium parvum activity in infected HCT-8 cells. SAR studies revealed that smaller, less polar substituents at the 3-position were generally associated with improved potency, whereas increasing substituent size and polarity resulted in diminished activity, although several larger polar analogues retained measurable potency. To develop gut-restricted agents, molecular weight, polarity, and conformational flexibility were intentionally increased to reduce intestinal permeability and systemic exposure. While these modifications were expected to preserve local intestinal activity, the resulting analogues exhibited substantially reduced antiparasitic potency. Because the molecular target of this chemotype remains unknown, the observed loss of activity may arise from reduced target engagement, impaired penetration across the parasite membrane barriers, or a combination of both.
ER -