Structure-Activity relationships of replacements for the triazolopyridazine of Anti-Cryptosporidium lead SLU-2633.

Cryptosporidiosis is a diarrheal disease particularly harmful to children and immunocompromised people. Infection is caused by the parasite Cryptosporidium and leads to dehydration, malnutrition, and death in severe cases. Nitazoxanide is the only FDA approved drug but is only modestly effective in children and ineffective in immunocompromised patients. To address this unmet medical need, we previously identified triazolopyridazine SLU-2633 as potent against Cryptosporidium parvum, with an EC50 of 0.17 µM. In the present study, we develop structure-activity relationships (SAR) for the replacement of the triazolopyridazine head group by exploring different heteroaryl groups with the aim of maintaining potency while reducing affinity for the hERG channel. 64 new analogs of SLU-2633 were synthesized and assayed for potency versus C. parvum. The most potent compound, 7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine 17a, was found to have a Cp EC50 of 1.2 µM, 7-fold less potent than SLU-2633 but has an improved lipophilic efficiency (LipE) score. 17a was found to decrease inhibition in an hERG patch-clamp assay by about two-fold relative to SLU-2633 at 10 µM despite having similar inhibition in a [3H]-dofetilide competitive binding assay. While most other heterocycles were significantly less potent than the lead, some analogs such as azabenzothiazole 31b, have promising potency in the low micromolar range, similar to the drug nitazoxanide, and represent potential new leads for optimization. Overall, this work highlights the important role of the terminal heterocyclic head group and represents a significant extension of the understanding of the SAR for this class of anti-Cryptosporidium compounds.

Addressing Health Inequities in the United States: A Case Report on Autism Spectrum Disorder (ASD) and Social Determinants of Health.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that presents with delays in developmental milestones, social impairment, and behavioral difficulties. Treatment relies upon an intensive individualized multidisciplinary medical and therapeutic approach. This case presents a child affected by ASD and other associated conditions, whose care was significantly limited by the effects of social determinants of health, including lack of transportation, housing instability, low income, and most importantly, lack of health insurance. Without universal health coverage, the US healthcare system requires that patients have insurance or pay out-of-pocket to access medical care. It is vital that healthcare providers are able to recognize and address these barriers in order to help pediatric patients and their families navigate a difficult and often inequitable healthcare system. It is also crucial to emphasize the importance of healthcare providers, policymakers, and advocacy organizations to work together to address the systemic barriers that limit access to quality care for children with ASD.