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Our previous work identified compound 1 (SLU-2633) as a potent lead compound toward the identification of a novel treatment for cryptosporidiosis, caused by the parasite Cryptosporidium (EC 50 = 0.17 μM). While this compound is potent and orally efficacious, the mechanism of action and biological target(s) of this series are currently unknown. In this study, we synthesized 70 compounds to develop phenotypic structure-activity relationships around the aryl "tail" group. In this process, we found that 2-substituted compounds are inactive, confirmed that electron withdrawing groups are preferred over electron donating groups, and that fluorine plays a remarkable role in the potency of these compounds. The most potent compound resulting from this work is SLU-10482 ( 52 , EC 50 = 0.07 μΜ), which was found to be orally efficacious with an ED 90 < 5 mg/kg BID in a Cryptosporidium -infection mouse model, superior to SLU-2633.

During 2018-2019, the Rhode Island Department of Health (RIDOH) and the Missouri Department of Health and Senior Services (DHSS) investigated cases of metal poisonings associated with commercially and home-prepared cakes decorated with products referred to as luster dust. Several types of glitters and dusts, broadly known as luster dust,* for use on prepared foods can be purchased online and in craft and bakery supply stores (1). Decorating foods with luster dust and similar products is a current trend, popularized on television programs, instructional videos, blogs, and in magazine articles. † Some luster dusts are specifically produced with edible ingredients that can be safely consumed. Companies that make edible luster dust are required by law to include a list of ingredients on the label (2). Luster dusts that are safe for consumption are typically marked "edible" on the label. Some luster dusts used as cake decorations are not edible or food grade; labeled as "nontoxic" or "for decorative purposes only," these luster dusts are intended to be removed before consumption (3). RIDOH (2018) and Missouri DHSS (2019), investigated heavy metal poisonings associated with commercially and home-prepared cakes decorated with luster dust after receiving reports of children (aged 1-11 years) who became ill after consuming birthday cake. Cases in Rhode Island were associated with copper ingestion, and the case in Missouri was associated with a child's elevated blood lead level. In Rhode Island, luster dust products that had been used in cake frosting were found to contain high levels of multiple metals. § These events indicate that increased vigilance by public health departments and further guidance to consumers and bakeries are needed to prevent unintentional poisonings. Labeling indicating that a product is nontoxic does not imply that the product is safe for consumption. Explicit labeling indicating that nonedible products are not safe for human consumption is needed to prevent illness from inappropriate use of inedible products on foods. Educating consumers, commercial bakers, and public health professionals about potential hazards of items used in food preparation is essential to preventing illness and unintentional poisoning from toxic metals and other nonedible ingredients., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Brendalee Viveiros reports grant support from the Food and Drug Administration Rapid Response Team. No other potential conflicts of interest were disclosed.

Cryptosporidiosis is caused by infection of the small intestine by Cryptosporidium parasites, resulting in severe diarrhea, dehydration, malabsorption, and potentially death. The only FDA-approved therapeutic is only partially effective in young children and ineffective for immunocompromised patients. Triazolopyridazine MMV665917 is a previously reported anti- Cryptosporidium screening hit with in vivo efficacy but suffers from modest inhibition of the hERG ion channel, which could portend cardiotoxicity. Herein, we describe our initial development of structure-activity relationships of this novel lead series with a particular focus on optimization of the piperazine-urea linker. We have discovered that piperazine-acetamide is a superior linker resulting in identification of SLU-2633, which has an EC 50 of 0.17 μM, an improved projected margin versus hERG, prolonged pharmacokinetic exposure in small intestine, and oral efficacy in vivo with minimal systemic exposure. SLU-2633 represents a significant advancement toward the identification of a new effective and safe treatment for cryptosporidiosis.