Anthelmintics Derived from the Kinase Inhibitor SGI-1776 for the Treatment of Gastrointestinal Worm Infections

Human gastrointestinal nematodes (GINs) infect at least one billion people, mostly children, with five billion people at risk of infection. Reduced and low efficacy of currently used anthelmintics, e.g., benzimidazoles against <i>Trichuris trichiura</i> whipworms, urges new anthelmintics to control these parasites. We previously discovered two human <i>pan</i>-PIM kinase inhibitors, CX-6258 and SGI-1776, with potent antihelmintic activity against GINs. Here, structure-activity relationship (SAR) studies were conducted to identify SGI-1776 analogs with improved cross-clade adulticidal activity (<i>Ancylostoma ceylanicum</i> hookworms and <i>Trichuris muris</i> whipworms). We further identified a new chemical series from <b>15</b> (imidazo[1,2-<i>b</i>]pyridazine-3-carboxamide) and novel derivatives from it. Differential cuticle permeability, quantified by the amount of bioaccumulated drugs, explained some unexpected observations regarding activity and correlated with their physicochemical properties. The compounds' physical properties were significantly predictive of their activity. <b>15</b> and <b>51</b> were the most potent against whipworm and showed decreased and no activity against human PIM kinases, suggesting increased selectivity against the GIN counterparts. The unexpected SAR of compound <b>15</b> can be explained by computational modeling. We demonstrate the efficacy of optimized compound <b>50</b> as a new oral anthelmintic, which demonstrated better gut restriction properties and significantly reduced the fecundity of <i>T. muris</i> whipworm adults in infected mice. We also report our findings on physicochemical properties and gut restriction ADME parameters that are essential for further lead optimization.