Despite the significant progress made in the fight against malaria over the last two decades, the ~429,000 deaths annually continues to make malaria a major health concern. The emergence of resistance to all known antimalarial drugs, represent major obstacles for the control of the disease. The major marker of clinical artemisinin resistance, PfKelch13, downregulates Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K) level in malarial parasites, while PfPI3K produces parasite phosphatidyl-3-phosphate (PI3P). Once mutated to be dominant negative, PfKelch13 fails to reduce PfPI3K and more PI3P is synthesized in the mutant parasites compared with wild type ones. We have found that Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K) is inhibited by dihydroartemisinin (DHA). However, DHA is not a potent PfPI3K inhibitor to kill the parasites with some PfKelch13 mutations, and more powerful PfPI3K inhibitors are urgently needed. Here we report synthetic imidazo[1,2-b]pyridazine analogues as novel PfPI3K inhibitors. This series were screened from a ~117,000 compounds library of Eli Lilly and Company against the blood stages of P. falciparum. Sixty-five new analogues were synthesized through a series of optimizations of the hit compound, and were screened against a parasite-PI3P reporter strain to yield potent inhibitors (IC50 7-11 nM) with acceptable (&gt; 30 fold) selectivity against human cells. These inhibitors reduced parasite infection in a murine model. They were also validated for parasite-stage specific PfPI3K activity characteristic of clinical resistance suggesting a foundation to rationally target artemisinin resistance.

Imidazopyridazine analogues as anti-malarial PfPI3K inhibitors

255th National Meeting (2018)

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