Antimicrob Agents Chemother. 2014 Feb 24. [Epub ahead of print]
Identification of Cryptosporidium parvum active chemical series by repurposing the Open Access Malaria Box
The apicomplexan parasites Cryptosporidium parvum and C. hominis are major etiologic agents of human cryptosporidiosis. Infection is typically self-limited in immunocompetent adults, but can cause chronic, fulminant diarrhea in immunocompromised patients, and malnutrition and stunting in children. Nitazoxanide, the current standard-of-care for cryptosporidiosis, is only partially efficacious for children and is no more effective than placebo in AIDS patients. Unfortunately, financial obstacles to drug discovery for diseases that disproportionately affect low-income countries and technical limitations associated with studies of Cryptosporidium biology both impede development of better drugs for cryptosporidiosis. Using a cell-based high-throughput screen, we queried the Medicines for Malaria Venture's (MMV) "Open Access Malaria Box" for activity against C. parvum. We identified 3 novel chemical series derived from the quinolin-8-ol, allopurinol-based, and 2,4-diamino-quinazoline chemical scaffolds that exhibited sub-micromolar potency against C. parvum. Potency was conserved in a sub-set of compounds from each scaffold with variable physicochemical properties, and two of the scaffolds identified exhibit more rapid inhibition of C. parvum growth than nitazoxanide, making them excellent candidates for further development. The 2,4-diamino-quinazoline and allopurinol-based compounds were also potent growth inhibitors of the related apicomplexan parasite Toxoplasma gondii, and a good correlation was observed in the relative activities of compounds in the allopurinol-based series against T. gondii and C. parvum. Taken together, these data illustrate the utility of the Open Access Malaria Box as a source of both potential leads for drug development and chemical probes to elucidate basic biological processes in C. parvum and other apicomplexan parasites.
- [PubMed - as supplied by publisher]