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J Med Chem. 2018 Dec 27;61(24):11349-11371. doi: 10.1021/acs.jmedchem.8b01578. Epub 2018 Dec 11.

Design, Synthesis, and Biological Evaluation of 2-Nitroimidazopyrazin-one/-es with Antitubercular and Antiparasitic Activity.

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Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences , University of California San Diego , La Jolla , California 92093 , United States.
Australian Infectious Diseases Research Centre , St. Lucia , Queensland 4067 Australia.
Discovery Biology, Griffith Institute for Drug Discovery , Griffith University , Nathan , Queensland 4111 , Australia.


Tuberculosis and parasitic diseases, such as giardiasis, amebiasis, leishmaniasis, and trypanosomiasis, all urgently require improved treatment options. Recently, it has been shown that antitubercular bicyclic nitroimidazoles such as pretomanid and delamanid have potential as repurposed therapeutics for the treatment of visceral leishmaniasis. Here, we show that pretomanid also possesses potent activity against Giardia lamblia and Entamoeba histolytica, thus expanding the therapeutic potential of nitroimidazooxazines. Synthetic analogues with a novel nitroimidazopyrazin-one/-e bicyclic nitroimidazole chemotype were designed and synthesized, and structure-activity relationships were generated. Selected derivatives had potent antiparasitic and antitubercular activity while maintaining drug-like properties such as low cytotoxicity, good metabolic stability in liver microsomes and high apparent permeability across Caco-2 cells. The kinetic solubility of the new bicyclic derivatives varied and was found to be a key parameter for future optimization. Taken together, these results suggest that promising subclasses of bicyclic nitroimidazoles containing different core architectures have potential for further development.

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