Design, Synthesis, and Biological Evaluation of 2-Nitroimidazopyrazin-one/-es with Antitubercular and Antiparasitic Activity
| Autor: | Angie M. Jarrad, Mark A. T. Blaskovich, Tomislav Karoli, Mark S. Butler, Chee Wei Ang, Nicholas P. West, Mark E. Cooper, Vicky M. Avery, Melissa Sykes, Kyra Woods, Anjan Debnath, Amy J. Jones, Hye Jee Hahn, Lendl Tan, Ruby Pelingon |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Antiparasitic medicine.drug_class Antitubercular Agents Drug Evaluation Preclinical Microbial Sensitivity Tests Pharmacology 01 natural sciences Article Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Entamoeba histolytica Drug Stability Drug Discovery medicine Animals Humans Structure–activity relationship Nitroimidazole Antiparasitic Agents Bicyclic molecule biology 010405 organic chemistry Chemistry medicine.disease biology.organism_classification 0104 chemical sciences 3. Good health 030104 developmental biology Visceral leishmaniasis Nitroimidazoles Drug Design Pretomanid Microsomes Liver Molecular Medicine Caco-2 Cells Giardia lamblia Delamanid medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.8b01578 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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