Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility
| Autor: | Janet C. Reid, Vicky M. Avery, Lendl Tan, Neda AbuGharbiyeh, Melissa Sykes, Chee Wei Ang, Mark E. Cooper, Mark A. T. Blaskovich, Anjan Debnath, Nicholas P. West |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Antiparasitic
medicine.drug_class Cell Survival Trypanosoma brucei brucei Substituent Antiprotozoal Agents Antitubercular Agents Microbial Sensitivity Tests 01 natural sciences Article Mycobacterium 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship Microsomes Drug Discovery medicine Structure–activity relationship Animals Humans 030304 developmental biology 0303 health sciences Nitroimidazole Bicyclic molecule Chemistry Aryl Blood Proteins Combinatorial chemistry 3. Good health 0104 chemical sciences 010404 medicinal & biomolecular chemistry Solubility Nitroimidazoles Pretomanid Drug Design Pyrazines Molecular Medicine Delamanid medicine.drug Half-Life Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Following the approval of delamanid and pretomanid as new drugs to treat drug-resistant tuberculosis, there is now a renewed interest in bicyclic nitroimidazole scaffolds as a source of therapeutics against infectious diseases. We recently described a nitroimidazopyrazinone bicyclic subclass with promising antitubercular and antiparasitic activity, prompting additional efforts to generate analogs with improved solubility and enhanced potency. The key pendant aryl substituent was modified by (i) introducing polar functionality to the methylene linker, (ii) replacing the terminal phenyl group with less lipophilic heterocycles, or (iii) generating extended biaryl side chains. Improved antitubercular and antitrypanosomal activity was observed with the biaryl side chains, with most analogs achieved 2- to 175-fold higher activity than the monoaryl parent compounds, with encouraging improvements in solubility when pyridyl groups were incorporated. This study has contributed to understanding the existing structure-activity relationship (SAR) of the nitroimidazopyrazinone scaffold against a panel of disease-causing organisms to support future lead optimization. |
| Databáze: | OpenAIRE |
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