Potent Synergy between Spirocyclic Pyrrolidinoindolinones and Fluconazole against Candida albicans
| Autor: | Premachandra, Ilandari Dewage Udara Anulal, Scott, Kevin A, Shen, Chengtian, Wang, Fuqiang, Lane, Shelley, Liu, Haoping, Van Vranken, David L |
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| Rok vydání: | 2015 |
| Předmět: |
Indoles
Antifungal Agents Molecular Structure Cell Survival spiro compounds Prevention Medicinal & Biomolecular Chemistry Organic Chemistry synergy Drug Synergism Pharmacology and Pharmaceutical Sciences Microbial Sensitivity Tests Dose-Response Relationship Vaccine Related Mice Structure-Activity Relationship Medicinal and Biomolecular Chemistry Biodefense Candida albicans fluconazole NIH 3T3 Cells Animals Antimicrobial Resistance Drug |
| Zdroj: | ChemMedChem, vol 10, iss 10 |
| Popis: | A spiroindolinone, (1S,3R,3aR,6aS)-1-benzyl-6'-chloro-5-(4-fluorophenyl)-7'-methylspiro[1,2,3a,6a-tetrahydropyrrolo[3,4-c]pyrrole-3,3'-1H-indole]-2',4,6-trione, was previously reported to enhance the antifungal effect of fluconazole against Candida albicans. A diastereomer of this compound was synthesized, along with various analogues. Many of the compounds were shown to enhance the antifungal effect of fluconazole against C. albicans, some with exquisite potency. One spirocyclic piperazine derivative, which we have named synazo-1, was found to enhance the effect of fluconazole with an EC50 value of 300 pM against a susceptible strain of C. albicans and going as low as 2 nM against some resistant strains. Synazo-1 exhibits true synergy with fluconazole, with an FIC index below 0.5 in the strains tested. Synazo-1 exhibited low toxicity in mammalian cells relative to the concentrations required for antifungal synergy. |
| Databáze: | OpenAIRE |
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