Potent Synergy between Spirocyclic Pyrrolidinoindolinones and Fluconazole against Candida albicans

• Published in: ChemMedChem 2015-10, Vol.10 (10), p.1672-1686
• Main Authors: Premachandra, Ilandari Dewage Udara Anulal, Scott, Kevin A., Shen, Chengtian, Wang, Fuqiang, Lane, Shelley, Liu, Haoping, Van Vranken, David L.
• Format: Article
• Language: English
• Subjects: Animals; antifungal agents; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Candida albicans; Candida albicans - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug Synergism; fluconazole; Fluconazole - chemical synthesis; Fluconazole - chemistry; Fluconazole - pharmacology; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Mice; Microbial Sensitivity Tests; Molecular Structure; NIH 3T3 Cells; spiro compounds; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Structure-Activity Relationship; synergy
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201500271

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. Synergy from stereochemical complexity: An attempt to synthesize analogues of a known spiroindolinone led to a series of diastereomers. One spiroindolinone, termed synazo‐1, was shown to exhibit potent activity (300 pM) against C. albicans in the presence of fluconazole. Synazo‐1 is a true synergizer and was also highly active against some drug‐resistant C. albicans strains.