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Potent Synergy between Spirocyclic Pyrrolidinoindolinones and Fluconazole against Candida albicans
Author(s) -
Premachandra Ilandari Dewage Udara Anulal,
Scott Kevin A.,
Shen Chengtian,
Wang Fuqiang,
Lane Shelley,
Liu Haoping,
Van Vranken David L.
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500271
Subject(s) - fluconazole , candida albicans , corpus albicans , chemistry , stereochemistry , antifungal , ec50 , diastereomer , microbiology and biotechnology , strain (injury) , biology , in vitro , biochemistry , anatomy
A spiroindolinone, (1 S ,3 R ,3a R ,6a S )‐1‐benzyl‐6′‐chloro‐5‐(4‐fluorophenyl)‐7′‐methylspiro[1,2,3 a ,6 a ‐tetrahydropyrrolo[3,4‐ c ]pyrrole‐3,3′‐1 H ‐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. albican s, some with exquisite potency. One spirocyclic piperazine derivative, which we have named synazo‐1, was found to enhance the effect of fluconazole with an EC 50 value of 300 p M against a susceptible strain of C. albicans and going as low as 2 n M 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.