Potent Synergy between Spirocyclic Pyrrolidinoindolinones and Fluconazole against Candida albicans.
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.
Department of Chemistry, University of California, Irvine, 1102 Natural Sciences 2, Irvine, CA 92697-2025 (USA).
Ilandari Dewage Udara Anulal
ID
Premachandra
Department of Chemistry, University of California, Irvine, 1102 Natural Sciences 2, Irvine, CA 92697-2025 (USA).
Kevin A
KA
Scott
Department of Chemistry, University of California, Irvine, 1102 Natural Sciences 2, Irvine, CA 92697-2025 (USA).
Chengtian
C
Shen
Department of Biological Chemistry, University of California, Irvine, 825 Health Sciences Road, Medical Sciences I, Irvine, CA 92697-1700 (USA).
Fuqiang
F
Wang
Department of Biological Chemistry, University of California, Irvine, 825 Health Sciences Road, Medical Sciences I, Irvine, CA 92697-1700 (USA).
Shelley
S
Lane
Department of Biological Chemistry, University of California, Irvine, 825 Health Sciences Road, Medical Sciences I, Irvine, CA 92697-1700 (USA).
Haoping
H
Liu
Department of Chemistry, University of California, Irvine, 1102 Natural Sciences 2, Irvine, CA 92697-2025 (USA). david.vv@uci.edu.
David L
DL
Van Vranken
D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015725:Fluconazole / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D007211:Indoles; D013141:Spiro Compounds; D015725:Fluconazole
Candida albicans; antifungal agents; fluconazole; spiro compounds; synergy