Synthesis, antifungal activity, and structure-activity relationships of coruscanone A analogues.
Coruscanone A, a plant-derived cyclopentenedione derivative, showed potent in vitro antifungal activity against Candida albicans and Cryptococcus neoformans comparable to amphotericin B and fluconazole. A series of analogues have been synthesized by modification of the cyclopentenedione ring, the enolic methoxy functionality, and the side chain styryl moiety of this natural product lead. A structurally close 1,4-benzoquinone analogue was also prepared. All the compounds were examined for their in vitro activity against major opportunistic fungal pathogens including C. albicans, C. neoformans, and Aspergillus fumigatus and fluconazole-resistant C. albicans strains, with several analogues demonstrating potent antifungal activity. Structure-activity relationship studies indicate that the 2-methoxymethylenecyclopent-4-ene-1,3-dione structural moiety is the pharmacophore responsible for the antifungal activity of this class of compounds while the side chain styryl-like moiety plays an important complementary role, presumably contributing to target binding.
Babu
K Suresh
KS
National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences and Department of Pharmacognosy, School of Pharmacy, The University of Mississippi, University, MS 38677, USA.
Li
Xing-Cong
XC
Jacob
Melissa R
MR
Zhang
Qifeng
Q
Khan
Shabana I
SI
Ferreira
Daneel
D
Clark
Alice M
AM
D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D003455:Cryptococcus neoformans / Q000187:drug effects*; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D025141:Drug Resistance, Fungal; D015725:Fluconazole / Q000494:pharmacology; D018374:LLC-PK1 Cells / Q000187:drug effects; D008825:Miconazole / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013552:Swine; D014709:Vero Cells / Q000187:drug effects
D000935:Antifungal Agents; D003517:Cyclopentanes; D008825:Miconazole; D015725:Fluconazole