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Comparative Study
. 2006 Dec 28;49(26):7877-86.
doi: 10.1021/jm061123i.

Synthesis, antifungal activity, and structure-activity relationships of coruscanone A analogues

K Suresh Babu  1 , Xing-Cong Li, Melissa R Jacob, Qifeng Zhang, Shabana I Khan, Daneel Ferreira, Alice M Clark
Affiliations
Comparative Study

Synthesis, antifungal activity, and structure-activity relationships of coruscanone A analogues

K Suresh Babu et al. J Med Chem. .

Abstract

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.

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Figures

Figure 1
Figure 1
Key structural moieties of coruscanone A (1).
Figure 2
Figure 2
Key butenolide intermediates 22–24.
Figure 3
Figure 3
Synthetic coruscanone A analogs.
Scheme 1
Scheme 1
General Reaction Scheme for Preparation of Coruscanone A (1) Analogs (R1,R2: H, CH3, alkyl, or phenyl; R3: aromatic, styryl, heteroaromatic, etc.; R4:CH3, alkyl, acyl, etc)
Scheme 2
Scheme 2
Synthesis of Benzoquinone 60a a Reagents and conditions: (a) MeOCH2Cl/NaH, THF, 0 °C, 24 hr, 75%. (b) C5H5NHBr3/MeOH/NaHCO3, r.t., 25 min, 89%. (c) (i) MeLi/THF, −78 °C, 1 hr; (ii) MeI, −78 °C, 1 hr, 90%. (d) (i) BuLi/THF, −78 °C, 1 hr, then warm to 0 °C, 5 hr, r.t., 3 hr; (ii) PhCH2CHO, 0 °C, 0.5 hr; 66%. (e) 3N HCl/dioxane, 50 °C, 3 hr, 95%. (f) DDQ/CH2Cl2-H2O, r.t., 12 hr, 65%.
Scheme 3
Scheme 3
Proposed Mechanism for Inhibition of Human Chymase by 61
Scheme 4
Scheme 4
Possible Interaction Mechanism of 1 With the Target
See this image and copyright information in PMC

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