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Research Project: Biobased Pesticide Discovery and Product Optimization and Enhancement from Medicinal and Aromatic Crops

Location: Natural Products Utilization Research

Title: Synthesis and antifungal activity evaluation of phloeodictine analogues

Author
item RAVU, RANGA RAO - University Of Mississippi
item JACOB, MELISSA - University Of Mississippi
item KHAN, SHABANA - University Of Mississippi
item Wang, Mei
item CAO, LIANG - University Of Mississippi
item AGARWAL, AMEETA - University Of Mississippi
item CLARK, ALICE - University Of Mississippi
item LI, XING-CONG - University Of Mississippi

Submitted to: Journal of Natural Products
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/6/2021
Publication Date: 7/20/2021
Citation: Ravu, R., Jacob, M.R., Khan, S.I., Wang, M., Cao, L., Agarwal, A.K., Clark, A.M., Li, X. 2021. Synthesis and Antifungal Activity Evaluation of Phloeodictine Analogues. Journal of Natural Products. 84,2129-2137. https://doi.org/10.1021/acs.jnatprod.1c00116.
DOI: https://doi.org/10.1021/acs.jnatprod.1c00116

Interpretive Summary: The phloeodictines are a small group of marine-derived alkaloids exhibiting antibacterial, cytotoxic, and antiplasmodial activities. In a search for antifungal natural products, the phloeodictines were identified to possess broad-spectrum antifungal activities against pathogenic fungi. To study the structure and antifungal activity relationship, synthetic analogues were prepared and evaluated for in vitro antifungal activities against the clinically important fungal pathogens including Cryptococcus neoformans, Candida albicans, Candida glabrata, Candida krusei, and Aspergillus fumigatus. Several analogues showed potent activities comparable to the antifungal drug amphotericin B, and exhibited low cytotoxicity against the mammalian Vero cell line. Useful structure-activity relationship information has been obtained to inform further preclinical studies of this new class of antifungal compounds.

Technical Abstract: The phloeodictine-based 6-hydroxy-2,3,4,6-tetrahydropyrrolo[1,2-a]pyrimidinium structural moiety with an n-tetradecyl side chain at C-6 has been demonstrated to be a new antifungal template. Thirty-four new synthetic analogues with modifications of the bicyclic tetrahydropyrrolopyrimidinium skeleton and the N-1 side chain have been prepared and evaluated for in vitro antifungal activities against the clinically important fungal pathogens including Cryptococcus neoformans ATCC 90113, Candida albicans ATCC 90028, Candida glabrata ATCC 90030, Candida krusei ATCC 6258, and Aspergillus fumigatus ATCC 90906. Nineteen compounds (5, 21-31, 34-38, 44, and 48) showed antifungal activities against the aforementioned five fungal pathogens with minimum inhibitory concentrations (MICs) in the range of 0.88-10 uM, and were all fungicidal with minimum fungicidal concentrations (MFCs) similar to the respective MIC values. Compounds 24, 36, and 48 were especially active against C. neoformans ATCC 90113 with MIC/MFC values of 1.0/1.0, 1.6/1.6, and 1.3/2.0 µM, but exhibited low cytotoxicity with an IC50 > 40 µM against the mammalian Vero cells. The structure and antifungal activity relationship indicates that synthetic modifications of the phloeodictines can afford analogues with potent antifungal activity and reduced cytotoxicity, necessitating further preclinical studies of this new class of antifungal compounds.