Synthesis of natural acylphloroglucinol-based antifungal compounds against Cryptococcus species

Authors: YU, QIAN - University Of Mississippi; RAVU, RANGA RAO - University Of Mississippi; JACOB, MELISSA - University Of Mississippi; KHAN, SHABANA - University Of Mississippi; AGARWAL, AMEETA - University Of Mississippi; YU, BO-YANG - China Pharmaceutical University; LI, XING-CONG - University Of Mississippi

Submitted to: Journal of Natural Products
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/1/2016
Publication Date: 9/1/2016
Citation: Yu, Q., Ravu, R., Jacob, M.R., Khan, S.I., Agarwal, A.K., Yu, B., Li, X. 2016. Synthesis of natural acylphloroglucinol-based antifungal compounds against Cryptococcus species. Journal of Natural Products. 79:2195-2201. doi:10.1021/acs.jnatprod.6b00224.

Interpretive Summary: Cryptococcosis is a fungal infection caused by Cryptococcus neoformans immunocompromised patients with AIDS, cancer, and organ transplants, or by Cryptococcus gattii in immunocompetent hosts. As part of our continued effort to search for new lead compounds for antifungal discovery in this therapeutic area, we designed and synthesized 35 analogs of naturally occurring acylphloroglucinols. In vitro antifungal testing showed that 17 compounds were active against C. neoformans ATCC 90113, C. neoformans H99, and C. gattii ATCC 32609. The most promising compound was 2-methyl-1-(2,4,6-trihydroxy-3-(4-isopropyl-benzyl)phenyl)propan-1-one that exhibited potent antifungal activity and low cytotoxicity against the mammalian Vero and LLC-PK 1 cell lines. This work led to the discovery of several potent antifungal acylphloroglucinols against Cryptoccocus spp. and a promising antifungal template. These findings will contribute to future antifungal discovery towards pharmaceutical development of new treatments for cryptococcosis.

Technical Abstract: Thirty-five analogs of naturally occurring acylphloroglucinols were designed and synthesized to identify antifungal compounds against Cryptococcus spp. that causes the life-threatening disseminated cryptococcosis. In vitro antifungal testing showed that 17 compounds were active against C. neoformans ATCC 90113, C. neoformans H99, and C. gattii ATCC 32609, with minimum inhibitory concentrations (MICs) in the range 1.0-16.7 pg/mL. Analysis of the structure and antifungal activity of these compounds indicated that 1,3-diacyl-and 1-acyl-3-alkylphloroglucinols were more active than 0-alkyl-acylphloroglucinols. Among the active compounds, 2-methyl-1-(2,4,6-trihydroxy-3-(4-isopropyl-bennzyl)phenyl)propan-1-one (llj)exhibited potent antifungal activity (MICs, 1.5-2.1 pg/mL)and low cytotoxicity against the mammalian Vero and LLC-PK1 cell lines (IC50s, >50 ftg/mL), and thus may serve as a template for further synthesis of compounds with improved antifungal activity. The fmdings of the present work will contribute to future antifungal discovery towards pharmaceutical development of new treatments for cryptococcosis.