Synthesis of Natural Acylphloroglucinol-Based Antifungal Compounds against Cryptococcus Species

Abstract

Thirty-three natural-product-based acylphloroglucinol derivatives were synthesized to identify antifungal compounds against Cryptococcus spp. that cause 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 μg/mL. Analysis of the structure and antifungal activity of these compounds indicated that the 2,4-diacyl- and 2-acyl-4-alkylphloroglucinols were more active than O-alkyl-acylphloroglucinols. The most promising compound found was 2-methyl-1-(2,4,6-trihydroxy-3-(4-isopropylbenzyl)phenyl)propan-1-one (11j), which exhibited potent antifungal activity (MICs, 1.5-2.1 μg/mL) and low cytotoxicity against the mammalian Vero and LLC-PK1 cell lines (IC50 values >50 μg/mL). This compound may serve as a template for further synthesis of new analogues with improved antifungal activity. The findings of the present work may contribute to future antifungal discovery toward pharmaceutical development of new treatments for cryptococcosis.

Synthesis and Anti-Inflammatory Activities of Phloroglucinol-Based Derivatives

“…Based on the concept that both natural and synthetic acylphloroglucinols possess potent biological activities [6,7,13,14,15,16,17], seven compounds representing monoacyl-, diacyl-, dimeric acyl-, alkylated monoacyl-, and the nitrogen-containing alkylated monoacylphloroglucinols were synthesized (Scheme 1). Diacylphloroglucinol ( 2 ) and monoacylphloroglucinol ( 3 ) were prepared first according to the procedures described previously [18,19,20].…”

Polycyclic Polyprenylated Acylphloroglucinols: An Emerging Class of Non‐Peptide‐Based MRSA‐ and VRE‐Active Antibiotics

“…Their core structure contains a bicyclo[3.3.1]nonane‐2,4,9‐trione that is substituted with a variety of unsaturated side chains (Figure ). Many of those compounds are known for their biological activity, for example, antifungal, antiprotozoal, antiviral, antiproliferative, antidepressant, and also antimicrobial activity . Depending on the position of the exocyclic acyl group, the PPAPs are divided into three subclasses, that is, type A (acyl group at C1), type B (acyl group at C3), and type C (acyl group at C5).…”

“…Many of those compounds are known for their biological activity,f or example,a ntifungal, antiprotozoal, antiviral, antiproliferative,a ntidepressant, and also antimicrobial activity. [19][20][21][22][23][24][25][26][27][28][29][30][31][32] Depending on the position of the exocyclica cylg roup,t he PPAPs are divided into three subclasses,t hat is,t ype A( acylg roup at C1), type B( acyl group at C3), and type C( acyl group at C5). Hyperforin, atype APPA P, has been reported to have high antimicrobial activity,b ut the C3 prenyl substituent has caused problems,s uch as photo-and oxidative degradation.…”

Polycyclische, polyprenylierte Acylphloroglucinole – eine Klasse nicht‐peptidbasierter MRSA‐ und VRE‐aktiver Antibiotika

“…[19][20][21][22][23][24][25][26][27][28][29][30][31][32] Die Naturstofffamilie der PPAPs wird abhängig von der Position der Acyl-Gruppe in drei Unterklassen unterteilt: Ty pA (Acyl-Gruppe an C-1), Ty pB (Acyl-Gruppe an C-3) und Ty pC (Acyl-Gruppe an C-5). [19][20][21][22][23][24][25][26][27][28][29][30][31][32] Die Naturstofffamilie der PPAPs wird abhängig von der Position der Acyl-Gruppe in drei Unterklassen unterteilt: Ty pA (Acyl-Gruppe an C-1), Ty pB (Acyl-Gruppe an C-3) und Ty pC (Acyl-Gruppe an C-5).…”

“…antiproliferative,A ntidepressions-und auch antibakterielle Aktivitätb ekannt. [19][20][21][22][23][24][25][26][27][28][29][30][31][32] Die Naturstofffamilie der PPAPs wird abhängig von der Position der Acyl-Gruppe in drei Unterklassen unterteilt: Ty pA (Acyl-Gruppe an C-1), Ty pB (Acyl-Gruppe an C-3) und Ty pC (Acyl-Gruppe an C-5). Über die hohe antibakterielle Aktivitätv on Hyperforin, einem Typ-A-PPAP, wurde bereits berichtet, jedoch erwies sich die C-3-Prenyl-Gruppe als photo-und oxidationslabil.…”