Synthesis and Antifungal Activity Evaluation of Phloeodictine Analogues

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 0.88–10 μM, and all were 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.

Advances in Antifungal Drug Development: An Up-To-Date Mini Review

“…Ravu and colleagues recently reported the synthesis and in vitro antifungal evaluation of a series of phloeodictine analogues [59]. Phloeodictines are marine-derived alkaloids, and the phloeodictine-based 6-hydroxy-2,3,4,6-tetrahydropyrrolo[1,2-a]pyrimidinium moiety with an n-tetradecyl side chain at C-6 has shown antifungal activity and serves as a template for further derivatization.…”

“…Phloeodictines are marine-derived alkaloids, and the phloeodictine-based 6-hydroxy-2,3,4,6-tetrahydropyrrolo[1,2-a]pyrimidinium moiety with an n-tetradecyl side chain at C-6 has shown antifungal activity and serves as a template for further derivatization. They identified three promising analogues (compounds 24, 36, and 48 in the original paper) with potent activity (MIC ≈ 1 µM) against Candida neoformans and low toxicity against mammalian Vero cells (IC 50 > 40 µM) [59].…”

“…Fungal ergosterol biosynthesis [59] Biphenylethylaminoacetamides Fungal cell wall integrity [60] Thiazoyl guanidine derivatives Fungal ergosterol biosynthesis [61] Carboline HDAC inhibitors Fungal histone deacetylase [62] Fungal ergosterol biosynthesis [59] Biphenylethylaminoacetamides scaffold required for dual activity for the first time, which shall serve as a template for future synthetic efforts. Among their prepared inhibitors, they identified 2-((1-(4-fluorophenyl)-3-oxo-3-phenylpropyl)thio)benzoate (compound 10 in original paper) as the most promising dual inhibitor, since it significantly decreased IL-1β release (IC50 = 2.3 ± 0.8 µM) without affecting mammalian cell viability (viability = 101.5 ± 1.4%) and exerted potent in vitro antifungal activity against Candida albicans (MIC = 6.4 ± 2.6 µM).…”

“…Fungal ergosterol biosynthesis [59] Biphenylethylaminoacetamides Fungal cell wall integrity [60] Thiazoyl guanidine derivatives Fungal ergosterol biosynthesis [61] Carboline HDAC inhibitors Fungal histone deacetylase [62] Fungal histone deacetylase [62] Acyl hydrazides Aside from the mentioned small molecules with intracellular targets, membrane-interacting antifungal antimicrobial peptides (AMPs) are another example of a promising class of antifungals. AMPs generally consist of 12 to 54 amino acids with a net positive charge at physiological pH [68].…”