Synthesis of a Small Library of Nature-Inspired Xanthones and Study of Their Antimicrobial Activity.

Diana I S P Resende,Luís Gales,Madalena M M Pinto,Patrícia Pereira-Terra,Joana Freitas-Silva,Paulo Martins Da Costa,Maria Emília De Sousa,Joana Moreira,Agostinho Lemos,Eugénia Pinto

doi:10.3390/molecules25102405

Abstract

A series of thirteen xanthones 3–15 was prepared based on substitutional (appendage) diversity reactions. The series was structurally characterized based on their spectral data and HRMS, and the structures of xanthone derivatives 1, 7, and 8 were determined by single-crystal X-ray diffraction. This series, along with an in-house series of aminated xanthones 16–33, was tested for in-vitro antimicrobial activity against seven bacterial (including two multidrug-resistant) strains and five fungal strains. 1-(Dibromomethyl)-3,4-dimethoxy-9H-xanthen-9-one (7) and 1-(dibromomethyl)-3,4,6-trimethoxy-9H-xanthen-9-one (8) exhibited antibacterial activity against all tested strains. In addition, 3,4-dihydroxy-1-methyl-9H-xanthen-9-one (3) revealed a potent inhibitory effect on the growth of dermatophyte clinical strains (T. rubrum FF5, M. canis FF1 and E. floccosum FF9), with a MIC of 16 µg/mL for all the tested strains. Compounds 3 and 26 showed a potent inhibitory effect on two C. albicans virulence factors: germ tube and biofilm formation.

Highlights

Multi-drug resistance is one of the major causes of the alarming level of infectious disease worldwide, with treatment failure being an increasing concern
In order to synthetize a collection of structurally diverse compounds, several straightforward transformations were performed for two simple oxygenated xanthones: 3,4-dimethoxy-1-methyl-9Htransformations were performed for two simple oxygenated xanthones: 3,4-dimethoxy-1-methyl-9Hxanthen-9-one (1) and 3,4,6-trimethoxy-1-methyl-9H-xanthen-9-one (2) (Scheme 1), obtained as xanthen-9-one (1) and 3,4,6-trimethoxy-1-methyl-9H-xanthen-9-one (2) (Scheme 1), obtained as previously described [19,20]
The low yields obtained in this reaction are due are due to failure of the reaction to go to completion and other complications in the purification step

Summary

Introduction

Multi-drug resistance is one of the major causes of the alarming level of infectious disease worldwide, with treatment failure being an increasing concern. Natural products have been the most successful source of potential drug leads for millennia, and the influence of natural product structures is nowadays quite marked in the anti-infective area, most related to their role in defense mechanisms of secondary metabolites. Xanthones are ubiquitous polyphenolic secondary metabolites, and, several naturally occurring xanthones have revealed potent metabolites, and, several naturally occurring xanthones have revealed potent antimicrobial antimicrobial activities (Figure 1) [1]. Norlichexanthone [2,3,4,5], 1,4,5-trihydroxy-2activities (Figure 1) [1]. Norlichexanthone [2,3,4,5], 1,4,5-trihydroxy-2-methylxanthone [6], methylxanthone [6], fischexanthone [7], and dimethyl 8-methoxy-9-oxo-9H-xanthene-1,6fischexanthone [7], and dimethyl 8-methoxy-9-oxo-9H-xanthene-1,6-dicarboxylate [8,9] (Figure 1)

Methods

Results

Conclusion