Structure–activity relationship of antibacterial chalcones
Graphical abstract
The antibacterial activity of thirty-one chalones is described. Some of the tested compounds showed fair to significant activity against Gram-positive bacteria.
Introduction
Flavonoids represent an outstanding class of naturally occurring compounds with a 1,3-diarylpropane skeleton, which may assume different cyclic or alicyclic arrangements, according to varying levels of oxidation. Chalcones are open chain flavonoids in which two aromatic rings are joined by a three carbon α,β-unsaturated carbonyl system, that is, 1,3-diphenyl-2-propen-1-one derivatives. The equilibrium between the open chalcone form and the cyclic flavanone isomer is the key step at the origin of the skeletal modifications of the biosynthetic pathway. Chalcones have shown a wide variety of anticancer,1 antiinflammatory,2 antiinvasive,3 and antifungal activities.4 In addition to the properties listed above, the antibacterial activity of chalcones is being increasingly documented. Depending on the substitution of the two aromatic rings the chalcones can display different spectra of activity. For instance, (E)-chalcones containing 4-alkylthio- or 4-alkoxy side chains and 4′-N-piperidine or 4′-N-methylpiperidine groups, as para substituents, exhibited a narrow spectrum of antibacterial activity, being affective against Gram-positive bacteria.5 Conversely, broad-spectrum compounds, effective against Gram-positive and Gram-negative bacteria, were obtained by introduction of piperazine or 2,5-dichlorothiophene on the basic skeleton of the chalcones.6 Finally, 5-[3-(4′-dimethylaminophenyl)acryolyl]-6-methoxybenzo-[1,3]-oxathiol-2-one was shown to display tuberculostatic activity against Mycobacterium tuberculosis.7 In earlier studies, concerning their antimicrobial effect, the activity of chalcones was mainly attributed to the presence of phenolic hydroxyl groups, which have high affinity for proteins and thus may inhibit microbial enzymes.8 It was generally agreed that at least one phenolic hydroxyl group and a certain degree of lipophilicity were required.9 The nature of the flavonoid was considered priority, e.g., the flavanone isoxanthoumol is 60 times less active than the corresponding chalcone,10 but the influence of the substitution pattern on the structure–activity relationship (SAR) was not further investigated. By contrast, a SAR study on the effect of 12 different chalcones, on both established and primary ovarian cancer cells, revealed some important remarks on the influence that structural changes may have on both antiproliferative and binding activity.11 This paper deals with an investigation on the influence of the substitution pattern, involving hydroxyl, methoxyl, acetoxyl, and methyledioxy groups as well as isoprenoid substituents, of both A and B rings of 31 chalcones on their antibacterial activity against human pathogenic microorganisms.
Section snippets
Results and discussion
Table 1 summarizes the results obtained for the MICs and MBCs of the 31 chalcones (Figs. 1 and 2) against the four bacterial species.
Although no definite structure–activity relationship could be determined, some conclusions on the structural changes that may influence the antimicrobial activity can be drawn by the comparison among the structures of compounds with different activities:
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4-Hydroxyderricin (18) was the most active compound, followed by 2′,4,4′-trihydroxy-3-prenyl-3′-geranylchalcone (
Conclusion
These studies, focused on the potentially active skeleton of chalcones, pointed out the importance of the positions of the phenolic hydroxyl groups and/or the isoprenyl side chain in the substitution pattern. The importance of prenyl and/or geranyl groups, which confer to the molecule a strong affinity to biological membranes14 must be once again noticed.15
Chalcones
Thirty-one natural and/or synthetic chalcones, available in our laboratories, have been assayed in this study. The chalcones (compounds 1–10 and 27) and dihydrochalcones (compounds 28–31) were earlier synthesized by Professor G. Bargellini (1879–1963) and co-worker at beginning of 20th century.16, 17, 18, 19 Afterwards, the compounds were inherited by Professor G.B. Marini Bettolo (1915–1996) and finally exhumed by one of us (F. Delle Monache). Their structures, initially suggested by the
Acknowledgments
We thank Giuliano Delle Monache for a discussion of the manuscript. This work was supported by Fundação de Apoio à Pesquisa Científica e Tecnológica do Estado de Santa Catarina (FAPESC) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).
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