Synthesis, Characterization, Cytotoxicity, and Antibacterial Properties of trans‐γ‐Halo‐δ‐lactones

Abstract

A new four‐step pathway for the synthesis of γ‐halo‐δ‐lactones is described from simple, commercially available substrates: aryl bromides and 3‐methyl crotonaldehyde. The halogenolactonization reaction of β,δ‐substituted, γ,δ‐unsaturated carboxylic acid 4 a–c is regio‐ and stereoselective and gives only the trans‐isomers of lactones 5 a–c, 6 a–c, and 7 a–c. The structures of all synthesized compounds were confirmed by using spectroscopic methods. For bromolactone, containing a naphthyl moiety in the structure, crystallographic analysis was also performed. The lactones were tested for their cytotoxic activity against L929 cell lines (mouse fibroblasts) and antibacterial activity against Escherichia coli strains ATCC 8739 and Staphylococcus aureus ATCC 65389. Compounds 5 a, 5 c, 7 a, and 7 b statistically significantly inhibited the metabolic activity of mouse fibroblasts L929. Compounds 5 b and 6 a were not cytotoxic towards L929 cells, but showed moderate bactericidal properties.

New γ-Halo-δ-lactones and δ-Hydroxy-γ-lactones with Strong Cytotoxic Activity

“…Halolactones were obtained as a result of the four-step reaction [23] shown in Figure 1. The first step of the synthesis was a Grignard reaction between selected aryl bromides 1a – c and trans-crotonaldehyde, which gave us unsaturated allyl alcohols 2a – c with yields 48–62% [24].…”

“…An analogous synthesis using γ,δ-unsaturated carboxylic acids with a methyl group in the β-position led to a mixture of products. Lactonization of unsaturated carboxylic acids with two methyl groups in the β-position have only one product, trans -γ-chloro-δ-lactone [23].…”

“…This interesting group of compounds also attracted our attention. Thus far, we have developed a synthesis of β-ayl-δ-iodo-γ-lactones [21], aryl-δ-hydroxy-γ-lactones [22], and trans-γ-halo-δ-lactones [23], and tested their cytotoxic and bactericidal activities. Here, we present stereoselective substrate-controlled synthesis of new γ-halo-δ-lactones.…”

Synthesis and Biological Activity of New 4‐tert‐Butylcyclohexanone Derivatives

“…However, it was effective against S. aureus, restricting the growth of the bacterial culture by more than 60 % at a 200 μg/mL concentration. [27] It is assumed that it is the effect of the compounds interaction with cellular membranes, resulting in their permeabilization and disruption. MIC 90 was not recorded within examined range of concentrations (50-250 μg/mL).…”

“…[25] Monoterpenes tend to exhibit weaker antibacterial activity towards Gram-negative strains, [26] in contrast to bromolactones that may affect the growth of both Gram-positive and Gram-negative bacteria. [27] It is assumed that it is the effect of the compounds interaction with cellular membranes, resulting in their permeabilization and disruption. [4][28] Wider spectrum of bromolactone derivatives activity confirmed in our studies may be the basis for a further search for novel antimicrobials, as the growing drug resistance of common pathogens is a known matter of concern.…”