Synthesis and Biological Evaluation of Carvacrol-Based Derivatives as Dual Inhibitors of H. pylori Strains and AGS Cell Proliferation

Abstract

This study reports on the synthesis, structural assessment, microbiological screening against several strains of H. pylori and antiproliferative activity against human gastric adenocarcinoma (AGS) cells of a large series of carvacrol-based compounds. Structural analyses consisted of elemental analysis, 1H/13C/19F NMR spectra and crystallographic studies. The structure-activity relationships evidenced that among ether derivatives the substitution with specific electron-withdrawing groups (CF3 and NO2) especially in the para position of the benzyl ring led to an improvement of the antimicrobial activity, whereas electron-donating groups on the benzyl ring and ethereal alkyl chains were not tolerated with respect to the parent compound (MIC/MBC = 64/64 µg/mL). Ester derivatives (coumarin-carvacrol hybrids) displayed a slight enhancement of the inhibitory activity up to MIC values of 8–16 µg/mL. The most interesting compounds exhibiting the lowest MIC/MBC activity against H. pylori (among others, compounds 16 and 39 endowed with MIC/MBC values ranging between 2/2 to 32/32 µg/mL against all the evaluated strains) were also assayed for their ability to reduce AGS cell growth with respect to 5-Fluorouracil. Some derivatives can be regarded as new lead compounds able to reduce H. pylori growth and to counteract the proliferation of AGS cells, both contributing to the occurrence of gastric cancer.

Synthesis and Evaluation of Thymol-Based Synthetic Derivatives as Dual-Action Inhibitors against Different Strains of H. pylori and AGS Cell Line

“…Only three derivatives (3,9,12) with linear and increasing alkyl chains (Et, n-Pr, n-Bu) presented improved MIC values with respect to thymol against some clinical isolates (MIC/MBC = 16 µg/mL). Similar results were obtained for the aliphatic derivatives of carvacrol in our previous paper [15]. Among the second cluster of benzyloxy and heteroarylmethyloxy derivatives (15-39), the simplest and unsubstituted compound (15) was slightly more potent than thymol, but the introduction of electron-withdrawing or electron-donating substituents at different positions induced an opposite trend on the inhibitory activity.…”

“…Similar results were obtained for the aliphatic derivatives of carvacrol in our previous paper [15]. Among the second cluster of benzyloxy and heteroarylmethyloxy derivatives (15-39), the simplest and unsubstituted compound (15) was slightly more potent than thymol, but the introduction of electron-withdrawing or electron-donating substituents at different positions induced an opposite trend on the inhibitory activity. Substitutions at the ortho position of the benzyl group were usually detrimental (compounds 16, 20, 31) except for the potent activity of compound 34 (o-NO 2 ) on specific strains (MIC range 4-8 µg/mL, MBC range 8-16 µg/mL).…”

“…For the synthesis of compounds 2 – 39, we employed the synthetic approach reported in Figure 1 . Compounds 2 – 7 and 9 – 39 ( Figure 1 a) have been synthesized taking advantage of the Williamson etherification procedure previously employed by our group for the synthesis of carvacrol derivatives [ 15 ]. Thymol ( 1 ) was reacted with the proper bromide in dry N , N ’-dimethylformamide (DMF), in the presence of anhydrous potassium carbonate (K 2 CO 3 ) and under nitrogen (N 2 ) atmosphere.…”

“…Collectively, the functionalization of the OH moiety with an unsubstituted benzyloxy group (15) or a linear alkyloxy chain ( 9) was preferred in eliciting the inhibitory activity below 100 µM. The substitution of the benzyl ring with NO 2 , F, and CN led to a reduction of the biological effect as well as the poly-substitution (26 and 30).…”

Dual Carbonic Anhydrase IX/XII Inhibitors and Carbon Monoxide Releasing Molecules Modulate LPS-Mediated Inflammation in Mouse Macrophages

“…The reaction was diluted with water (50 mL) and extracted with CHCl 3 (3 × 20 mL), dried (anhydrous Na 2 SO 4 ), and the solvent removed. The crude product obtained was purified by column chromatography on silica gel with the eluent being a mixture of n -hexane and ethyl acetate to afford the title compounds [ 27 ].…”