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

Francesca Sisto,Mattia Spano,Simone Carradori,Maria Carmela Di Marcantonio,Daniela Secci,Cristina Campestre,Gabriella Mincione,Anatoly P Sobolev,Rossella Grande,Paolo Guglielmi,Arianna Granese

doi:10.3390/molecules26071829

Abstract

Following a similar approach on carvacrol-based derivatives, we investigated the synthesis and the microbiological screening against eight strains of H. pylori, and the cytotoxic activity against human gastric adenocarcinoma (AGS) cells of a new series of ether compounds based on the structure of thymol. Structural analysis comprehended elemental analysis and 1H/13C/19F NMR spectra. The analysis of structure–activity relationships within this molecular library of 38 structurally-related compounds reported that some chemical modifications of the OH group of thymol led to broad-spectrum growth inhibition on all isolates. Preferred substitutions were benzyl groups compared to alkyl chains, and the specific presence of functional groups at para position of the benzyl moiety such as 4-CN and 4-Ph endowed the most anti-H. pylori activity toward all the strains with minimum inhibitory concentration (MIC) values up to 4 µg/mL. Poly-substitution on the benzyl ring was not essential. Moreover, several compounds characterized by the lowest minimum inhibitory concentration/minimum bactericidal concentration (MIC/MBC) values against H. pylori were also tested in order to verify a cytotoxic effect against AGS cells with respect to 5-fluorouracil and carvacrol. Three derivatives can be considered as new lead compounds alternative to current therapy to manage H. pylori infection, preventing the occurrence of severe gastric diseases. The present work confirms the possibility to use natural compounds as templates for the medicinal semi-synthesis.

Highlights

Thymol, a major natural monoterpene phenol in the essential oils of Lamiaceae and Apiaceae families, has been approved by European Union and Food and Drug Administration as a safe food additive as well as in cosmetics and agriculture industry
Following a similar approach on carvacrol-based derivatives, we investigated the synthesis and the microbiological screening against eight strains of H. pylori, and the cytotoxic activity against human gastric adenocarcinoma (AGS) cells of a new series of ether compounds based on the structure of thymol
For the synthesis of compound 8 (Figure 1b) we started from compound 13 that underwent the hydrolysis of the ethyl ester group to afford the carboxylic acid moiety

Summary

Introduction

A major natural monoterpene phenol in the essential oils of Lamiaceae and Apiaceae families, has been approved by European Union and Food and Drug Administration as a safe food additive as well as in cosmetics and agriculture industry. The triple therapy based on the administration on proto-pump inhibitor and two antibiotics has been considered the standard therapy for many years, the increasing rate of triple-therapy failure was registered in many countries as well as the spreading of H. pylori antibiotic resistance. In this context, novel compounds such as components of essential oils endowed with alternative mechanisms of action and the ability to disaggregate lipidic multilayer structures are strongly suggested [7]. Thymol derivatives have been proposed as inhibitors of CagA and VacA (cytotoxin-associated gene A and vacuolization cytotoxin) oncoproteins of Helicobacter pylori [8] and, recently, Bkhaitan et al prepared a thymol-metronidazole ester hybrid and assessed its discrete anti-Helicobacter pylori activity and limited cytotoxicity on normal cell lines [9]

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Results

Conclusion