The hydroxyl moiety on carbon one (C1) in the monoterpene nucleus of thymol is indispensable for anti-bacterial effect of thymol

Abstract

Background: Thymol, a natural monoterpene phenol is not only relevant clinically as an anti-microbial, antioxidant and anti-inflammatory agent but also holds the prospect as a natural template for pharmaceutical semisynthesis of therapeutic agents. It is a major component of essential oils from many plants. Evidence abound linking overall bioactivity of thymol to its monoterpene nucleus, specifically, the hydroxyl (-OH) substituent on carbon number one (C1) on the monoterpene nucleus. Other studies have posited that the overall bioactivity of thymol is not substantially altered by chemical modification of-OH on the C1 of the monoterpene nucleus. In view of this, it is still unclear as to whether removal or modification of the-OH on C1 of the monoterpene nucleus relates generally or context-dependently to bioactivity of thymol. Objective: The present study investigated anti-bacterial effects of ester-and-ether substituted derivatives of thymol on S. aureus, P. aeruginosa and E. coli. Materials and methods: twelve ester-and-ether substituted derivatives of thymol (6TM1s and 6TM2s) were synthesized and characterized by using HPLC, Mass spectrometry, and IR techniques. Anti-bacterial activity of the 12 thymol derivatives was evaluated using broth macrodilution and turbidimetric methods against pure clinical isolates (S. aureus, P. aeruginosa and E. coli). Standard antibiotics used were Thymol Streptomycin and flucloxacillin, while DMSO was used as vehicle for thymol derivatives. MIC and MBC were determined. Results: Thymol produced broad-spectrum growth inhibition on all isolates. At equimolar concentrations, thymol and reference drugs produced concentration-dependent growth inhibition against the isolates (Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli) compared to DMSO. Although the growth inhibitory effects of the ester-and-ether derivatives of thymol was significant (P 0.05) compared to DMSO, it was however insignificant (P ! 0.05) compared to thymol and reference antibiotics. Comparatively, at equimolar concentrations, ester-substituted derivatives of thymol, particularly the branched chain derivative (TM1C) produced more effective growth inhibition on the isolates than the ether-substituted derivatives of thymol. Thymol was twice as potent (MIC and MBC, 500 μg/ml) than both ester-and-ether substituted derivatives of thymol (MIC and MBC, > 1000 μg/ml) on all the three clinical isolates. Increase in side chain bulkiness of-OH moiety on the monoterpene nucleus of thymol decreased growth inhibition on isolates. Conclusion: Thymol has demonstrated broad-spectrum anti-bacterial effects attributable to the hydroxyl moiety on C1 of the monoterpene nucleus. Structural modification of the hydroxyl moiety on C1 of the monoterpene nucleus of thymol with either ether-or-ester substitutions yielded no significant anti-bacterial effects.

Synthesis of 1,2,3-triazole-thymol derivatives as potential antimicrobial agents

“…The substitution of chlorine on the carbon-4 positions of the thymol nucleus played vital role that afforded the superior activity of compounds 6,7, 8, 9 and 10 over the other compounds and the parent compound, thymol. The hydroxyl moiety on thymol also did confer an activity as thymol showed a mean zone of inhibition against all the bacteria with mean zone of inhibition ranging between 13.7 and 2.7 mm which confirms earlier results that [ 15 ], the hydroxyl group of thymol is indispensable for its antimicrobial activity.

Figure 1 Mean zones of inhibition (mm) of compounds 1–10 (100 μg/ml) against tested bacteria.

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“…The chemical modification of the hydroxy (–OH) group into its ether and ester derivatives afforded new lead compounds found to be effective against Helicobacter pylori infection to prevent the occurrence of severe gastric disease conditions [ 14 ]. A recent study also showed that the hydroxyl functional group of thymol was indispensable for its anti-bacterial effect [ 15 ]. Modification of the hydroxy group into ester and ether derivatives resulted in low anti-bacterial activities on the following organisms Staphylococcus aureus (Gram positive), Escherichia coli (Gram negative) and Pseudomonas aeruginosa (Gram negative) compared to the parent compound, thymol [ 15 ].…”

“…A recent study also showed that the hydroxyl functional group of thymol was indispensable for its anti-bacterial effect [ 15 ]. Modification of the hydroxy group into ester and ether derivatives resulted in low anti-bacterial activities on the following organisms Staphylococcus aureus (Gram positive), Escherichia coli (Gram negative) and Pseudomonas aeruginosa (Gram negative) compared to the parent compound, thymol [ 15 ].…”

Abrus precatorius Leaf Extract Reverses Alloxan/Nicotinamide‐Induced Diabetes Mellitus in Rats through Hormonal (Insulin, GLP‐1, and Glucagon) and Enzymatic (α‐Amylase/α‐Glucosidase) Modulation

“…This paradigm is quiet common in poorer tropical countries of the world, where most people rely on herbal medicine to meet their primary health care needs [8]. Also, this may probably affirm the usual assertion that use of herbs predates modern medicine and that natural products continue to serve as templates for pharmaceutical semisynthesis of new drugs [10] including antidiabetic agents. Importantly, these herbs and herb-derived therapies are used as adjunctive therapy in a manner that reflects the belief systems and ethnobotanical heritage of most local communities across Afro-Asian regions of the world.…”

Antibacterial mechanism of ultrasound combined with thymol against Shewanella putrefaciens: implications for cell integrity and biofilm control

“…Additionally, the inhibitory effect of Thy on S. putrefaciens showed a positive correlation with the concentration within a certain concentration range. Boye et al (2020) assessed the antimicrobial activity of 12 thymol derivatives against pure clinical isolates, including Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. They discovered that thymol exhibited a broad-spectrum antibacterial effect, resulting in concentration-dependent growth inhibition, primarily attributed to the hydroxyl moiety on the C1 position of the monoterpenoid core.…”