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

Abstract

Background: Thymol as a natural biological template can be modified chemically since the hydroxyl group makes it a candidate for structural modification. Thus, this study incorporated the triazole moiety on thymol and the chlorination of thymol moiety to help improve its biological potency.

Materials and methods: A series of ten 1,2,3-triazole-thymol derivatives 1-10 were synthesized from thymol, by a click reaction between O-propargyl terminal alkyne of thymol and its chlorothymol with benzyl azide and substituted benzyl azides. Their structures were confirmed by spectroscopic methods (¹H-NMR, ¹³C-NMR, IR, GC-MS-EI/CI and LC-ESI-QTOF-MS). The Well diffusion method using Müeller-Hinton agar plates was used to demonstrate the antimicrobial activities of the synthesized triazole-thymol derivatives on selected bacterial strains; Escherichia coli ATCC 25922, Staphylococcus aureus ATCC25923, Methicillin resistant S. aureus (MRSA), Pseudomonas aeruginosa ATCC 29853, E. coli ESBL, K l ebsiella pneumoniae NCTC 13438 and Meropenem Resistant E. coli.

Results: All the synthesized triazole-thymol derivatives showed significant but variable antibacterial activity against the seven medically important bacterial strains tested. The compound 4-((4-chloro-2-isopropyl-5-methylphenoxy)methyl)-1-(2-nitrobenzyl)-1H-1,2,3triazole (9) demonstrated a higher antibacterial activity with a mean zone of inhibition (38.7 mm) compared with ampicillin as the positive control which gave a zone size of 30.0 mm. In addition, the compound showed a three-fold potency than the parent compound, thymol (11.0 mm) against MRSA at a concentration of 100 μg/ml.

Conclusion: These results provide additional evidence of the exploitation of natural products like thymol as leads for drug development against medically important bacterial pathogens.

Keywords: Ampicillin; Antibacterial activity; Essential oil; Monoterpenoid; Thymol; Triazole.

Scheme 1

Synthesis of 1-substituted 1,2,3-triazole derivatives of thymol moiety.

Scheme 2

Synthesis of 1-substituted 1,2,3-triazole derivatives with two thymol groups.

Figure 1

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

Figure 2

Mean zones of inhibition (mm) of compounds 1–10 (50 μg/ml) against tested bacteria.

Figure 3

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