Synthesis and Biological Evaluation of New Eugenol-Derived 1,2,3- Triazoles as Antimyco bacterial Agents

Eugenol has diverse biological properties including antimycobacterial activity, and the triazole ring is an important heterocycle in antimycobacterial compounds. Therefore, this research aimed to synthesize novel eugenol-derived 1,2,3-triazole as antimycobacterial agents with interesting cytotoxic profile and pharmacological assets. Sixteen compounds were obtained and characterized by nuclear magnetic resonance (NMR), infrared (IR), and high-resolution mass spectrometry (HRMS). Among them, the best growth inhibition properties from a microdilution assay were observed for three derivatives: a benzylic ether (minimum inhibitory concentration (MIC) = 48.89 µM) against Mycobacterium abscessus (ATCC 19977), an O-galactosyde (MIC = 31.76 µM) against Mycobacterium massiliense (ATCC 48898) and a sulfonate (MIC = 88.64 µM) against Mycobacterium fortuitum (ATCC 6841). They can form biofilms, and the infection progression is challenging to control due to multi-drug resistance profiles against diverse antibiotics. In conclusion, the above-mentioned compounds represent starting points in the search of bioactive molecules against mycobacteria with low cytotoxicity and better pharmacological profiles.

Keywords:
eugenol; rapid growing mycobacteria; 1,2,3-triazoles; mycobacterium

Authorship

Thiago dos Santos

Departamento de Alimentos e Medicamentos, Faculdade de Ciências Farmacêuticas, Universidade Federal de Alfenas, 37130-001 Alfenas-MG, BrazilUniversidade Federal de AlfenasBrazilAlfenas, MG, BrazilDepartamento de Alimentos e Medicamentos, Faculdade de Ciências Farmacêuticas, Universidade Federal de Alfenas, 37130-001 Alfenas-MG, Brazil

Camila M. Coelho

https://orcid.org/0000-0002-6904-8681

Thiago C. Elias

Departamento de Microbiologia e Imunologia, Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, 37130-001 Alfenas-MG, BrazilUniversidade Federal de AlfenasBrazilAlfenas, MG, BrazilDepartamento de Microbiologia e Imunologia, Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, 37130-001 Alfenas-MG, Brazil

Fallon S. Siqueira

Departamento de Análises Clínicas e Toxicológicas, Universidade Federal de Santa Maria, 97105-900 Santa Maria-RS, BrazilUniversidade Federal de Santa MariaBrazilSanta Maria, RS, BrazilDepartamento de Análises Clínicas e Toxicológicas, Universidade Federal de Santa Maria, 97105-900 Santa Maria-RS, Brazil

Eloísa S. S. D. Nora

Marli M. A. de Campos

Gabriel A. P. de Souza

Laboratório de Modelagem Molecular e Simulação Computacional, Universidade Federal de Alfenas, 37130-001 Alfenas-MG, BrazilUniversidade Federal de AlfenasBrazilAlfenas, MG, BrazilLaboratório de Modelagem Molecular e Simulação Computacional, Universidade Federal de Alfenas, 37130-001 Alfenas-MG, Brazil

Luiz F. L. Coelho

Diogo T. Carvalho ^** e-mail: diogo.carvalho@unifal-mg.edu.br

https://orcid.org/0000-0002-6362-2822

* e-mail: diogo.carvalho@unifal-mg.edu.br

SCIMAGO INSTITUTIONS RANKINGS

Figures | Tables

Figures (2)
Tables (3)

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Figure 1
Eugenol-derived 1,2,3-triazoles.

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Scheme 1
The employed synthetic route. Reagents and conditions: (i) TIPSCl, imidazole, MW, 8 min, 87%; (ii) BH₃.SMe₂, THF, 0 °C-r.t., followed by NaOH, H₂O₂, 0 °C-r.t., 80%; (iii) MsCl, Et₃N, DCM, 0 °C-r.t., 90%; (iv) NaN₃, DMF, 80 °C; (v) phenylacetylene, sodium ascorbate, copper acetate, DCM:H₂O 1:1, r.t., 96%; (vi) TBAF, THF, 0 °C, 20 min, 85%; (vii) acetyl chloride or benzoyl chloride, pyridine, DCM, 0 °C-r.t., except for TS10 (Bz2O, Et3N, DCM, 4-DMAP, r.t.) and TS11 (EDAC, 4-DMAP, DCM, p-toluic acid, r.t.), 40-92%; (viii) respective alkyl halide or benzyl halide, K₂CO₃, TBAB, H₂O, r.t., 37-61%; (ix) peracetylated glycosyl bromide or peracetylated galactosyl bromide, TBAB, CHCl₃, K₂CO₃ 10% m/v, r.t., 34-35%; (x) respective benzenesulfonyl chloride, THF: H₂O, K₂CO₃ 10% m/m, 0 °C-r.t., 52-90%.

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Table 1
Antimycobacterial activity of the synthesized compounds

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Table 2
Drug-likeness and important parameters

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Table 3
Cytotoxicity to Vero cells and selectivity index

Figure 1 Eugenol-derived 1,2,3-triazoles.

Scheme 1 The employed synthetic route. Reagents and conditions: (i) TIPSCl, imidazole, MW, 8 min, 87%; (ii) BH₃.SMe₂, THF, 0 °C-r.t., followed by NaOH, H₂O₂, 0 °C-r.t., 80%; (iii) MsCl, Et₃N, DCM, 0 °C-r.t., 90%; (iv) NaN₃, DMF, 80 °C; (v) phenylacetylene, sodium ascorbate, copper acetate, DCM:H₂O 1:1, r.t., 96%; (vi) TBAF, THF, 0 °C, 20 min, 85%; (vii) acetyl chloride or benzoyl chloride, pyridine, DCM, 0 °C-r.t., except for TS10 (Bz2O, Et3N, DCM, 4-DMAP, r.t.) and TS11 (EDAC, 4-DMAP, DCM, p-toluic acid, r.t.), 40-92%; (viii) respective alkyl halide or benzyl halide, K₂CO₃, TBAB, H₂O, r.t., 37-61%; (ix) peracetylated glycosyl bromide or peracetylated galactosyl bromide, TBAB, CHCl₃, K₂CO₃ 10% m/v, r.t., 34-35%; (x) respective benzenesulfonyl chloride, THF: H₂O, K₂CO₃ 10% m/m, 0 °C-r.t., 52-90%.

Table 1 Antimycobacterial activity of the synthesized compounds

Compound	MIC / µM
Compound	M. abscessus	M. massiliense	M. fortuitum
TS5	671.03	671.03	1342.07
TS6	N.A.	N.A.	N.A.
TS7	17039	681.57	681.57
TS8	N.A.	N.A.	N.A.
TS9	N.A.	N.A.	N.A.
TS10	1571.95	1571.95	196.49
TS11	N.A.	N.A.	N.A.
TS12	N.A.	N.A.	N.A.
TS13	N.A.	N.A.	N.A.
TS14	N.A.	N.A.	N.A.
TS15	N.A.	N.A.	N.A.
TS16	222.30	222.30	222.30
TS17	48.89	782.23	391.11
TS18	709.12	354.56	88.64
TS19	N.A.	N.A.	N.A.
TS20	N.A.	N.A.	N.A.
TS21	N.A.	N.A.	N.A.
TS22	254.07	31.76	127.03
CLR	21.39	1.34	42.78
SMZ	31.59	126.34	505.37

MIC: minimum inhibitory concentration; N.A.: no activity at the tested concentrations; CLR: clarithromycin; SMZ: sulfamethoxazole.

Table 2 Drug-likeness and important parameters

Compound	Descriptor
Compound	MM / (g moL^-1)	log P_o/w^a a Lipophilicity descriptor. (MlogP)	H donor	H acceptor	Lipinski’s violation
TS5	465.70	4.35	0	4	1
TS6	309.36	2.41	1	4	0
TS7	458.47	3.04	0	7	0
TS8	447.91	4.40	0	5	1
TS9	351.40	2.80	0	5	0
TS10	413.47	3.92	0	5	0
TS11	427.50	4.13	0	5	0
TS12	444.48	2.81	0	6	0
TS13	433.93	4.20	0	4	1
TS14	413.51	3.93	0	4	0
TS15	323.39	2.64	0	4	0
TS16	365.47	3.31	0	4	0
TS17	399.48	3.73	0	4	0
TS18	449.52	3.66	0	6	0
TS19	463.55	3.87	0	6	0
TS20	494.52	2.81	0	8	0
TS21	639.65	1.72	0	13	2
TS22	639.65	1.72	0	13	2
CLR	747.95	–0.54	4	14	2
SMZ	253.28	–0.15	2	4	0

^a
Lipophilicity descriptor.
MM: molecular mass; log P_o/w: octanol water partition coefficient; CLR: clarithromycin; SMZ: sulfamethoxazole.

Table 3 Cytotoxicity to Vero cells and selectivity index

Compound	CC₅₀/ µM	Selectivity index
Compound	CC₅₀/ µM	M. abscessus	M. massiliense	M. fortuitum
TS5	62.16 ± 4.47	0.09	0.09	0.05
TS6	275.95 ± 23.11	–	–	–
TS7	114.22 ± 4.65	0.67	0.17	0.17
TS8	114.13 ± 11.14	–	–	–
TS9	105.55 ± 23.97	–	–	–
TS10	78.63 ± 2.06	0.05	0.05	0.40
TS11	68.91 ± 1.22	–	–	–
TS12	59.48 ± 0.38	–	–	–
TS13	67.13 ± 0.62	–	–	–
TS14	50.69 ± 5.80	–	–	–
TS15	86.05 ± 12.09	–	–	–
TS16	74.34 ± 5.86	0.33	0.33	0.33
TS17	117.42 ± 40.90	2.40	0.15	0.30
TS18	52.86 ± 1.00	0.07	0.15	0.60
TS19	42.13 ± 2.69	–	–	–
TS20	37.84 ± 2.34	–	–	–
TS21	61.36 ± 15.44	–	–	–
TS22	227.46 ± 21.62	0.90	7.16	1.79

CC₅₀: cytotoxic concentration for 50%; –: selectivity index was not calculated (no activity against the tested RGM strains). The best results are highlighted.

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Synthesis and Biological Evaluation of New Eugenol-Derived 1,2,3- Triazoles as Antimyco bacterial Agents

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[1] * e-mail: diogo.carvalho@unifal-mg.edu.br