Synthesis and Antibacterial Activity of Mefloquine-Based Analogs Against Sensitive and Resistant Mycobacterium tuberculosis Strains
| Autor: | Adriele da Silva Araújo, Cláudia Pessoa, Emerson Teixeira da Silva, Maria C.S. Lourenço, Adriana M Moraes, Marcus V. N. de Souza |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Cell Survival
Antitubercular Agents Microbial Sensitivity Tests 01 natural sciences Mycobacterium tuberculosis 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor Drug Discovery Drug Resistance Bacterial medicine Humans MTT assay Cell Proliferation Trifluoromethyl biology Molecular Structure Mefloquine Quinoline Isoniazid General Medicine biology.organism_classification 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry 030220 oncology & carcinogenesis Sodium azide Antibacterial activity Nuclear chemistry medicine.drug |
| Zdroj: | Current topics in medicinal chemistry. 19(9) |
| ISSN: | 1873-4294 |
| Popis: | Background and Introduction:Mefloquine, a drug used to prevent and treat malaria is described possessing activity against the Mycobacterium tuberculosis (Mtb) as well as against multidrugresistant tuberculosis (MDR) and other types of bacteria. Despite their importance, few compounds based on the Mefloquine nucleus have been synthesized and evaluated against TB.Materials and Methods:For the synthesis of all the compounds based on the Mefloquine nucleus we used a synthetic route which utilized the key derivative 4-methoxy-2,8-bis(trifluoromethyl)quinoline 2 as starting material. The compounds 3 (a-c), 4 (a-b) were synthesized after one step by reaction of 2 with appropriate amines substituted. The chloro derivatives 5 and 6 were obtained from compounds 4b and 4a by treatment with SOCl2 in CH2Cl2 at reflux in 75 and 80% yield, respectively. The analogue 6 was converted to 7 after treatment with ethanolamine under heating at 90oC in 64% yield and to the azido derivative 8 in 56% after reaction with sodium azide in MeOH at reflux for 2 h. The analogue 9 was obtained after reaction of 5 with ethanolamine at 90oC for 1 h in 90% yield. All the new compounds were identified by detailed spectral data, including 1H NMR, 13C NMR and high resolution mass spectra. All the compound were evaluated for their in vitro antibacterial activity against sensitive Mycobacterium tuberculosis ATCC 27294, using the microplate Alamar Blue assay (MABA). The more active compounds 3c, 7, and 9 were also evaluated against resistant strain SR 2571/0215 (resistant to Rifampicin and Isoniazid) by above method. All compounds were tested against three cancer cell lines: SF-295 (glioblastoma), HCT-116 (colon) and PC-3 (prostate) using the MTT assay.Results:All the planned ten compounds were synthetically obtained in good global yield, displaying activity against sensitive Mycobacterium tuberculosis in vitro, with exception of one, with MIC values between 37.2 and 154.8 µM. The compounds 3c (37.2 µM), 7 (68.1 µM) and 9 (65.6 µM) showed the highest activity in this series with MIC values similar when compare to the standard Mefloquine (30 – 60 µM), being 3c the most potent. The more active compounds 3c, 7, and 9 were also evaluated against resistant strain, displaying MIC of 37.2, 136.2 and 65.6 µM, respectively. All compounds were tested against three cancer cell lines and showed low cytotoxicity.Conclusion:All synthesized compounds, with the exception of 5, exhibited activity against the Mtb. Compound 3c was the most potent against resistant and sensitive Mtb in this series, with MIC value of 37.2 µM. All compounds showed low cytotoxicity. These findings could be considered a good model to develop possible lead compounds in the fight against TB based on Mefloquine nucleus. |
| Databáze: | OpenAIRE |
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