Synthesis and Antibacterial Activity of Mefloquine-Based Analogs Against Sensitive and Resistant Mycobacterium tuberculosis Strains
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.Journal Title:
Current Topics in Medicinal Chemistry