Synthesis and Antibacterial Activity of Mefloquine-Based Analogs Against Sensitive and Resistant Mycobacterium tuberculosis Strains

Abstract

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.

4‐Quinolinylhydrazone analogues kill Leishmania (Leishmania) amazonensis by inducing apoptosis and mitochondria‐dependent pathway cell death

“…The synthesis methodology was based on the construction of the quinoline nucleus, through the condensation of substituted aniline with ethyl trifluoracetoacetate, with due incorporation in position 4 of the ring of a leaving group, furnishing a key intermediate. In this position, hydrazine was added, for the resulting product to be transformed into the referred quinolinylhydrazone analogues (Scheme 1, MHZ02 – MHZ15 , Table 1), after reaction with the appropriate substituted aromatic aldehydes (Teixeira da Silva et al., 2023).…”

“…In this work, a series of previously synthesized 4‐quinolinylhydrazone (Teixeira da Silva et al., 2023) analogues were evaluated against L . amazonensis .…”

Overcoming the Prokaryote/Eukaryote Barrier in Tuberculosis Treatment: A Prospect for the Repurposing and Use of Antiparasitic Drugs

“…Mefloquine-oxazolidine derivatives slightly improved the activity against pan-susceptible and MDR M. tuberculosis strains [50,51]. In another study on mefloquine derivatives with hybridization between the mefloquine nucleus and ethambutol, the majority of compounds showed activity against the M. tuberculosis pan-susceptible and MDR strains [52].…”

Synthesis of 7-Chloroquinoline Derivatives Using Mixed Lithium-Magnesium Reagents

“…In this context, 4-anilinoquinolines (e.g., bosutinib ( 1 )) show high inhibitory activity for the epidermal growth factor receptor (EGFR), a highly expressed receptor in solid tumors. − Additionally, analogous 4-phenoxyquinoline derivatives, including some important anticancer pharmaceutical compounds such as foretinib ( 2a ), cabozantinib ( 2b ), and lenvatinib ( 3 ) (Figure ), have been reported as antiproliferative compounds. − Interestingly, Charris and co-workers reported that quinolin-4-ylsulfonyl acrylate derivatives ( 4 ) based on the parent chloroquine structure are bioactive substances against malaria and cancer . Moreover, the historical antimalarial alkaloid, quinine ( 5 ), and the synthetic therapeutic agent for chloroquine-resistant malaria, mefloquine ( 6 ), are further examples of bioactive carbinol derivatives. , Recently, de Souza and co-workers reported molecular modifications at the C4 position on the quinoline core to synthesize bioactive mefloquine-based analogues against Mycobacterium tuberculosis …”

“…10,11 Recently, de Souza and co-workers reported molecular modifications at the C4 position on the quinoline core to synthesize bioactive mefloquine-based analogues against Mycobacterium tuberculosis. 12 Substituted quinolines can be synthesized by using classic cyclization reactions such as Doebner−von Miller, Combes, Conrad−Limpach−Knorr, Friedlander syntheses, and others, 13−18 whereas aryl(quinolin-4-yl)methanols can be prepared through the reaction of quinoline-4-carboxaldehydes with aromatic organometallic reagents; 19−24 quinolines bearing different functional groups at the C4 position are more commonly accessed from halogenated substrates by exploiting the reactivity of the corresponding lithium, 25−27 magnesium, 28 and zinc 29 organometallic intermediates. For example, Mongin and co-workers have explored a Br/Mg exchange reaction promoted by a tributylmagnesium ate complex to prepare 4substituted quinolines.…”