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1.
Bioorg Chem ; 110: 104786, 2021 05.
Article in English | MEDLINE | ID: mdl-33740676

ABSTRACT

Studies displaying the combination of mefloquine (MFL) with anti-tuberculosis (TB) substances are limited in the literature. In this work, the effect of MFL-association with two first-line anti-TB drugs and six fluoroquinolones was evaluated against Mycobacterium tuberculosis drug resistant strains. MFL showed synergistic interaction with isoniazid, pyrazinamide, and several fluoroquinolones, reaching fractional inhibitory concentration indexes (FICIs) ranging from 0.03 to 0.5. In order to better understand the observed results, two approaches have been explored: (i) spectroscopic responses attributed to the effect of MFL on physicochemical properties related to a liposomal membrane model composed by soybean asolectin; (ii) molecular dynamics (MD) simulation data regarding MFL interaction with a membrane model based on PIM2, a lipid constituent of the mycobacterial cell wall. FTIR and NMR data showed that MFL affects expressively the region between the phosphate and the first methylene groups of soybean asolectin membranes, disordering these regions. MD simulations results detected high MFL density in the glycolipid interface and showed that the drug increases the membrane lateral diffusion, enhancing its permeability. The obtained results suggest that synergistic activities related to MFL are attributed to its effect of lipid disorder and membrane permeability enhancement.


Subject(s)
Antitubercular Agents/pharmacology , Mefloquine/pharmacology , Molecular Dynamics Simulation , Mycobacterium tuberculosis/drug effects , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Dose-Response Relationship, Drug , Magnetic Resonance Spectroscopy , Mefloquine/chemical synthesis , Mefloquine/chemistry , Microbial Sensitivity Tests , Molecular Structure , Phosphorus Isotopes , Spectroscopy, Fourier Transform Infrared , Structure-Activity Relationship
2.
Curr Top Med Chem ; 19(9): 683-689, 2019.
Article in English | MEDLINE | ID: mdl-30836914

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.


Subject(s)
Antitubercular Agents/pharmacology , Drug Resistance, Bacterial/drug effects , Mefloquine/pharmacology , Mycobacterium tuberculosis/drug effects , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Humans , Mefloquine/chemical synthesis , Mefloquine/chemistry , Microbial Sensitivity Tests , Molecular Structure
3.
Eur J Med Chem ; 127: 334-340, 2017 Feb 15.
Article in English | MEDLINE | ID: mdl-28068604

ABSTRACT

Zika virus (ZIKV), an arthropod-born Flavivirus, has been associated with a wide range of neurological diseases in adults, foetuses and neonates. Since no vaccine is available, repurposing of antiviral drugs currently in medical use is necessary. Mefloquine has confirmed anti-ZIKV activity. We used medicinal chemistry-driven approaches to synthesize and evaluate the ability of a series of new 2,8-bis(trifluoromethyl)quinoline derivatives to inhibit ZIKV replication in vitro, in order to improve the potency of mefloquine. We found that quinoline derivatives 3a and 4 were the most potent compounds within this series, both with mean EC50 values of 0.8 µM, which represents a potency 5 times that of mefloquine. These results indicate that new 2,8-bis(trifluoromethyl)quinoline chemical structures may be promising for the development of novel anti-ZIKV drugs.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Mefloquine/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Zika Virus/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/toxicity , Chlorocebus aethiops , Drug Design , Quinolines/chemical synthesis , Quinolines/toxicity , Structure-Activity Relationship , Vero Cells , Virus Replication/drug effects , Zika Virus/physiology
4.
Sci Pharm ; 84(3): 467-483, 2015 Oct 18.
Article in English | MEDLINE | ID: mdl-28117313

ABSTRACT

Both sonochemical and classical methodologies have been employed to convert camphor, 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one, C9H16C=O, into a number of derivatives including hydrazones, C9H16C=N-NHAr 3, imines, C9H16C=N-R 7, and the key intermediate nitroimine, C9H16C=N-NO2 6. Reactions of nitroamine 6 with nucleophiles by classical methods provided the desired compounds in a range of yields. In evaluations of activity against Mycobacterium tuberculosis, compound 7j exhibited the best activity (minimal inhibitory concentration (MIC) = 3.12 µg/mL), comparable to that of the antitubercular drug ethambutol. The other derivatives displayed modest antimycobacterial activities at 25-50 µg/mL. In in vitro tests against cancer cell lines, none of the synthesized camphor compounds exhibited cytotoxic activities.

5.
Acta Crystallogr C ; 61(Pt 1): o15-20, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15640584

ABSTRACT

In the structures of 5-(1-hydroxyethylidene)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione, C8H10N2O4, (I), 1,3-dimethyl-5-[1-(propylamino)ethylidene]pyrimidine-2,4,6(1H,3H,5H)-trione, C11H17N3O3, (II), and 5-[1-(2,2-dimethoxyethylamino)ethylidene]-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione, C12H19N3O5, (III), there are no direction-specific intermolecular interactions. The molecules in 5-[1-(benzylamino)ethylidene]-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione, C15H17N3O3, (IV), are linked into chains of edge-fused rings by a combination of one C-H...O hydrogen bond and one C-H...pi(arene) hydrogen bond, while the molecules in 5-(1-hydrazinoethylidene)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione, C8H12N4O3, (V), are linked into a continuous framework structure by three distinct N-H...O hydrogen bonds, each involving a different O-atom acceptor. Each of compounds (I)-(V) contains an intramolecular hydrogen bond, of the O-H...O type in (I) and of the N-H...O type in (II)-(V).

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