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Current Topics in Medicinal Chemistry 2019Background and Introduction: Mefloquine, a drug used to prevent and treat malaria is described possessing activity against the Mycobacterium tuberculosis (Mtb) as well...
UNLABELLED
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.
Topics: Antitubercular Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Bacterial; Humans; Mefloquine; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis
PubMed: 30836914
DOI: 10.2174/1568026619666190304124952 -
The Journal of Pharmacy and Pharmacology Nov 1997The pharmacokinetics of the enantiomers of mefloquine were studied in the rat after administration of a racemic mixture and of the separate enantiomers (+)-mefloquine... (Comparative Study)
Comparative Study
The pharmacokinetics of the enantiomers of mefloquine were studied in the rat after administration of a racemic mixture and of the separate enantiomers (+)-mefloquine and (-)-mefloquine. When 50 mg kg-1 racemic mixture was administered orally for 22 days, plasma concentrations of the (+) enantiomer were 2-3 times higher than those of the (-) enantiomer whereas the opposite was true in every part of the brain (cerebellum, cortex, hippocampus, hypothalamus and striatum). Different concentrations of mefloquine were found in the different regions of the brain; the lowest concentrations of (+/-)-mefloquine (27.0 nmol g-1) were in the cerebellum and the highest (110.0 nmol g-1) in the hippocampus. The main metabolite, carboxymefloquine, was detected in plasma but not in the brain. The results indicate the mefloquine crosses the blood-brain barrier stereoselectively.
Topics: Animals; Antimalarials; Blood-Brain Barrier; Brain Chemistry; Half-Life; Male; Mefloquine; Molecular Structure; Organ Size; Rats; Rats, Wistar; Stereoisomerism; Tissue Distribution
PubMed: 9401943
DOI: 10.1111/j.2042-7158.1997.tb06047.x -
The New England Journal of Medicine Jun 1990
Topics: Humans; Malaria; Mefloquine; Nervous System Diseases; Psychoses, Substance-Induced
PubMed: 2342544
DOI: 10.1056/nejm199006143222416 -
The Journal of Infectious Diseases Aug 2023Mpox virus (MPXV) is a zoonotic orthopoxvirus and caused an outbreak in 2022. Although tecovirimat and brincidofovir are approved as anti-smallpox drugs, their effects...
BACKGROUND
Mpox virus (MPXV) is a zoonotic orthopoxvirus and caused an outbreak in 2022. Although tecovirimat and brincidofovir are approved as anti-smallpox drugs, their effects in mpox patients have not been well documented. In this study, by a drug repurposing approach, we identified potential drug candidates for treating mpox and predicted their clinical impacts by mathematical modeling.
METHODS
We screened 132 approved drugs using an MPXV infection cell system. We quantified antiviral activities of potential drug candidates by measuring intracellular viral DNA and analyzed the modes of action by time-of-addition assay and electron microscopic analysis. We further predicted the efficacy of drugs under clinical concentrations by mathematical simulation and examined combination treatment.
RESULTS
Atovaquone, mefloquine, and molnupiravir exhibited anti-MPXV activity, with 50% inhibitory concentrations of 0.51-5.2 μM, which was more potent than cidofovir. Whereas mefloquine was suggested to inhibit viral entry, atovaquone and molnupiravir targeted postentry processes. Atovaquone was suggested to exert its activity through inhibiting dihydroorotate dehydrogenase. Combining atovaquone with tecovirimat enhanced the anti-MPXV effect of tecovirimat. Quantitative mathematical simulations predicted that atovaquone can promote viral clearance in patients by 7 days at clinically relevant drug concentrations.
CONCLUSIONS
These data suggest that atovaquone would be a potential candidate for treating mpox.
Topics: Humans; Atovaquone; Mefloquine; Monkeypox virus
PubMed: 36892247
DOI: 10.1093/infdis/jiad058 -
Bulletin of the World Health... 1995Between 1990 and 1994, a series of prospective studies were conducted to optimize the treatment of multidrug-resistant falciparum malaria on the borders of Thailand. The... (Clinical Trial)
Clinical Trial
Between 1990 and 1994, a series of prospective studies were conducted to optimize the treatment of multidrug-resistant falciparum malaria on the borders of Thailand. The tolerance of various treatment regimens containing either mefloquine 15 mg/kg (M15) or 25 mg/kg (M25) was evaluated in 3673 patients aged between 6 months and 88 years. Early vomiting (within 1 hour) is an important determinant of treatment outcome in these areas, despite re-administration of the dose. Overall, 7 % of the patients vomited within an hour. Significant risk factors were age < or = 6 years (relative risk (RR), 3.9) or > or 50 years (RR, 2.7), the higher mefloquine dose (M25) (RRm 2.7), vomiting < 24 hours before enrolment (RR, 2.5), axillary temperature > 38.0 degrees C (RR, 1.6), and parasitaemia > 10,000/microliter (RR, 1.3). In children < or = 2 years, 30% vomited with M25, and 13% did not tolerate a repeat dose. Vomiting was reduced 40% by splitting the higher dose (RR, 0.6; 95% CI, 0.4-0.8), and 50% by giving mefloquine on the second day in combination with artesunate (RR, 0.5; CI, 0.3-0.9). Anorexia, nausea, vomiting, dizziness, and sleeping disorders were 1.1-1.4 times more frequent with M25 than M15 in the three days following treatment, but were similar in the single or split-dose M25 groups, despite twofold higher mefloquine concentrations obtained with the latter. There was no evidence that diarrhoea, headache, and abdominal pain were associated with mefloquine use. High-dose mefloquine is well tolerated but should be given as a split dose.
Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Antimalarials; Child; Child, Preschool; Dizziness; Drug Resistance, Multiple; Female; Gastrointestinal Diseases; Humans; Infant; Malaria, Falciparum; Male; Mefloquine; Middle Aged; Prospective Studies; Sleep Wake Disorders
PubMed: 8846489
DOI: No ID Found -
Antimicrobial Agents and Chemotherapy Jun 2012Interesting antischistosomal properties have been documented for the antimalarial mefloquine, a 4-quinolinemethanol. We evaluated the antischistosomal activities of nine...
Interesting antischistosomal properties have been documented for the antimalarial mefloquine, a 4-quinolinemethanol. We evaluated the antischistosomal activities of nine mefloquine-related compounds belonging to the 4-pyridinemethanols, 9-phenanthrenmethanols, and 4-quinolinemethanols. Eight compounds revealed high activities against Schistosoma mansoni in vitro, with two drugs (the 4-quinolinemethanols WR7573 and WR7930) characterized by significantly lower half-maximal inhibitory concentrations (IC(50)s) (2.7 and 3.5 μM, respectively) compared to mefloquine (11.4 μM). Mefloquine and WR7930 showed significantly decreased IC(50)s when incubated in the presence of hemoglobin. High worm burden reductions (WBR) were obtained with enpiroline (WBR, 82.7%; dosage, 200 mg/kg of body weight) and its threo isomers (+)-threo (WBR, 100%) and (-)-threo (WBR, 89%) and with WR7930 (WBR, 87%; dosage, 100 mg/kg) against adult S. mansoni in mice. Furthermore, excellent in vitro and in vivo antischistosomal activity was observed for two WR7930-related structures (WR29252 and WR7524). In addition, mefloquine (WBR, 81%), enpiroline (WBR, 77%), and WR7930 (WBR, 100%) showed high activities against S. haematobium harbored in mice following single oral doses of 200 mg/kg. These results provide a deeper insight into the structural features of the arylmethanols that rule antischistosomal activity. Further studies should be launched with enpiroline and WR7930.
Topics: Animals; Antimalarials; Female; Inhibitory Concentration 50; Mefloquine; Mice; Molecular Structure; Pyridines; Schistosoma mansoni; Schistosomiasis mansoni
PubMed: 22470113
DOI: 10.1128/AAC.06177-11 -
Travel Medicine and Infectious Disease Sep 2010The recommended dosage of mefloquine to treat Plasmodium falciparum infection is 25 mg/kg, with no recommendation for dosage exceeding 1500 mg. We describe an original...
BACKGROUND
The recommended dosage of mefloquine to treat Plasmodium falciparum infection is 25 mg/kg, with no recommendation for dosage exceeding 1500 mg. We describe an original case of adverse reaction to mefloquine in an overweight patient.
METHOD
Case report.
RESULTS
A 32-year-old woman weighing 139 kg presented with uncomplicated P. falciparum infection after returning from Cameroon. She received 3250 mg of mefloquine (i.e. 23 mg/kg) administered in four doses. On day 2, she developed neuropsychiatric disorders and facial lesions. Nasal mucocutaneous vesicles and bullae, depressive mood, mild thrombocytopenia and hepatic cytolysis were evidenced. Parasitemia was negative. Recovery was complete on day 17. High mefloquine serum levels were measured (8.030 mg/L on day 3, 6.880 mg/L on day 8, and 3.370 mg/L on day 17).
CONCLUSIONS
The causal relationship between mefloquine and the occurrence of these adverse effects is probable. However, as no viral or bacteriological investigations were performed, the drug responsibility remains uncertain. Mefloquine-induced bullous and facial lesions reversible upon drug withdrawal have already been described. The associated neuropsychiatric symptoms were strongly suggestive of mefloquine adverse effects, as such events are more frequently observed in cases of overdosage. Our case emphasizes the difficulties of dosage adaptation in overweight patients.
Topics: Adult; Antimalarials; Blister; Drug Overdose; Female; Humans; Malaria, Falciparum; Mefloquine; Nose; Overweight
PubMed: 20971443
DOI: 10.1016/j.tmaid.2010.06.003 -
Revista Da Sociedade Brasileira de... 1993In a randomised double-blind study 122 volunteers living in an endemic malarious area in Amazonian Rondônia state were divided into 4 groups to study malaria... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
In a randomised double-blind study 122 volunteers living in an endemic malarious area in Amazonian Rondônia state were divided into 4 groups to study malaria suppression. . The first group received 500 mg of mefloquine every month, group II 250 mg every two weeks, group III a tablet of Fansidar (500 mg sulphadoxine + 25mg pyrimethamine) a week and group IV placebo. Acute attacks of malaria occurred in one individual in group I, 2 subject in group II, and 6 individuals in groups III and IV. Protection with mefloquine was significant compared with the placebo group. Both treatment regimens with mefloquine were effective suppressants in an area of high prevalence of drug multiresistant Plasmodium falciparum transmission.
Topics: Adolescent; Adult; Brazil; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Malaria, Falciparum; Malaria, Vivax; Male; Mefloquine; Middle Aged; Time Factors
PubMed: 8146390
DOI: 10.1590/s0037-86821993000300005 -
BMJ (Clinical Research Ed.) Dec 2015
Topics: Antimalarials; Humans; Malaria, Falciparum; Mefloquine; Military Personnel
PubMed: 26655347
DOI: 10.1136/bmj.h6584 -
Drug and Chemical Toxicology Jul 2021Malaria is a global public health problem that causes approximately 445 000 deaths annually worldwide, especially in underdeveloped countries. Because of the high... (Comparative Study)
Comparative Study
Malaria is a global public health problem that causes approximately 445 000 deaths annually worldwide, especially in underdeveloped countries. Because of the high prevalence and mortality of the disease, new and less toxic therapeutic agents need to be developed, such as MEFAS, a low-cost hybrid salt that consists of artesunate and mefloquine. However, the efficacy of MEFAS has been systematically demonstrated, its safety requires further investigation. This study investigated the acute toxicity of MEFAS and its precursors, artesunate, and mefloquine. A total of 42 female Swiss mice were divided into seven groups ( = 6/group) that were treated orally by gavage with vehicle (filtered water, negative control), MEFAS (50, 500, and 1000 mg/kg), and 1:1 concentrations of artesunate + mefloquine (50, 500, and 1000 mg/kg). Clinical signs of toxicity were observed for 14 d after treatment. On day 15, the animals were weighed, deeply anesthetized with isoflurane, and euthanized for subsequent collection of the liver, spleen, and kidneys. The relative organ weights were determined, followed by histopathological analysis. Artesunate + mefloquine produced toxic effects compared with the negative control group, reflected by changes in clinical signs, relative organ weights, and histopathological alterations. In MEFAS-treated animals, no changes were observed compared with the negative control group. These findings demonstrate that MEFAS is safer than artesunate + mefloquine after acute administration in mice.
Topics: Animals; Antimalarials; Artesunate; Dose-Response Relationship, Drug; Drug Combinations; Drug Therapy, Combination; Female; Mefloquine; Mice
PubMed: 31060457
DOI: 10.1080/01480545.2019.1607371