Marcus V. N. de Souza

Synthesis and in vitro antitubercular activity of a series of quinoline derivatives.

A series of 33 quinoline derivatives have been synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H(37)Rv using the Alamar Blue susceptibility test and the activity expressed as the minimum inhibitory concentration (MIC) in microg/mL. Compounds 5e and 5f exhibited a significant activity at 6.25 and 3.12 microg/mL, respectively, when compared with first line drugs such as ethambutol and could be a good starting point to develop new lead compounds in the fight against multi-drug resistant tuberculosis.

Synthesis and biological activity of natural thiazoles: An important class of heterocyclic compounds

The class of heterocyclic compounds known as thiazole is found in many natural and synthetic products with a wide range of pharmacological activities, such as antiviral, anticancer, antibacterial, antifungal, anticonvulsant, antiparkinsonian and anti-inflammatory activities that can be well illustrated by the large number of drugs in the market containing this function group. Due to its importance, the aim of this review is to highlight the synthesis and biological activity of the thiazole natural products reported between 2000 and 2004.The class of heterocyclic compounds known as thiazole is found in many natural and synthetic products with a wide range of pharmacological activities, such as antiviral, anticancer, antibacterial, antifungal, anticonvulsant, antiparkinsonian and anti-inflammatory activities that can be well illustrated by the large number of drugs in the market containing this function group. Due to its importance, the aim of this review is to highlight the synthesis and biological activity of the thiazole natural products reported between 2000 and 2004.

Biological activity and synthetic metodologies for the preparation of fluoroquinolones, a class of potent antibacterial agents.

In this present review we report different synthetic methodologies for the preparation of fluoroquinolones and their biological properties. The appearance of the fluoroquinolones, a new class of antibacterial agents (based on nalidixic acid, 4-quinolone-3-carboxylates), in early 1980s, gave a new impulse for the international competition to synthesize more effective drugs. Fluoroquinolones have a broad spectrum of activity against Gram-positive, Gram-negative and mycobacterial organisms as well as anaerobes. The fluoroquinolone ciprofloxacin hydrochloride is an important bioterrorist weapon and also an antibiotic used to treat bacterial infection in many different parts of the body, approved for use in patients who have been exposed to the inhaled form of anthrax.

Synthesis, Antimalarial Activity, and Intracellular Targets of MEFAS, a New Hybrid Compound Derived from Mefloquine and Artesunate

ABSTRACT A new synthetic antimalarial drug, a salt derived from two antimalarial molecules, mefloquine (MQ) and artesunate (AS), here named MEFAS, has been tested for its pharmacological activity. Combinations of AS plus MQ hydrochloride are currently being used in areas with drug-resistant Plasmodium falciparum parasites; although AS clears parasitemia in shorter time periods than any other antimalarial drug, it does not cure infected patients; in addition, MQ causes side effects and is rather expensive, important problems considering that malaria affects mostly populations in poor countries. Here, we show that MEFAS is more effective than the combination of AS and MQ, tested in parallel at different mass proportions, against P. falciparum (chloroquine-resistant clone W2 and chloroquine-sensitive clone 3D7) in vitro and in mice infected with Plasmodium berghei, promoting cure of this infection. MEFAS tested against HepG2 hepatoma cells exhibited lower toxicity than the antimalarials AS and MQ alone or combined. Possible targets of MEFAS have been studied by confocal microscopy using fluorescent probes (Fluo-4 AM and BCECF-AM) in P. falciparum synchronous culture of W2-infected red blood cells. Dynamic images show that MEFAS exhibited intracellular action increasing cytoplasmic Ca2+ at 1.0 ng/ml. This effect was also observed in the presence of tapsigargin, an inhibitor of SERCA, suggesting an intracellular target distinct from the endoplasmic reticulum. Trophozoites loaded with BCECF-AM, when treated with MEFAS, were still able to mobilize protons from the digestive vacuole (DV), altering the pH gradient. However, in the presence of bafilomycin A1, an inhibitor of the H+ pump from acidic compartments of eukaryotic cells, MEFAS had no action on the DV. In conclusion, the endoplasmic reticulum and DV are intracellular targets for MEFAS in Plasmodium sp., suggesting two modes of action of this new salt. Our data support MEFAS as a candidate for treating human malaria.

Assessing the persistence of the N–H⋯N hydrogen bonding leading to supramolecular chains in molecules related to the anti-malarial drug, chloroquine

Crystal packing patterns for a range of chloroquine derivatives have been investigated. For species where the amine-bound R substituent carries atoms not capable of forming significant hydrogen bonding interactions, i.e. R = methyl (1), n-propyl (2), n-butyl (3), 2-chloroethyl (4), 2-azidoethyl (5), N–H⋯N hydrogen bonding between the amine and pyridine groups predominate leading to supramolecular chains. In species carrying hydroxyl groups, i.e. R = 2-hydroxylethyl (6), 1-butanol (7), and (S)-1-butanol (8), the N–H⋯N interactions are subverted by O–H⋯N and N–H⋯O hydrogen bonding that results in the formation of 2-D arrays, establishing an hierarchy of hydrogen bonding interactions in these systems. Despite the differences in hydrogen bonding, globally, the crystal packing in all structures is similar in that the N–H⋯N mediated supramolecular chains of (1–5) aggregate into layers usually via C–H⋯π, C–Cl⋯π and π⋯π interactions. These layers, as with those formed in (6–8), stack into a 3-D arrangement being consolidated via C–H⋯Cl and π⋯π or C–Cl⋯π interactions.

Synthesis and antitubercular activity of 7-chloro-4-quinolinylhydrazones derivatives

A series of twenty-one 7-chloro-4-quinolinylhydrazones (3a-u) have been synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H(37)Rv. The compounds 3f, 3i and 3o were non-cytotoxic and exhibited an important minimum inhibitory concentration (MIC) activity (2.5 microg/mL), which can be compared with that of the first line drugs, ethambutol (3.12 microg/mL) and rifampicin (2.0 microg/mL). These results can be considered an important start point for the rational design of new leads for anti-TB compounds.

Drogas anti-VIH: passado, presente e perspectivas futuras

Currently available anti-HIV drugs can be classified into three categories: nucleoside analogue reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). In addition to the reverse transcriptase (RT) and protease reaction, various other events in the HIV replicative cycle can be considered as potential targets for chemotherapeutic intervention: (1) viral adsorption, through binding to the viral envelope glycoprotein gp120; (2) viral entry, through blockage of the viral coreceptors CXCR4 and CCR5; (3) virus-cell fusion, through binding to the viral envelope glycoprotein gp 41; (4) viral assembly and disassembly through NCp7 zinc finger-targeted agents; (5) proviral DNA integration, through integrase inhibitors and (6) viral mRNA transcription, through inhibitors of the transcription (transactivation) process. Also, various new NRTIs, NNRTIs and PIs have been developed, possessing different improved characteristics.

Simultaneous determination of first-line anti-tuberculosis drugs by capillary zone electrophoresis using direct UV detection.

An alternative methodology for simultaneous analysis of ethambutol, isoniazid, rifampicin and pyrazinamide in pharmaceutical formulations by capillary zone electrophoresis under UV direct detection with an analysis time of 8.0 min is proposed. Background running was based on the effective mobility curve of the analytes and an optimum separation condition was achieved using a 3(3) Box-Behnken design, with Brij 35, Cu(2+) and acetic acid/sodium acetate buffer as factors. An electrolyte consisting of 50.0 mmol L(-1) of acetic acid/sodium acetate buffer, 12.5 mmol L(-1) of CuSO(4), and standard and sample solutions prepared in 2.00 mmol L(-1) of Brij 35 and 12.5 mmol L(-1) of CuSO(4) were optimized. After evaluating validation parameters, the method was successfully applied to the analysis of samples in the form of tablets and sachets.

Fármacos no combate à tuberculose: passado, presente e futuro

Approximately every minute, somewhere in the world four people die from tuberculosis (TB), an infection of Mycobacterium tuberculosis with about 3 million deaths per year. In spite of these problems, unfortunaly, it is about 40 years that a novel drug was last introduced on the market. Due to the rapid spread of multi-drug resistant TB strains, resistant against all major anti-tuberculosis drugs, and the recent resurgence of the incidence of tuberculosis in association with the human immunodeficiency virus (HIV) infection and AIDS, we need urgently the development of new drugs to fight tuberculosis. This is covered in the present article.

Mefloquine-oxazolidine derivatives, derived from mefloquine and arenecarbaldehydes: In vitro activity including against the multidrug-resistant tuberculosis strain T113.

Ten new mefloquine-oxazolidine derivatives, 4-[(1S,8aR)-3-(aryl)hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinoline (1: aryl=substituted phenyl) and 4-[(1S,8aR)-3-(heteroaryl)hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinoline [2: heteroaryl=5-nitrothien-2-yl (2a); 5-nitrofuran-2-yl (2b) and 4H-imidazol-2-yl) (2c)], have been synthesized and evaluated against Mycobacterium tuberculosis. Compounds 1f (aryl=3-ethoxyphenyl), 1g (Ar=3,4,5-(MeO)(3)-C(6)H(2)) and 2c were slightly more active than mefloquine (MIC=33μM) with MICs=24.5, 22.5 and 27.4, respectively, whereas compounds 1e (aryl=3,4-(MeO)(2)-C(6)H(3)) and 2a (MICs=11.9 and 12.1μM, respectively) were ca. 2.7 times more active than mefloquine, with a better tuberculostatic activity than the first line tuberculostatic agent ethambutol (MIC=15.9). The compounds were also assayed against the MDR strain T113 and the same MICs were observed. Thus the new derivatives have advantages over such anti-TB drugs as isoniazid, rifampicin, ethambutol and ofloxacin, for which this strain is resistant. The most active compounds were not cytotoxic to Murine Macrophages Cells in a concentration near their MIC values.