RESUMO
Leishmaniasis is a disease caused by protozoa Leishmania spp., considered as a significant and urgent public health problem mainly in developing countries. In the absence of an effective vaccine, the treatment of infected people is one of the most commonly prophylactic measures used to control this disease. However, the therapeutic arsenal is reduced to a few drugs, with serious side effects and variability in efficacy. Attempting to this problem, in this work, a series of benzothiazole derivatives was synthetized and assayed against promastigotes and intracellular amastigotes of L. amazonensis, as well as the toxicity on macrophages. In addition, studies about the mechanism of action were also performed. Among the synthesized molecules, the substitution at position 4 of the aromatic ring appears to be critical for activity. The best compound exhibited IC50 values of 28.86 and 7.70 µM, against promastigotes and amastigotes of L. amazonensis, respectively, being more active than miltefosine, used as reference drug. The in silico analysis of physicochemical and pharmacokinetic (ADMET) properties of this compound suggested a good profile of oral bioavailability and safety. In conclusion, the strategy of using benzothiazole nucleous in the search for new antileishmanial agents was advantageous and preliminar data provide information about the mechanism of action as well as in silico parameters suggest a good profile for preclinical studies.
Assuntos
Antiprotozoários , Benzotiazóis , Hidrazonas , Leishmania , Benzotiazóis/química , Benzotiazóis/farmacologia , Benzotiazóis/síntese química , Antiprotozoários/farmacologia , Antiprotozoários/química , Antiprotozoários/síntese química , Animais , Hidrazonas/química , Hidrazonas/farmacologia , Hidrazonas/síntese química , Camundongos , Leishmania/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Relação Estrutura-Atividade , HumanosRESUMO
Human toxocariasis is a neglected anthropozoonosis with global distribution. Treatment is based on the administration of anthelmintics; however, their effectiveness at the tissue level is low to moderate, necessitating the discovery of new drug candidates. Several groups of synthetic compounds, including coumarin derivatives, have demonstrated bioactivity against fungi, bacteria, and even parasites, such as Dactylogyrus intermedius, Leishmania major, and Plasmodium falciparum. The aim of this study was to evaluate the effect of ten coumarin-derived compounds against Toxocara canis larvae using in vitro, cytotoxicity, and in silico tests for selecting new drug candidates for preclinical tests aimed at evaluating the treatment of visceral toxocariasis. The compounds were tested in vitro in duplicate at a concentration of 1 mg/mL, and compounds with larvicidal activity were serially diluted to obtain concentrations of 0.5 mg/mL; 0.25 mg/mL; 0.125 mg/mL; and 0.05 mg/mL. The tests were performed in a microculture plate containing 100 T. canis larvae in RPMI-1640 medium. One compound (COU 9) was selected for cytotoxicity analysis using J774.A1 murine macrophages and it was found to be non-cytotoxic at any concentration tested. The in silico analysis was performed using computational models; the compound presented adequate results of oral bioavailability. To confirm the non-viability of the larvae, the contents of the microplate wells of COU 9 were inoculated intraperitoneally (IP) into female Swiss mice at 7-8 weeks of age. This confirmed the larvicidal activity of this compound. These results show that COU 9 exhibited larvicidal activity against T. canis larvae, which, after exposure to the compound, were non-viable, and that COU 9 inhibited infection in a murine model. In addition, COU 9 did not exhibit cytotoxicity and presented adequate bioavailability in silico, similar to albendazole, an anthelmintic, which is the first choice for treatment of human toxocariasis, supporting the potential for future investigations and preclinical tests on COU 9.
Assuntos
Cumarínicos , Larva , Toxocara canis , Animais , Larva/efeitos dos fármacos , Toxocara canis/efeitos dos fármacos , Cumarínicos/farmacologia , Cumarínicos/química , Anti-Helmínticos/farmacologia , Anti-Helmínticos/química , Disponibilidade Biológica , Camundongos , Simulação por Computador , Toxocaríase/tratamento farmacológico , Toxocaríase/parasitologiaRESUMO
Trichomoniasis is a great public health burden worldwide and the increase in treatment failures has led to a need for finding alternative molecules to treat this disease. In this study, we present in vitro and in silico analyses of two 2,8-bis(trifluoromethyl) quinolines (QDA-1 and QDA-2) against Trichomonas vaginalis. For in vitro trichomonacidal activity, up to seven different concentrations of these drugs were tested. Molecular docking, biochemical, and cytotoxicity analyses were performed to evaluate the selectivity profile. QDA-1 displayed a significant effect, completely reducing trophozoites viability at 160 µM, with an IC50 of 113.8 µM, while QDA-2 at the highest concentration reduced viability by 76.9%. QDA-1 completely inhibited T. vaginalis growth and increased reactive oxygen species production and lipid peroxidation after 24 h of treatment, but nitric oxide accumulation was not observed. In addition, molecular docking studies showed that QDA-1 has a favorable binding mode in the active site of the T. vaginalis enzymes purine nucleoside phosphorylase, lactate dehydrogenase, triosephosphate isomerase, and thioredoxin reductase. Moreover, QDA-1 presented a level of cytotoxicity by reducing 36.7% of Vero cells' viability at 200 µM with a CC50 of 247.4 µM and a modest selectivity index. In summary, the results revealed that QDA-1 had a significant anti-T. vaginalis activity. Although QDA-1 had detectable cytotoxicity, the concentration needed to eliminate T. vaginalis trophozoites is lower than the CC50 encouraging further studies of this compound as a trichomonacidal agent.
Assuntos
Quinolinas , Tricomoníase , Trichomonas vaginalis , Animais , Chlorocebus aethiops , Humanos , Simulação de Acoplamento Molecular , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Tricomoníase/tratamento farmacológico , Trofozoítos , Células VeroRESUMO
The development of new drugs requires a lot of time and high financial investments. It involves a research network in which there is the participation of several researchers from different areas. For a new drug to reach the market, thousands of substances must be evaluated. There are several tools for this and the use of suitable building blocks can facilitate the process by allowing a lead compound to have suitable parameters. These compounds are key structures containing special functional groups that also permit adequate synthetic transformations, leading to several structures of interest in a short period of time. In this review, the use of camphor nitroimine as a potential key building block is explored. Derived from camphor, an abundant natural product present in various plant species, this nitroimine has proved to be quite versatile, allowing the access to substances with miscellaneous biological activities, ligands to asymmetric catalysis, asymmetric oxidants, O-N transfer agents and other applications. Its easy conversion to camphecene and other derivatives is described, as well as their applications in medicinal chemistry. Druglikeness analyses were performed on these studied agents as well as on their bioactive derivatives in order to assess their use in the development of potential drugs.
Assuntos
Produtos Biológicos , Cânfora , CatáliseRESUMO
A novel method was proposed for simultaneous determination of artesunate (ATS) and mefloquine (MFQ) in fixed-dose combination tablets by capillary zone electrophoresis with simultaneous direct and indirect detection by ultraviolet (CZE-UV). The background electrolyte, consisting of 30/15 mmol L-1 TRIS/3,5-dinitrobenzoic acid buffer at pH 8.2, a chromophore buffer, was selected taking into account a detailed study involving the effective mobility vs. pH curves of the analytes and electrolyte compounds in association with the very low molar absorptivity of ATS. Suitable separation conditions, considering voltage, temperature and buffer concentration as factors, were achieved through the 33 Box-Behnken design investigation. The optimum baseline separation conditions were: injection pressure of 30 mbar for 10 s, cartridge temperature of 22.5 °C and positive voltage of +30 kV. The method proved to be rapid (5 minutes), simple, selective, linear (r2 > 0.98), precise (relative standard deviation (RSD): ATS < 2.9% and MFQ < 2.2%) and accurate (recoveries: ATS 98.13-102.96% and MFQ 98.75-106.77%), proving to be suitable for routine quality control analysis.
RESUMO
The effect of N-geranyl-ethane-1,2-diamine dihydochloride (GIB24), a synthetic diamine, was assayed against different developmental forms of the parasitic protozoan Trypanosoma cruzi (strain Dm28c). The compound was effective against culture epimastigote forms (IC50/24h = 5.64 µM; SI = 16.4) and intracellular amastigotes (IC50/24h = 12.89 µM; SI = 7.18), as detected by the MTT methodology and by cell counting, respectively. Incubation of epimastigotes for 6h with 6 µM GIB24 (IC50/24h value) resulted in significant dissipation of the mitochondrial membrane potential, prior to permeabilization of the plasma membrane. Rounded epimastigotes with cell size reduction were observed by scanning electron microscopy. These morpho-physiological changes induced by GIB24 suggest an incidental death process. Treatment of infected Vero cells did not prevent the intracellular amastigotes from completing the intracellular cycle. However, there was a decrease in the number of released parasites, increasing the ratio amastigotes/trypomastigotes. Proteomic analysis of 15 µM GIB24 resistant epimastigotes indicated that the compound acts mainly on mitochondrial components involved in the Krebs cycle and in maintaining the oxidative homeostasis of the parasites. Our data suggest that GIB24 is active against the main morphological forms of T. cruzi.
Assuntos
Diaminas/farmacologia , Resistência a Medicamentos , Espaço Intracelular/efeitos dos fármacos , Proteômica , Terpenos/química , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/crescimento & desenvolvimento , Animais , Chlorocebus aethiops , Diaminas/química , Espaço Intracelular/parasitologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/metabolismo , Células VeroRESUMO
BACKGROUND: Trichomonas vaginalis is the causative agent of trichomoniasis, which is one of the most common sexually transmitted diseases worldwide. Trichomoniasis has a high incidence and prevalence and is associated with serious complications such as HIV transmission and acquisition, pelvic inflammatory disease and preterm birth. Although trichomoniasis is treated with oral metronidazole (MTZ), the number of strains resistant to this drug is increasing (2.5-9.6%), leading to treatment failure. Therefore, there is an urgent need to find alternative drugs to combat this disease. METHODS: Herein, we report the in vitro and in silico analysis of 12 furanyl N-acylhydrazone derivatives (PFUR 4, a-k) against Trichomonas vaginalis. Trichomonas vaginalis ATCC 30236 isolate was treated with seven concentrations of these compounds to determine the minimum inhibitory concentration (MIC) and 50% inhibitory concentration (IC50). In addition, compounds that displayed anti-T. vaginalis activity were analyzed using thiobarbituric acid reactive substances (TBARS) assay and molecular docking. Cytotoxicity analysis was also performed in CHO-K1 cells. RESULTS: The compounds PFUR 4a and 4b, at 6.25 µM, induced complete parasite death after 24 h of exposure with IC50 of 1.69 µM and 1.98 µM, respectively. The results showed that lipid peroxidation is not involved in parasite death. Molecular docking studies predicted strong interactions of PFUR 4a and 4b with T. vaginalis enzymes, purine nucleoside phosphorylase, and lactate dehydrogenase, while only PFUR 4b interacted in silico with thioredoxin reductase and methionine gamma-lyase. PFUR 4a and 4b led to a growth inhibition (< 20%) in CHO-K1 cells that was comparable to the drug of choice, with a promising selectivity index (> 7.4). CONCLUSIONS: Our results showed that PFUR 4a and 4b are promising molecules that can be used for the development of new trichomonacidal agents for T. vaginalis.
Assuntos
Antiprotozoários , Hidrazonas , Trichomonas vaginalis/efeitos dos fármacos , Animais , Antiprotozoários/farmacologia , Antiprotozoários/toxicidade , Células CHO , Cricetulus , Humanos , Hidrazonas/farmacologia , Hidrazonas/toxicidade , Técnicas In Vitro , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular/métodos , Tricomoníase/tratamento farmacológicoRESUMO
PURPOSE: Due to serious problems with the treatment of leishmaniasis all around the world, here is an urgent need in the search for new drugs that are more effective and safer for the treatment of the various forms of leishmaniasis. Actual therapy is limited and lacks sufficient efficacy due to incomplete elimination of the parasites form of patients. In this sense, we decided to evaluate, by first-time, a series of seventeen camphor hydrazone derivatives (2a-2p) against Leishmania amazonensis. METHODS: The compounds previously synthesized from camphor, an abundant natural compound, were evaluated in vitro against the extra and intracellular forms of Leishmania amazonensis, and murine macrophages. RESULTS: The majority of compounds, fourteen, displayed activity against the intracellular form of the parasite (amastigote) with IC50 values ranging from 21.78 to 58.23 µM, being six compounds active for both forms of the parasite. The compound 2i exhibited higher activity against the amastigote form with the value of IC50 (21.78 µM) close to standard utilized miltefosine (12.74 µM) and selectivity index of at least 6.9. Six compounds displayed activity against promastigote form of Leishmania amazonensis 2g, 2j-2n (41.17-69.59 µM), with the compound 2m being the more active with IC50 = 41.17 µM, 1.9 times less active than the reference drug (IC50 = 21.39 µM). The compound 2m was the more selective to this form, with a selectivity index of at least 3.6. All the compounds were non-cytotoxic to macrophages. CONCLUSIONS: Most compounds showed activity against amastigote form of Leishmania amazonensis, being that they were not cytotoxic to macrophage at the maximum tested concentration, showing the selective property of these compounds. Since amastigotes are the parasite stages that cause the disease in humans, these results highlight the antileishmanial effect of the compounds. This study indicates the possible development of candidates to leishmanicidal drugs from an abundant natural compound of easy access.
Assuntos
Cânfora/farmacologia , Hidrazonas/farmacologia , Leishmania mexicana/efeitos dos fármacos , Animais , Cânfora/química , Descoberta de Drogas , Feminino , Hidrazonas/síntese química , Concentração Inibidora 50 , Leishmania mexicana/crescimento & desenvolvimento , Estágios do Ciclo de Vida , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos BALB CRESUMO
The culture of preantral follicles as an in vitro model to evaluate the toxicity of new anticancer drug has being established. Therefore, the aim of this study was to evaluate the effect of quinoxaline derivative the 2 2- (XYZC 6H 3 -CH=N-NH)-quinoxaline, 1 (QX) on caprine preantral follicles. We evaluate the follicular morphology and activation, proliferation and apoptosis of granulosa cells and finally the protein (ABCB1) and genes expression (cyclin/Cdks), respectively involved in multidrug resistance and cell cycle progression. Ovarian fragments containing primordial and developing follicles were exposed (in vitro culture) to different concentrations of QX (QX1.5, QX3.0 or QX6.0 µM/mL) during 6 days. To evaluate the effect of QX, the ovarian tissue was exposed to Paclitaxel 0.1 µg/mL (PTX - negative control) or in culture media without QX (MEM). At the end of exposure time, we realized that the QX (all concentrations) increased (P < .05) the normal morphology of preantral follicles compared to control (not treated ovarian tissue) or MEM. However, QX6.0 showed a enhanced (P < .05) on follicular activation (burnout) and apoptosis than QX1.5 and QX3.0. Expression of ABCB1 was similar between QX1.5 and QX6.0 and both were lower than control, MEM and PTX. Interestingly, the apoptosis rate in QX3.0 was similar to control and MEM and lower then QX1.5; QX6.0 and PTX. We conclude that quinoxaline may be a promising chemotherapeutic agent, however, other concentrations within a defined range (2-5.5 µM) could be widely investigated.
Assuntos
Células da Granulosa/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Quinoxalinas/farmacologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Cabras , Células da Granulosa/metabolismo , Células da Granulosa/patologia , Técnicas In Vitro , Folículo Ovariano/citologia , Quinoxalinas/toxicidadeRESUMO
Quinoxaline derivatives are reported as antineoplastic agents against a variety of human cancer cell lines, with some compounds being submitted to clinical trials. In this work, we report the synthesis, characterization and cytotoxicity potential of a new series of quinoxalinyl-hydrazones. The most cytotoxic compound was (E)-2-[2-(2-pyridin-2-ylmethylene)hydrazinyl]quinoxaline (PJOV56) that presented a time-dependent effect against HCT-116 cells. After 48 h of incubation, PJOV56 was able to induce autophagy and apoptosis of HCT-116 cells, mediated by upregulation of Beclin 1, upregulation of LC3A/B II and activation of caspase 7. Apoptosis was induced along with G0/G1 cell cycle arrest at the highest concentration of PJOV56 (6.0 µM). Thus, PJOV56 showed a dose-dependent mode of action related to induction of autophagy and apoptosis in HCT-116 cells.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Hidrazonas/síntese química , Quinoxalinas/síntese química , Humanos , Hidrazonas/química , Quinoxalinas/química , Relação Estrutura-AtividadeRESUMO
Nowadays, tuberculosis (TB) is an important global public health problem, being responsible for millions of TB-related deaths worldwide. Due to the increased number of cases and resistance of Mycobacterium tuberculosis to all drugs used for the treatment of this disease, we desperately need new drugs and strategies that could reduce treatment time with fewer side effects, reduced cost and highly active drugs against resistant strains and latent disease. Considering that, 4H-1,3-benzothiazin-4-one is a promising class of antimycobacterial agents in special against TB-resistant strains being the aim of this review the discussion of different aspects of this chemical class such as synthesis, mechanism of action, medicinal chemistry and combination with other drugs.
Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Farmacorresistência Bacteriana Múltipla , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Mycobacterium tuberculosis/efeitos dos fármacos , Descoberta de Drogas , Humanos , Estrutura MolecularRESUMO
BACKGROUND: 1,2,3-triazoles are an important class of organic compounds and because of their aromatic stability, they are not easily reduced, oxidized or hydrolyzed in acidic and basic environments. Moreover, 1,2,3-triazole derivatives are known by their important biological activities and have drawn considerable attention due to their variety of properties. The synthesis of this nucleus, based on the click chemistry concept, through the 1,3-dipolar addition reaction between azides and alkynes is a well-known procedure. This reaction has a wide range of applications, especially on the development of new drugs. METHODS: The most prominent eco-friendly methods for the synthesis of triazoles under microwave irradiation published in articles from 2012-2018 were reviewed. RESULTS: In this review, we cover some of the recent eco-friendly CuAAC procedures for the click synthesis of 1,2,3-triazoles with remarks to new and easily recoverable catalysts, such as rhizobial cyclic ß-1,2 glucan; WEB (water extract of banana); biosourced cyclosophoraose (CyS); egg shell powder (ESP); cyclodextrin (ß- CD); fish bone powder; nanoparticle-based catalyst, among others. CONCLUSION: These eco-friendly procedures are a useful tool for the synthesis of 1,2,3-triazoles, providing many advantages on the synthesis of this class, such as shorter reaction times, easier work-up and higher yields when compared to classical procedures. Moreover, these methodologies can be applied to the industrial synthesis of drugs and to other areas.
RESUMO
Molecular dynamics (MD) simulations of 12 aqueous systems of the NADH-dependent enoyl-ACP reductase from Mycobacterium tuberculosis (InhA) were carried out for up to 20-40 ns using the GROMACS 4.5 package. Simulations of the holoenzyme, holoenzyme-substrate, and 10 holoenzyme-inhibitor complexes were conducted in order to gain more insight about the secondary structure motifs of the InhA substrate-binding pocket. We monitored the lifetime of the main intermolecular interactions: hydrogen bonds and hydrophobic contacts. Our MD simulations demonstrate the importance of evaluating the conformational changes that occur close to the active site of the enzyme-cofactor complex before and after binding of the ligand and the influence of the water molecules. Moreover, the protein-inhibitor total steric (ELJ) and electrostatic (EC) interaction energies, related to Gly96 and Tyr158, are able to explain 80% of the biological response variance according to the best linear equation, pKi=7.772-0.1885×Gly96+0.0517×Tyr158 (R²=0.80; n=10), where interactions with Gly96, mainly electrostatic, increase the biological response, while those with Tyr158 decrease. These results will help to understand the structure-activity relationships and to design new and more potent anti-TB drugs.
Assuntos
Proteínas de Bactérias/metabolismo , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/metabolismo , Simulação de Dinâmica Molecular , Mycobacterium tuberculosis/enzimologia , Éteres Fenílicos/farmacologia , Motivos de Aminoácidos , Proteínas de Bactérias/antagonistas & inibidores , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/antagonistas & inibidores , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Mycobacterium tuberculosis/efeitos dos fármacos , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , TermodinâmicaRESUMO
A series of 32 L-serinyl hydrazone derivatives have been synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv, being also evaluated their cell viabilities in non infected and infected macrophages with Mycobacterium bovis Bacillus Calmette-Guerin (BCG). The compounds 8c, 8e, 8h and 8i, were non-cytotoxic and exhibited an important minimum inhibitory concentration (MIC) activity between 25 and 100 µg/mL, which can be compared with that of the tuberculostatic drug D-cicloserine (5-20 µg/mL).
Assuntos
Antituberculosos/farmacologia , Hidrazonas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Serina/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Sobrevivência Celular/efeitos dos fármacos , Ciclosserina/química , Ciclosserina/farmacologia , Relação Dose-Resposta a Droga , Hidrazonas/síntese química , Hidrazonas/química , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Mycobacterium bovis/isolamento & purificação , Mycobacterium tuberculosis/citologia , Serina/síntese química , Serina/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of twenty-one 7-chloro-4-quinolinylhydrazones derivatives (3a-u) have been synthesized and evaluated for their cytotoxic potential against three cancer cell lines using MTT assay. The compounds 3b, 3e, 3f, 3h, 3j, 3n, 3r and 3u displayed more than 90% of growth inhibition (GI) and they were selected for in vitro anticancer activities evaluation against four human cancer cell lines. These results were expressed as the concentrations that induce 50% inhibition of cell growth (IC50) in µg/mL. Considering that, compounds 3b, 3e, 3h, 3n, 3r and 3u exhibited good cytotoxic activity against at least three cancer cell lines (0.7967-4.200 µg/mL). In general, we observed that the presence of electron-withdrawing groups in the benzene ring is important for the anticancer activity in this series, such as fluorine (3h), chlorine (3b) amd bromine (3e) groups in meta position and nitro group (3r) in para position. These derivatives could be considered interesting start points to develop a new anticancer drug and confirm the potential of chloroquine derivatives as lead compounds in anticancer drug discovery.
Assuntos
Antineoplásicos/farmacologia , Hidrazonas/farmacologia , Quinolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-AtividadeRESUMO
In the twenty first century the interest in new anti-tuberculosis drugs based on natural products, specially against MDR (multidrug-resistant) and XDR (extensively drug resistant) tuberculosis (TB) is growing, as indicated by the increasing number of publications in this field. Some natural products, semisynthetic or synthetic compounds based on nature are in clinical studies and are the subject of this article.
Assuntos
Antituberculosos/uso terapêutico , Farmacorresistência Bacteriana Múltipla , Proteínas Fúngicas/uso terapêutico , Fungos/química , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Antituberculosos/síntese química , Produtos Biológicos/uso terapêutico , Ensaios Clínicos como Assunto , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , HumanosRESUMO
A series of 22 (E)-N'-(monosubstituted-benzylidene)isonicotinohydrazide derivatives have been synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H(37)Rv using Alamar Blue susceptibility test and the activity expressed as the minimum inhibitory concentration (MIC) in mug/mL. Compounds 2f, 2g, 2j, 2k and 2q exhibited a significant activity (0.31-0.62 microg/mL) when compared with first line drugs such as isoniazid (INH) and rifampicin (RIP) and could be a good starting point to develop new lead compounds in the fight against multi-drug resistant tuberculosis.
Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Hidrazinas/síntese química , Hidrazinas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Espectrofotometria InfravermelhoRESUMO
The antimalarial activity of combinations of mefloquine or artesunic acid with ciprofloxacin and other synthetic fluoroquinolone was tested in vitro against Plasmodium falciparum using a strain (BHz26/86) partially resistant to chloroquine and a resistant clone (W2); both are sensitive to mefloquine. Inhibition of parasite growth was measured in relation to controls without drugs, either by counting parasitemia in Giemsa-stained blood smears or by measuring the reduction in [(3)H]-hypoxanthine uptake. Combinations containing artesunic acid or mefloquine with ciprofloxacin had significant in vitro activity, inhibiting by more than 90% of the growth of both strains of P. falciparum at doses significantly lower than those of the antimalarials alone. When tested in mice inoculated with P. berghei chloroquine-sensitive parasites (NK65 strain), ciprofloxacin was inactive, whereas mefloquine and artesunic acid were active (IC(50)=2.5 and 4.2 mg/kg, respectively); combinations containing mefloquine at an equivalent dose of 0.5 mg/kg reduced parasitemia by 59% and artesunic acid activity was also improved by ciprofloxacin. Our data support the idea that ciprofloxacin in combination with antimalarials may be useful in the treatment of chloroquine-resistant human malaria, allowing the use of lower doses of these drugs.
Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Ciprofloxacina/farmacologia , Malária/tratamento farmacológico , Mefloquina/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Succinatos/farmacologia , Animais , Antimaláricos/uso terapêutico , Sinergismo Farmacológico , Camundongos , Parasitemia/tratamento farmacológico , Plasmodium bergheiRESUMO
PURPOSE OF REVIEW: Nowadays tuberculosis is becoming a worldwide problem, and according to the World Health Organization, which declared tuberculosis a global health emergency in 1993, each year 8 million people worldwide develop the active disease and almost 3 million die. RECENT FINDINGS: Due to this problem there is an urgent need for new strategies and drugs to fight against this disease. In this context, this review describes promising new classes of compounds against tuberculosis that are under study, as well as promising drugs that may soon be introduced onto the market. Another subject reported in this review is inhaled therapy, an important route under study for delivering antitubercular drugs directly to the lungs. SUMMARY: The implications of new drugs and inhaled therapy in tuberculosis treatment are fewer toxic side-effects, improved pharmacokinetics properties, extensive and potent activity against Gram-positive and Gram-negative bacteria, including resistant strains, and a reduction in the total treatment time.
Assuntos
Antituberculosos/uso terapêutico , Revisão de Uso de Medicamentos/tendências , Tuberculose Pulmonar/tratamento farmacológico , HumanosRESUMO
Tuberculosis (TB) is a global health problem due to the lack of new drugs in the market and also due to the advent of multidrug resistant strains (MDR). This disease affects around 8 million people and kills almost 3 million people each year and it is estimated that there are 1 billion infected with TB worldwide. Due to this problem fluoroquinolones have attracted much attention as the new class of anti TB drugs due to their fewer toxic side effects, improved pharmacokinetic properties and extensive and potent activity against Gram-positive and Gram-negative bacteria, including resistant strains. In this present review we report fluoroquinolones as a promising new class of anti TB.