Design, Synthesis and Characterization of N-oxide-containing Heterocycles with In vivo Sterilizing Antitubercular Activity

Tuberculosis, caused by the Mycobacterium tuberculosis (Mtb), is the infectious disease responsible for the highest number of deaths worldwide. Herein, 22 new N-oxide- containing compounds were synthesized followed by in vitro and in vivo evaluation of their antitubercular potential against Mtb. Compound 8 was found to be the most promising compound, with MIC90 values of 1.10 and 6.62 μM against active and non- replicating Mtb, respectively. Additionally, we carried out in vivo experiments to confirm the safety and efficacy of compound 8; the compound was found to be orally bioavailable and highly effective leading to the reduction of the number of Mtb to undetected levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound 8 blocks the process of translation. Altogether, these results indicated benzofuroxan derivative 8 to be a promising lead compound for the development of a novel chemical class of antitubercular drugs

Planejamento, sintese e avaliação biológica de derivados furoxânicos e benzofuroxânicos potencialmente antichagásicos

Há mais de um século de sua descrição, a doença de Chagas continua sendo um dos maiores problemas de saúde pública. Resultante da infecção pelo protozoário hemoflagelado Trypanosoma cruzi, a doença é endêmica nos 21 países da América Latina e estima-se que 10 milhões de pessoas estejam infectadas e aproximadamente 100 milhões estão sob o risco de contaminação. Apenas dois fármacos são disponíveis para tratamento da doença, nifurtimox e benznidazol. Ambos são ativos somente na fase aguda da doença, além de causarem efeitos colaterais graves. No Brasil apenas o benznidazol é comercializado. Neste sentido, a desenvolvimento de fármacos tripanossomicidas é de extrema importância. Estudos mostraram que derivados nitrofurânicos inibem a tripanotiona redutase, considerada enzima chave do metabolismo antioxidativo do T. cruzi. Pesquisas com o hidroximetilnitrofural (NFOH) tem demonstrado maior atividade in vitro e in vivo contra T. cruzi com menor toxicidade quando comparado ao fármaco matriz, nitrofural. Um amplo espectro de atividades biológicas tem sido relatada para compostos furoxânicos (N-óxido-1,2,5-oxadiazol) e benzofuroxânicos (N-óxido-benzo[1,2-c]1,2,5-oxadiazol), sendo assim, foi obtida uma série de derivados isósteros de nitrofural, substituindo o anel nitrofurano pelos respectivos furoxanos e benzofuroxanos. Os compostos obtidos foram avaliados quanto à atividade tripanossomicida in vitro em formas epimastigotas e amastigotas de T. cruzi, capacidade de doação de óxido nítrico e mutagenicidade in vivo. Foram sintetizados, identificados e caracterizados oito compostos. Os derivados benzofuroxânicos (compostos 20 e 21) foram os mais ativos contra as formas epimastigotas de T. cruzi, entretanto no ensaio contra as formas amastigotas, sete apresentaram...For more than a century of his description, Chagas disease remains a major public health problems. Resulting from infection flagellate protozoan Trypanosoma cruzi, is endemic in 21 Latin American countries and it is estimated that 10 million people are infected and about 100 million are at risk of contamination. Only two drugs are available for treating the disease, nifurtimox and benznidazole. Both are active only during the acute phase of the disease, and cause serious side effects. In Brazil only benznidazole is marketed. In this sense, the development of drugs trypanosomicide is extremely important. Studies demonstrated that nitrofurans derivatives inhibit the trypanothione reductase, the key enzyme in the metabolism considered antioxidant T. cruzi. Research with hydroxymethylnitrofurazone (NFOH) has shown greater activity in vitro and in vivo against T. cruzi with less toxicity when compared to the drug matrix, nitrofurazone (NF). A wide spectrum of biological activities have been reported for compounds furoxans (1,2,5-oxadiazol-2-N-oxide) and benzofuroxans (benzo[1,2-c]-1,2,5-oxadiazol-1-N-oxide) and thus was obtained a series of derivatives of Nitrofural isosteres, nitrofuran ring by replacing the respective furoxans and benzofuroxans. The compounds were evaluated for in vitro trypanocidal activity in epimastigotes and amastigotes of T. cruzi, ability to donate nitric oxide and mutagenicity in vivo. Were synthesized, characterized and identified eight compounds. Benzofuroxans derivatives (compounds 20 and 21) were the most active against epimastigotes of T. cruzi, however the assay against amastigotes, seven showed IC50 higher than or equal to a drug used as reference (benznidazole) and less mutagenic potential when compared with the results obtained for the drugs nitrofurazone... (Complete abstract click electronic access below)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Avaliação da presença do grupo nitro na atividade antichagásica e mutagênica do candidato a fármaco hidroximetilnitrofural (NFOH)

A doença de Chagas constitui um dos maiores problemas de Saúde Pública em países do cone sul das Américas. Estima-se que 16 a 18 milhões de pessoas estejam infectadas e aproximadamente cento e vinte milhões estão sob risco de contaminação. No Brasil, apenas o benznidazol (BNZ) está disponível para o tratamento da doença, e apesar de seu uso clínico, este fármaco apresenta efeitos secundários indesejáveis, sendo ativo apenas na fase aguda da doença. O nitrofural (NF) é ativo contra o Trypanossoma cruzi, entretanto, a alta toxicidade impede o seu uso na parasitose. O hidroximetilnitrofural (NFOH) é um pró-fármaco do nitrofural, que apresenta maior atividade contra T. cruzi, e, além disso, pesquisas vêm demonstrando menor toxicidade do NFOH quando comparado ao fármaco matriz, nitrofural. Resultados obtidos nos testes de toxicidade aguda para o NFOH com camundongos e ratos, sugeriram baixa toxicidade deste, obtendo-se uma dose letal mediana (DL50) maior em relação ao fármaco de partida, NF (556,3 mg/kg). Por via oral os resultados caracterizaram o NFOH como pouco tóxico, segundo a OMS com um valor de DL50 acima de 2000mg/kg. No Teste de Ames os resultados indicaram que a latenciação do NF em NFOH foi capaz de diminuir a atividade mutagênica em aproximadamente quatro vezes, nos ensaios com (+S9) ou sem ativação metabólica (-S9), nas linhagens testadas. Contudo, este trabalho avaliou a influência do grupo nitro na molécula de nitrofural, através da substituição deste grupo por isósteros do grupo nitro e também o potencial mutagênico dos fármacos NF e BNZ, e do candidato a fármaco NFOH empregando-se o teste de micronúcleo em células do sangue periférico de camundongos. A atividade dos compostos sintetizados neste trabalho modificou-se drasticamente, ou seja, os compostos não apresentaram atividade antichagásica nas formas epimastigotas em nenhuma...Chagas' disease is a major public health problem in countries of the southern cone of the Americas. It is estimated that 16 to 18 million people are infected and about hundred and twenty million are at risk of contamination. In Brazil, only benznidazole is available for the treatment of the disease, although its clinical use, this drug shows toxic side effects and is active only in the acute phase of illness. The nitrofurazone (NF) is active against Trypanossoma cruzi, although, it`s high toxicity prevents it from being used in parasitosis. The hydroxymethylnitrofurazone (NFOH) is the nitrofurazone prodrugs that presents the highest level of activity against the T. Cruzi, fact which is supported by researches that have been evidentiating it`s less significant toxicity when compared to the matrix drug nitrofurazone. Results obtained in tests of acute toxicity to the NFOH with mice and rats, suggested that low toxicity, resulting in a median lethal dose (LD50) more than in the drug of departure, NF (556,3 mg/kg). Orally NFOH characterized the results as somewhat toxic, according to the WHO with a value of LD50 over 2000 mg/kg. In the Ames Test results indicate that NF latentiation in the NFOH was able to reduce the mutagenic activity in about 4 times in trials with (S9 +) or without metabolic activation (-S9), the strains tested. However, this study evaluated the influence of nitro group in the molecule of nitrofurazone, by replacing this group by isosteric the nitro group and also the mutagenic potential of drugs NF and BNZ, and the drug candidate NFOH by using the test micronucleus test in cells in the peripheral blood of mice. The activity of compounds synthesized in this work has changed dramatically, ie the compound showed no activity in epimastigotes antichagasic in any of the concentrations used. However, the results obtained in the testing of mutagenicity by the micronucleus test... (Complete abstract click electronic access below

A Prodrug Approach to Improve the Physico-Chemical Properties and Decrease the Genotoxicity of Nitro Compounds

In therapeutics research, the nitro compounds are part of an important group of drugs with multiple pharmacological activities. However, in drug design, the inclusion of a nitro group in a molecule changes the physico-chemical and electronic properties and is associated with increased mutagenicity and carcinogenicity. In addition, several studies have related the relationship between the antimicrobial and/or anti-protozoal activity and the mutagenic effect to reduction of the nitro group. This work reviews the toxicity of nitro compounds and shows how the use of prodrugs can increase the biological activity and decrease the genotoxicity of nitro compounds, without any modification in nitro reduction behavior, but rather by physico-chemical improvement. Examples are given of metronidazole and nitrofurazone prodrugs.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Assessment of the In Vivo Genotoxicity of New Lead Compounds to Treat Sickle Cell Disease

The compounds 1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl nitrate (C1), (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) ethyl nitrate (C2), 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) benzyl nitrate (C3), 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-hydroxy-benzenesulfonamide (C4), 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) benzyl nitrate (C5), and 2-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) phenyl] ethyl nitrate (C6) were evaluated with a micronucleus test using mouse peripheral blood to identify new candidate drugs for the treatment of sickle cell disease (SCD) that are safer than hydroxyurea. The compounds induced an average frequency of micronucleated reticulocytes (MNRET) of less than six per 1,000 cells at 12.5, 25, 50, and 100 mg/kg, whereas hydroxyurea induced an average MNRET frequency of 7.8, 9.8, 15, and 33.7 per 1000 cells respectively, at the same concentrations. Compounds C1-C6 are new non-genotoxic in vivo candidate drugs for the treatment of SCD symptoms.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Advances in drug design based on the amino acid approach: Taurine analogues for the treatment of CNS diseases

Amino acids are well known to be an important class of compounds for the maintenance of body homeostasis and their deficit, even for the polar neuroactive aminoacids, can be controlled by supplementation. However, for the amino acid taurine (2-aminoethanesulfonic acid) this is not true. Due its special physicochemical properties, taurine is unable to cross the blood-brain barrier. In addition of injured taurine transport systems under pathological conditions, CNS supplementation of taurine is almost null. Taurine is a potent antioxidant and anti-inflammatory semi-essential amino acid extensively involved in neurological activities, acting as neurotrophic factor, binding to GABA A/glycine receptors and blocking the excitotoxicity glutamate-induced pathway leading to be a neuroprotective effect and neuromodulation. Taurine deficits have been implicated in several CNS diseases, such as Alzheimer's, Parkinson's, epilepsy and in the damage of retinal neurons. This review describes the CNS physiological functions of taurine and the development of new derivatives based on its structure useful in CNS disease treatment.&; 2012 by the authors; licensee MDPI, Basel, Switzerland

Anti-inflammatory drug design by molecular hybridization approach

The design of new drugs with better physiochemical properties, adequateabsorption, distribution, metabolism, and excretion, effective pharmacologic potency andlacking toxicity remains is a challenge. Inflammation is the initial trigger of severaldifferent diseases, such as Alzheimer s disease, asthma, atherosclerosis, colitis, rheumatoidarthritis, depression, cancer; and disorders such as obesity and sexual dysfunction.Although inflammation is not the direct cause of these disorders, inflammatory processesoften increase related pain and suffering. New anti-inflammatory drugs developed usingmolecular hybridization techniques to obtain multiple-ligand drugs can act at one or multipletargets, allowing for synergic action and minimizing toxicity. This work is a review of newanti-inflammatory drugs developed using the molecular modification approach

Antiplatelet and Antithrombotic Activities of Non-Steroidal Anti-Inflammatory Drugs Containing an N-Acyl Hydrazone Subunit

Nonsteroidal anti-inflammatory drugs (NSAIDs) 1-5 containing an N-acyl hydrazone subunit were prepared and their antiplatelet and antithrombotic activities assessed in vitro and in vivo. Compounds 1-5 inhibited the platelet aggregation induced by adenosine diphosphate and/or arachidonic acid, with inhibition rates of 18.0%-61.1% and 65.9%-87.3%, respectively. Compounds 1 and 5 were the most active compounds, inhibiting adenosine-diphosphate-induced platelet aggregation by 57.2% and 61.1%, respectively. The inhibitory rates for arachidonic-acid-induced platelet aggregation were similar for compound 2 (80.8%) and acetylsalicylic acid (ASA, 80%). After their oral administration to mice, compounds 1, 3, and 5 showed shorter mean bleeding times than ASA. Compounds 1 and 5 also protected against thromboembolic events, with survival rates of 40% and 33%, respectively, compared with 30% for ASA. In conclusion, these results indicate that these novel NSAIDs containing an NAH subunit may offer better antiplatelet and antithrombotic activities than ASA.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq