RESUMO
OBJECTIVES: The most recent survey conducted by the World Health Organization described Tuberculosis (TB) as one of the top 10 causes of death and the leading cause of death from a single infectious agent. The increasing number of TB-resistant cases has contributed to this scenario. In light of this, new strategies to control and treat the disease are necessary. Our research group has previously described furoxan derivatives as promising scaffolds to be explored as new antitubercular drugs. RESULTS: Two of these furoxan derivatives, (14b) and (14c), demonstrated a high selectivity against Mycobacterium tuberculosis. The compounds (14b) and (14c) were also active against a latent M. tuberculosis strain, with MIC90 values of 6.67 µM and 9.84 µM, respectively; they were also active against monoresistant strains (MIC90 values ranging from 0.61 to 20.42 µM) and clinical MDR strains (MIC90 values ranging from 3.09 to 42.95 µM). Time-kill experiments with compound (14c) showed early bactericidal effects that were superior to those of the first- and second-line anti-tuberculosis drugs currently used in therapy. The safety of compounds (14b) and (14c) was demonstrated by the Ames test because these molecules were not mutagenic under the tested conditions. Finally, we confirmed the safety, and high efficacy of compounds (14b) and (14c), which reduced M. tuberculosis to undetectable levels in a mouse aerosol model of infection. CONCLUSION: Altogether, we have identified two advanced lead compounds, (14b) and (14c), as novel promising candidates for the treatment of TB infection.
Assuntos
Antituberculosos/uso terapêutico , Oxidiazóis/uso terapêutico , Tuberculose/tratamento farmacológico , Animais , Antituberculosos/farmacologia , Antituberculosos/toxicidade , Bactérias/efeitos dos fármacos , Farmacorresistência Bacteriana , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Testes de Mutagenicidade , Mycobacterium tuberculosis/efeitos dos fármacos , Oxidiazóis/farmacologia , Oxidiazóis/toxicidade , Tuberculose/microbiologiaRESUMO
A series of highly active hybrids were discovered as novel antiparasitic agents. Two heterocyclic scaffolds (1,2,4-oxadiazole and 3-hydroxy-2-oxindole) were linked, and the resulting compounds showed in vitro activities against intracellular amastigotes of two protozoan parasites, Trypanosoma cruzi and Leishmania infantum. Their cytotoxicity was assessed using HFF-1 fibroblasts and HepG2 hepatocytes. Compounds 5b, 5d, 8h and 8o showed selectivity against L. infantum (IC50 values of 3.89, 2.38, 2.50 and 2.85 µM, respectively). Compounds 4c, 4q, 8a and 8k were the most potent against T. cruzi, exhibiting IC50 values of 6.20, 2.20, 2.30 and 2.20 µM, respectively. Additionally, the most potent anti-T. cruzi compounds showed in vitro efficacies comparable or superior to that of benznidazole. These easy-to-synthesize molecules represent novel chemotypes for the design of potent and selective lead compounds for Chagas disease and leishmaniasis drug discovery.
Assuntos
Oxidiazóis/farmacologia , Oxindóis/farmacologia , Tripanossomicidas/farmacologia , Células Hep G2 , Humanos , Leishmania infantum/efeitos dos fármacos , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/toxicidade , Oxindóis/síntese química , Oxindóis/toxicidade , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/toxicidade , Trypanosoma cruzi/efeitos dos fármacosRESUMO
Tuberculosis (TB) remains a serious health problem responsible to cause millions of deaths annually. The scenario becomes alarming when it is evaluated that the number of new drugs does not increase proportionally to the emergence of resistance to the current therapy. Furoxan derivatives, known as nitric oxide (NO) donors, have been described to exhibit antitubercular activity. Herein, a novel series of hybrid furoxan derivatives (1,2,5-oxadiazole 2-N-oxide) (compounds 4a-c, 8a-c and 14a-c) were designed, synthesized and evaluated in vitro against Mycobacterium tuberculosis (MTB) H37Rv (ATCC 27294) and a clinical isolate MDR-TB strain. The furoxan derivatives have exhibited MIC90 values ranging from 1.03 to 62 µM (H37Rv) and 7.0-50.0 µM (MDR-TB). For the most active compounds (8c, 14a, 14b and 14c) the selectivity index ranged from 3.78 to 52.74 (MRC-5 cells) and 1.25-34.78 (J774A.1 cells). In addition, it was characterized for those compounds logPo/w values between 2.1 and 2.9. All compounds were able to release NO at levels ranging from 0.16 to 44.23%. Among the series, the phenylsulfonyl furoxan derivatives (compounds 14a-c) were the best NO-donor with the lowest MIC90 values. The most active compound (14c) was also stable at different pHs (5.0 and 7.4). In conclusion, furoxan derivatives were identified as new promising compounds useful to treat tuberculosis.
Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Antituberculosos/química , Antituberculosos/toxicidade , Linhagem Celular Tumoral , Técnicas de Química Sintética , Desenho de Fármacos , Humanos , Oxidiazóis/química , Oxidiazóis/toxicidadeRESUMO
The development of resistance to antibiotics by microorganisms is a major problem for the treatment of bacterial infections worldwide, and therefore, it is imperative to study new scaffolds that are potentially useful in the development of new antibiotics. In this regard, we propose the design, synthesis and biological evaluation of hybrid sulfonylhydrazone bioisosters/furoxans with potential antibacterial (Escherichia coli) activity. The most active compound of the series, (E)-3-methyl-4-((2-tosylhydrazono)methyl)-1,2,5-oxadiazole 2-oxide, with a MIC=0.36µM, was not cytotoxic when tested on Vero cells (IC50>100µM). To complement the in vitro screening, we also studied the interaction of the test compounds with ß-ketoacyl acyl carrier protein synthase (FabH), the target for the parent compounds, and we observed three important hydrogen-bonding interactions with two important active site residues in the catalytic site of the enzyme, providing complementary evidence to support the target of the new hybrid molecules.
Assuntos
Acetiltransferases/antagonistas & inibidores , Antibacterianos/química , Inibidores Enzimáticos/química , Proteínas de Escherichia coli/antagonistas & inibidores , Escherichia coli/enzimologia , 3-Oxoacil-(Proteína de Transporte de Acila) Sintase , Acetiltransferases/metabolismo , Animais , Antibacterianos/síntese química , Antibacterianos/toxicidade , Sítios de Ligação , Candida albicans/efeitos dos fármacos , Domínio Catalítico , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/toxicidade , Escherichia coli/efeitos dos fármacos , Proteínas de Escherichia coli/metabolismo , Ácido Graxo Sintase Tipo II/antagonistas & inibidores , Ácido Graxo Sintase Tipo II/metabolismo , Ligação de Hidrogênio , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Oxidiazóis/toxicidade , Eletricidade Estática , Relação Estrutura-Atividade , Células VeroRESUMO
An altered form of the cellular prion protein, the PrPScor PrPRes, is implicated in the occurrence of the still untreatable transmissible spongiform encephalopathies. We have previously synthesized and characterized aromatic compounds that inhibit protease-resistant prion protein (PrPRes) accumulation in scrapie-infected cells. These compounds belong to different chemical classes, including acylhydrazones, chalcones and oxadiazoles. Some of the active compounds were non-toxic to neuroblastoma cells in culture and seem to possess drugable properties, since they are in agreement with the Lipinski´s rule of 5 and present desirable pharmacokinetic profiles as predicted in silico. Before the evaluation of the in vivo efficacy of the aromatic compounds in scrapie-infected mice, safety assessment in healthy mice is needed. Here we used Swiss mice to evaluate the acute toxicity profile of the six most promising anti-prionic compounds, the 2,4,5-trimethoxychalcones (J1, J8, J20 and J35) and the 1,3,4-oxadiazoles (Y13 and Y17). One single oral administration (300 mg/kg) of J1, J8, J20, J35, Y13 and Y17 or repeated intraperitoneal administration (10 mg/kg, 3 times a week, for 4 weeks) of J1, J8 and J35, did not elicit toxicity in mice. We strongly believe that the investigated trimethoxychalcones and oxadiazoles are interesting compounds to be further analyzed in vivo against prion diseases.
Assuntos
Chalconas/toxicidade , Oxidiazóis/toxicidade , Príons/antagonistas & inibidores , Scrapie/tratamento farmacológico , Animais , Relação Dose-Resposta a Droga , Feminino , Dose Letal Mediana , Masculino , CamundongosRESUMO
The anti-Trypanosoma cruzi activity of 5-nitro-2-furfuriliden derivatives as well as the cytotoxicity of these compounds on J774 macrophages cell line and FN1 human fibroblast cells were investigated in this study. The most active compounds of series I and II were 4-butyl-[N'-(5-nitrofuran-2-yl) methylene] benzidrazide (3g; IC50=1.05µM±0.07) and 3-acetyl-5-(4-butylphenyl)-2-(5-nitrofuran-2-yl)-2,3-dihydro,1,3,4-oxadiazole (4g; IC50=8.27µM±0.42), respectively. Also, compound 3g was more active than the standard drugs, benznidazole (IC50=22.69µM±1.96) and nifurtimox (IC50=3.78µM±0.10). Regarding the cytotoxicity assay, the 3g compound presented IC50 value of 28.05µM (SI=26.71) against J774 cells. For the FN1 fibroblast assay, 3g showed IC50 value of 98µM (SI=93.33). On the other hand, compound 4g presented a cytotoxicity value on J774 cells higher than 400µM (SI >48), and for the FN1 cells its IC50 value was 186µM (SI=22.49). Moreover, an exploratory data analysis, which comprises hierarchical cluster (HCA) and principal component analysis (PCA), was carried out and the findings were complementary. The molecular properties that most influenced the compounds' grouping were ClogP and total dipole moment, pointing out the need of a lipophilic/hydrophilic balance in the designing of novel potential anti-T. cruzi molecules.
Assuntos
Desenho de Fármacos , Oxidiazóis/farmacologia , Tripanossomicidas/síntese química , Trypanosoma cruzi/efeitos dos fármacos , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Análise por Conglomerados , Humanos , Camundongos , Simulação de Dinâmica Molecular , Oxidiazóis/química , Oxidiazóis/toxicidade , Análise de Componente Principal , Eletricidade Estática , Tripanossomicidas/farmacologia , Tripanossomicidas/toxicidadeRESUMO
Parasitic flatworms are responsible for serious infectious diseases that affect humans as well as livestock animals in vast regions of the world. Yet, the drug armamentarium available for treatment of these infections is limited: praziquantel is the single drug currently available for 200 million people infected with Schistosoma spp. and there is justified concern about emergence of drug resistance. Thioredoxin glutathione reductase (TGR) is an essential core enzyme for redox homeostasis in flatworm parasites. In this work, we searched for flatworm TGR inhibitors testing compounds belonging to various families known to inhibit thioredoxin reductase or TGR and also additional electrophilic compounds. Several furoxans and one thiadiazole potently inhibited TGRs from both classes of parasitic flatworms: cestoda (tapeworms) and trematoda (flukes), while several benzofuroxans and a quinoxaline moderately inhibited TGRs. Remarkably, five active compounds from diverse families possessed a phenylsulfonyl group, strongly suggesting that this moiety is a new pharmacophore. The most active inhibitors were further characterized and displayed slow and nearly irreversible binding to TGR. These compounds efficiently killed Echinococcus granulosus larval worms and Fasciola hepatica newly excysted juveniles in vitro at a 20 µM concentration. Our results support the concept that the redox metabolism of flatworm parasites is precarious and particularly susceptible to destabilization, show that furoxans can be used to target both flukes and tapeworms, and identified phenylsulfonyl as a new drug-hit moiety for both classes of flatworm parasites.
Assuntos
Anticestoides/farmacologia , Antiplatelmínticos/farmacologia , Echinococcus granulosus/efeitos dos fármacos , Fasciola hepatica/efeitos dos fármacos , Proteínas de Helminto/antagonistas & inibidores , Complexos Multienzimáticos/antagonistas & inibidores , NADH NADPH Oxirredutases/antagonistas & inibidores , Animais , Anticestoides/química , Anticestoides/toxicidade , Antiplatelmínticos/química , Antiplatelmínticos/toxicidade , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Echinococcus granulosus/enzimologia , Fasciola hepatica/enzimologia , Fibroblastos/efeitos dos fármacos , Proteínas de Helminto/química , Humanos , Larva/efeitos dos fármacos , Larva/enzimologia , Linfócitos/efeitos dos fármacos , Camundongos , Modelos Moleculares , Complexos Multienzimáticos/química , NADH NADPH Oxirredutases/química , Oxidiazóis/química , Oxidiazóis/farmacologia , Oxidiazóis/toxicidade , Teoria Quântica , Quinoxalinas/química , Quinoxalinas/farmacologia , Quinoxalinas/toxicidade , Relação Estrutura-Atividade , Tiadiazóis/química , Tiadiazóis/farmacologia , Tiadiazóis/toxicidadeRESUMO
The convergent synthesis of an unusual (but simple) class of compounds 5a-g has been achieved by the copper-catalyzed [3+2] cycloaddition reaction of 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl azide 4 with propynyl 3-[3-(aryl)-1,2,4-oxadiazol-5-yl] propionates 3a-g. The formerly known azide 4 has been prepared according to the literature procedure; however, the synthesis of esters 3a-g is being reported for the first time. The infrared as well as (1)H NMR spectra of all new products are in agreement with their proposed structures. By carrying out the nOe experiment of one of the final compounds 5a, we have been able to establish that only the 1,4-regioisomers have been formed in the cycloaddition reaction. All final products presented weak cytotoxic activity, but 5e and 5g had somewhat better behaviour showing 22-25% cell growth inhibition against two cell strains: NCI-H(292) (lung carcinoma) and HEp-2 (larynx carcinoma).
Assuntos
Antineoplásicos/química , Antineoplásicos/toxicidade , Oxidiazóis/química , Oxidiazóis/toxicidade , Triazóis/química , Triazóis/toxicidade , Antineoplásicos/síntese química , Carbono/química , Carcinoma/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Glicosilação , Humanos , Neoplasias Laríngeas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Oxidiazóis/síntese química , Oxigênio/química , Triazóis/síntese químicaRESUMO
4-(5-Substituted-1,3,4-oxadiazol-2-yl)pyridine derivatives 1-12 were synthesized and evaluated for their in vitro antimycobacterial activity. Some compounds showed an interesting activity against Mycobacterium tuberculosis H(37)Rv and five clinical isolates (drug-sensitive and -resistant strains). Compound 4 [4-(5-pentadecyl-1,3,4-oxadiazol-2-yl)pyridine] was 10 times more active than isoniazid, 20 times more active than streptomycin, and 28 times more potent than ethambutol against drug-resistant strain CIBIN 112. Compound 5 [4-(5-heptadecyl-1,3,4-oxadiazol-2-yl)pyridine] showed the same behavior as compound 4. Both of the above structures bear a high lipophilic chain bonded to the 5-position of the oxadiazole moiety. This fact implies that there exists a contribution of lipophilicity, which could facilitate the entrance of these molecules through lipid-enriched bacterial cell membrane.
Assuntos
Antituberculosos/síntese química , Antituberculosos/toxicidade , Oxidiazóis/síntese química , Oxidiazóis/toxicidade , Piridinas/síntese química , Piridinas/toxicidade , Animais , Antituberculosos/química , Células Cultivadas , Fenômenos Químicos , Físico-Química , Chlorocebus aethiops , Humanos , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Oxidiazóis/química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
Furoxan derivatives with in vitro cytotoxic activity were investigated as antitumoral agents in vivo. The compounds were tested in murine models of both CCRFS-180 II sarcoma and mammary adenocarcinoma. Two of the furoxan derivatives considered here, 3-formyl-4-phenyl-1,2,5-oxadiazole N2-oxide and 3-carbonitrile-4-phenyl-1,2,5-oxadiazole N2-oxide, present in vivo antitumoral activity. They were able to produce more than 90% of tumoral necrosis under the experimental protocol of administration and posology employed. NO-releasing capacity of furoxans may explain the anti-neoplastic activity of these compounds.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Animais , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Fenômenos Químicos , Química Farmacêutica , Físico-Química , Feminino , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Oxidiazóis/toxicidade , Quinoxalinas/farmacologia , Sarcoma Experimental/tratamento farmacológico , Sarcoma Experimental/patologiaRESUMO
Compounds derived from 1,2,4-oxadiazole have being reported for their anti-inflammatory activity. However, those compounds should be devoid of any genotoxic side effect. In this work, the genotoxic activity of peptidomimetic moiety-containing 1,2,4-oxadiazoles derivatives was tested based on the Ames and SOS Chromotest. The results showed no mutagenic activity on the Ames test for 3-[3-phenyl-1,2,4-oxadiazol-5-yl] propionic acid (POPA) parental drug, but a weak SOS response induction on Chromotest. The chemical modifications reduced that response to a non-significative level, with l-phenylalanine peptidomimetic derivative being showing the lowest induction response. The results pointed out for the effectiveness of promoting chemical modifications of biological active compounds to increase its mode of action, showed in previous work, without increasing and even decreasing its DNA damage effect.
Assuntos
Mutagênicos/química , Mutagênicos/toxicidade , Oxidiazóis/química , Oxidiazóis/toxicidade , Resposta SOS em Genética/efeitos dos fármacos , Animais , DNA/efeitos dos fármacos , Dano ao DNA , Testes de Mutagenicidade/métodos , Ratos , Salmonella typhimurium/efeitos dos fármacosRESUMO
A simple, convenient and straightforward synthesis of 3-aryl-1,2,4-oxadiazoles 4a-f from arylamidoximes 1a-f and palmitic acid 2 is described. Compounds 4a-f are non-lethal in mice at four times the therapeutic dose (i.p., LD50>1 g kg(-1) of the animals' body weight). These heterocycles have been found to possess antiinflammatory property similar to aspirin and ibuprofen. Three compounds, viz., 4a, d, e have also been evaluated for antitumor activity, where 4d exhibited an excellent activity comparable to lapachol.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Antineoplásicos/síntese química , Oxidiazóis/síntese química , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/toxicidade , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Carragenina , Modelos Animais de Doenças , Ensaios de Seleção de Medicamentos Antitumorais , Edema/induzido quimicamente , Edema/prevenção & controle , Dose Letal Mediana , Camundongos , Oxidiazóis/farmacologia , Oxidiazóis/toxicidade , Relação Estrutura-AtividadeRESUMO
The synthesis of six 3-aryl-5-(n-propyl)-4,5dihydro-1,2,4-oxadiazoles 3a-f has been achieved in a facile manner by the reaction of an appropriate arylamidoxime 1a-f with butyraldehyde 2. Oxidation of 3a-f individually using MnO(2) in CH(2)Cl(2) or sodium hypochlorite in THF/H(2)O furnished 1,2,4-oxadiazoles 4a-f in good to excellent yields. Compounds 4a-f were also evaluated against inflammation. Except 4e, all of them reduced inflammation, however, 4c presented better antiinflammatory activity. A preliminary antimicrobial activity tests of 3a-f showed that these compounds possess activity against some microorganisms. In fact, 3c and 3f have been found to be more effective against Staphylococcus aureus, Mycobacterium smegmatis, and Candida albicans.