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

Coordinative versatility of a Schiff base containing thiophene: Synthesis, characterization and biological activity of zinc(II) and silver(I) complexes

The synthesis, spectroscopic characterization and crystal description based on powder diffraction data, and antimycobacterial assays of silver(I) and zinc(II) complexes with Schiff base N,N\u2032-bis(thiophen-2-ylmethylene) ethane-1,2-diamine ThioEn, are here reported. The [Ag(ThioEn)]NO3, AgThioEn, [Ag(ThioEn)2]NO3, Ag(ThioEn)2 and [ZnCl2(ThioEn)], ZnThioEn complexes were obtained by reaction of the ThioEn with silver(I) nitrate or zinc(II) chloride in methanolic solution. ThioEn was previously obtained by reacting ethylenediamine (En) with 2-thiophenecarboxaldehyde (Thio). The complexes were characterized by elemental (C, H and N) and thermal (TG-DTA) analyses and 13C and 1H NMR and FT-IR spectroscopic measurements. The three crystal structures were determined and refined from laboratory powder diffraction data only. The AgThioEn complex has a polymeric structure where the ligand acts as bridge between Ag(I) ions, while Ag(ThioEn)2 and ZnThioEn are monomers complexes with ThioEn acting as chelating ligand. Both silver(I) complexes showed to be effective against Mycobacterium tuberculosis

Análise fitoquímica e atividade antimicobacteriana de extratos metanólicos de Jacaranda cuspidifolia Mart. (Bignoniaceae)

Jacaranda cuspidifolia Mart., conhecida popularmente como caroba, jacarandá ou bolacheira, é utilizada medicinalmente para o tratamento da sífilis e da gonorréia. A atividade antimicobacteriana dessa espécie foi avaliada em ensaios in vitro com os extratos metanólicos das cascas e folhas, segundo o Método Analítico Alamar Blue (MABA). Os valores de concentração inibitória mínima para os extratos metanólicos das cascas e das folhas de J. cuspidifolia foram iguais a CIM = 250 μg mL-1 para ambos os extratos. A análise fitoquímica, por Cromatografia em Camada Delgada de gel de sílica, dos extratos metanólicos das cascas e folhas revelou a presença de taninos, flavonóides, terpenos, cumarinas e esteróides. A análise dos perfis dos extratos metanólicos por Cromatografia Líquida de Alta Eficiência de Fase Reversa registrou a presença de compostos fenólicos derivados do verbascosídeo sugerindo a provável responsabilidade pela ação antimicobacteriana.Jacaranda cuspidifolia Mart., popularly known as caroba, jacaranda or bolacheira, is used as medicine for the treatment of syphilis and gonorrhea. The antimycobacterial activity of this species was assessed by means of in vitro assays with methanol extracts of barks and leaves according to the Microplate Alamar Blue Assay (MABA). The minimal inhibitory concentration values for methanol extracts of barks and leaves from J. cuspidifolia were MIC = 250 μg mL-1 for both extracts. Phytochemical analysis, by Thin Layer Chromatography on silica gel, of methanol extracts of barks and leaves revealed the presence of tannins, flavonoids, terpenes, cumarins and steroids. Analysis of the profiles of methanol extracts by High Performance Liquid Chromatography - Reversed Phase recorded the presence of phenolic compounds derivatives of verbascoside, suggesting their probable responsibility for the antimycobacterial action.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Synthesis and SAR evaluation of novel thioridazine derivatives active against drug-resistant tuberculosis

The neuroleptic drug thioridazine has been recently repositioned as possible anti-tubercular drug. Thioridazine showed anti-tubercular activity against drug resistant mycobacteria but it is endowed with adverse side effects. A small library of thioridazine derivatives has been designed through the replacement of the piperidine and phenothiazine moieties, with the aim to improve the anti-tubercular activity and to reduce the cytotoxic effects. Among the resulting compounds, the indole derivative 12e showed an antimycobacterial activity significantly better than thioridazine and a cytotoxicity 15-fold lower

Silver complexes with fluoroanthranilic acid isomers: Spectroscopic characterization, antimycobacterial activity and cytotoxic studies over a panel of tumor cells

This manuscript presents three silver(I) complexes with fluoroanthranilic acid (fa) isomers, [Ag(4fa)]n, [Ag(5fa)]n and [Ag(6fa)]n, which were named as Ag4fa, Ag5fa and Ag6fa, respectively. The 1:1 metal/ligand molar composition of the complexes was determined by elemental, thermal and high-resolution mass spectrometric (ESI(+)-MS) analyses. Infrared and 1H, 13C and {15N,1H} nuclear magnetic resonance spectroscopy evidenced the coordination of the fluoroanthranilic acid isomers to silver via the nitrogen atom of the amino group and by the oxygen atoms of the carboxylate group. The structure of the Ag5fa complex was determined by single crystal X-ray diffraction analysis. The complex forms an extended polymeric structure organized in layers with coordination by the amino and carboxylate moieties. Antibacterial activity assays showed that the silver complexes were active against M. tuberculosis (MIC90 between 2.6 and 4.2 µg/mL) and also over S. aureus, B. cereus, E. coli and P. aeruginosa (MIC = 62.25 µg/mL) strains. The complexes have also shown in vitro cytotoxicity over cancer cell lines and selectivity (SI) especially against epithelial colorectal adenocarcinoma cells (IC50 = 2.1 µg/mL and SI > 3). Also, the silver complexes are non-mutagenic, which is essential when considering the development of new bioactive compounds for therapeutic purposes502CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP407012/2018-42017/25995-6; 2018/12062-4; 2018/14512-7; 2017/16278-9; 2018/00163-

Surface application of lime ameliorates subsoil acidity and improves root growth and yield of wheat in an acid soil under no-till system Calagem superficial em solo ácido no sistema plantio direto melhora a acidez do subsolo e beneficia o crescimento radicular e a produção de trigo

Crop root growth and grain yield can be affected by chemical modifications in the soil profile due to surface lime application. A field trial was carried out on a loamy dystrophic Typic Hapludox at Ponta Grossa, State of Paraná, Brazil, to evaluate root growth and grain yield of wheat (Triticum aestivum L. cv. CD 104, moderately susceptible to Al), about 10 years after surface liming (0, 2, 4, and 6 Mg ha-1) and three years after surface re-liming (0 and 3 Mg ha-1), in a long-term no-till cultivation system. Soil acidity limited wheat root growth and yield severely, probably as a result of extended water deficits during the vegetative stage. Surface liming caused increases up to 66% in the root growth (0-60 cm) and up to 140% in the grain yield. Root density and grain yield were correlated positively with soil pH and exchangeable Ca2+, and negatively with exchangeable Al3+ and Al3+ saturation, in the surface and subsurface layers.<br>A calagem na superfície do solo em plantio direto ocasiona modificações químicas no perfil que podem influenciar o crescimento do sistema radicular e a produção de grãos das culturas. O crescimento de raízes e a produção de trigo (Triticum aestivum L. cv. CD 104, moderadamente sensível ao Al), foram estudados cerca de 10 anos após a aplicação superficial de calcário (0, 2, 4 e 6 Mg ha-1) e três anos da reaplicação de calcário na superfície (0 e 3 Mg ha-1), em um Latossolo Vermelho distrófico textura média, manejado durante longo período no sistema plantio direto, em Ponta Grossa (PR). A acidez do solo limitou drasticamente o crescimento radicular e a produção de trigo, provavelmente por causa de prolongada falta de água ocorrida durante a fase de desenvolvimento vegetativo da cultura. A calagem na superfície ocasionou aumento de até 66% no crescimento radicular (0-60 cm) e de até 140% na produção de trigo. A densidade de raízes e a produção de trigo correlacionaram-se positivamente com o pH e o teor de Ca2+ trocável, e negativamente com o teor de Al3+ trocável e a saturação por Al3+, nas camadas superficiais e do subsolo