Identification of novel imidazo[1,2-a]pyridine inhibitors targeting M. tuberculosis QcrB.

Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. Through the use of high throughput whole cell screening of an extensive compound library a number of imidazo[1,2-a]pyridine (IP) compounds were obtained as potent lead molecules active against M. tuberculosis and Mycobacterium bovis BCG. The IP inhibitors (1–4) demonstrated minimum inhibitory concentrations (MICs) in the range of 0.03 to 5 µM against a panel of M. tuberculosis strains. M. bovis BCG spontaneous resistant mutants were generated against IP 1, 3, and 4 at 5× MIC and subsequent whole genome sequencing identified a single nucleotide polymorphism 937ACC>937GCC (T313A) in qcrB, which encodes the b subunit of the electron transport ubiquinol cytochrome C reductase. This mutation also conferred cross-resistance against IP 1, 3 and 4 demonstrating a common target. Gene dosage experiments confirmed M. bovis BCG QcrB as the target where over-expression in M. bovis BCG led to an increase in MIC from 0.5 to >8 µM for IP 3. An acute murine model of TB infection established bacteriostatic activity of the IP series, which await further detailed characterization

Tetrahydropyrazolo[1,5-a]Pyrimidine-3-Carboxamide and N-Benzyl-6′,7′-Dihydrospiro[Piperidine-4,4′-Thieno[3,2-c]Pyran] analogues with bactericidal efficacy against Mycobacterium tuberculosis targeting MmpL3

Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. As part of our efforts towards the discovery of new anti-tubercular leads, a number of potent tetrahydropyrazolo[1,5-a]pyrimidine-3-ca​rboxamide(THPP) and N-benzyl-6′,7′-dihydrospiro[piperidine-4,​4′-thieno[3,2-c]pyran](Spiro) analogues were recently identified against Mycobacterium tuberculosis and Mycobacterium bovis BCG through a high-throughput whole-cell screening campaign. Herein, we describe the attractive in vitro and in vivo anti-tubercular profiles of both lead series. The generation of M. tuberculosis spontaneous mutants and subsequent whole genome sequencing of several resistant mutants identified single mutations in the essential mmpL3 gene. This ‘genetic phenotype’ was further confirmed by a ‘chemical phenotype’, whereby M. bovis BCG treated with both the THPP and Spiro series resulted in the accumulation of trehalose monomycolate. In vivo efficacy evaluation of two optimized THPP and Spiro leads showed how the compounds were able to reduce >2 logs bacterial cfu counts in the lungs of infected mice

Easy-To-Synthesize Spirocyclic Compounds Possess Remarkable in Vivo Activity against Mycobacterium tuberculosis

Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits, and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogues. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome

The Courel Mountains UNESCO Global Geopark: An Amazing Geological History Extended Along 600 Million Years

[EN] The Courel Mountains UNESCO Global Geopark (2019) stands out in SW of Europe because of its geoheritage, its biodiversity and its cultural heritage, all of it considered of international interest. These aspects shape the local development economic and cultural improvement and development. The geoheritage is the result of three geological cycles since the Proterozoic, involving the Cadomian-Avalonian-Pan-African orogeny, the opening of the Rheic Ocean and the Variscan orogeny, and finally the Permian-Mesozoic continental expansion and the Alpine orogeny. The geological history of Courel Mountains is one of singular rocks, huge recumbent folds, valuable metallic mineralization, and invertebrate fossils preserved within metamorphic rocks. This long history is recorded in an exceptional Variscan basement that we can ravel thanks to the exhumation during the Alpine uplifting, when the present-day Courel Mountains were built.Peer reviewe

Design of a GIS-database for the management of the Courel Mountains UNESCO Global Geopark (Spain)

X Congreso Geológico de España, 5-7 Julio 2021, Vitoria - GasteizSe ha desarrollado una base de datos en un sistema de información geográfica (SIG) para la gestión del Geoparque Mundial de la UNESCO Montañas do Courel (NO de España). El SIG incluye 66 capas de información topográfica, geológica, minera, biológica, arqueológica y etnográfica, que pueden ser combinadas entre sí para elaborar mapas temáticos adaptados a la finalidad y al usuario. Los mapas generados son empleados en actividades de divulgación, en el diseño de cartografías técnicas de apoyo a los gestores del Geoparque, en el desarrollo de estudios científicos y en acciones de geoconservació

Biochemical and structural characterization of mycobacterial aspartyl-tRNA synthetase AspS, a promising TB drug target.

The human pathogen Mycobacterium tuberculosis is the causative agent of pulmonary tuberculosis (TB), a disease with high worldwide mortality rates. Current treatment programs are under significant threat from multi-drug and extensively-drug resistant strains of M. tuberculosis, and it is essential to identify new inhibitors and their targets. We generated spontaneous resistant mutants in Mycobacterium bovis BCG in the presence of 10× the minimum inhibitory concentration (MIC) of compound 1, a previously identified potent inhibitor of mycobacterial growth in culture. Whole genome sequencing of two resistant mutants revealed in one case a single nucleotide polymorphism in the gene aspS at 535GAC>535AAC (D179N), while in the second mutant a single nucleotide polymorphism was identified upstream of the aspS promoter region. We probed whole cell target engagement by overexpressing either M. bovis BCG aspS or Mycobacterium smegmatis aspS, which resulted in a ten-fold and greater than ten-fold increase, respectively, of the MIC against compound 1. To analyse the impact of inhibitor 1 on M. tuberculosis AspS (Mt-AspS) activity we over-expressed, purified and characterised the kinetics of this enzyme using a robust tRNA-independent assay adapted to a high-throughput screening format. Finally, to aid hit-to-lead optimization, the crystal structure of apo M. smegmatis AspS was determined to a resolution of 2.4 Å

Criterios en la selección de betabloqueadores

Sin resume

Criterios en la selección de betabloqueadores

Sin resume

Direct organocatalytic and highly enantio- and diastereoselective Mannich reactions of alpha-substituted alpha-cyanoacetates

Metal-free catalysis: Highly functionalized molecules with two contiguous stereocenters are easily accessed in high yield with high enantio- and diastereoselectivity by using a commercially available organocatalyst ((DHQD)2PYR, see scheme). The easily removed Boc protecting group in the product is an added value to this method as an important tool in asymmetric synthesis