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Your search keyword '"Joaquín Rullas"' showing total 2 results
Start Over Author "Joaquín Rullas" Journal journal of medicinal chemistry
2 results on '"Joaquín Rullas"'

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

Author

Lourdes Encinas, Montserrat Ortega-Guerra, Ana Guardia, Joaquín Rullas, Esther Porras de Francisco, Juan Miguel-Siles, Cristina Rivero, Jorge Esquivias, Matthew H. Todd, Carlos Alemparte, Setshaba D. Khanye, Jessica Baiget, Raquel Vida Fernández, Winston Nxumalo, María Teresa Fraile-Gabaldón, Peter J. Rutledge, Esther Pérez-Herrán, Javier G. Osende, Modesto J. Remuiñán, Katrina A. Badiola, Marta León Alonso, Arancha Pérez, Ilaria Giordano, Elena Jimenez, Monica Cacho, and Fátima Ortega

Subjects
0301 basic medicine, ERG1 Potassium Channel, Maximum Tolerated Dose, 030106 microbiology, Antitubercular Agents, Drug Evaluation, Preclinical, Administration, Oral, Biological Availability, Computational biology, Mycobacterium tuberculosis, 03 medical and health sciences, Structure-Activity Relationship, In vivo, Drug Discovery, Animals, Humans, Tuberculosis, Spiro Compounds, biology, Low toxicity, Dose-Response Relationship, Drug, Chemistry, Heart, biology.organism_classification, Mice, Inbred C57BL, 030104 developmental biology, Open source, Molecular Medicine, Administration, Intravenous, Female, Rabbits
Abstract

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.

Published
2018

2. Discovery of a Potent and Specific M. tuberculosis Leucyl-tRNA Synthetase Inhibitor: (S)-3-(Aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol (GSK656)

Author

Joaquín Rullas, Manisha Mohan, Wai Choi, David Barros, M. R. K. Alley, Vincent Hernandez, Wuxin Zou, Sabrinia D. Crouch, Weimin Mao, Jacob J. Plattner, Ilaria Giordano, Yasheen Zhou, Iñigo Angulo-Barturen, Fátima Ortega, Carlos Alemparte, Alfonso Mendoza-Losana, Eric E. Easom, Esther Pérez-Herrán, Xianfeng Li, Fernando Rock, and Yvonne Mak

Subjects
0301 basic medicine, Boron Compounds, 030106 microbiology, Antitubercular Agents, Heterocyclic Compounds, 2-Ring, Substrate Specificity, Mycobacterium tuberculosis, 03 medical and health sciences, Mice, Structure-Activity Relationship, Drug Discovery, Structure–activity relationship, Animals, Humans, Enzyme Inhibitors, Mode of action, IC50, chemistry.chemical_classification, biology, Chemistry, Drug discovery, Leucyl-tRNA synthetase, respiratory system, bacterial infections and mycoses, biology.organism_classification, In vitro, Mice, Inbred C57BL, 030104 developmental biology, Enzyme, Biochemistry, Molecular Medicine, Female, Leucine-tRNA Ligase
Abstract

There is an urgent need to develop new and safer antitubercular agents that possess a novel mode of action. We synthesized and evaluated a novel series of 3-aminomethyl 4-halogen benzoxaboroles as Mycobacterium tuberculosis (Mtb) leucyl-tRNA synthetase (LeuRS) inhibitors. A number of Mtb LeuRS inhibitors were identified that demonstrated good antitubercular activity with high selectivity over human mitochondrial and cytoplasmic LeuRS. Further evaluation of these Mtb LeuRS inhibitors by in vivo pharmacokinetics (PK) and murine tuberculosis (TB) efficacy models led to the discovery of GSK3036656 (abbreviated as GSK656). This molecule shows potent inhibition of Mtb LeuRS (IC50 = 0.20 μM) and in vitro antitubercular activity (Mtb H37Rv MIC = 0.08 μM). Additionally, it is highly selective for the Mtb LeuRS enzyme with IC50 of >300 μM and 132 μM for human mitochondrial LeuRS and human cytoplasmic LeuRS, respectively. In addition, it exhibits remarkable PK profiles and efficacy against Mtb in mouse TB infection ...

Published
2017

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