Mechanism-Based Regiocontrol in SNAr: A Case Study of Ortho-Selective Etherification with Chloromagnesium Alkoxides.

Although nucleophilic aromatic substitution (SNAr) is routinely employed as a practical alternative to transition-metal-catalyzed cross-coupling, the mechanistic basis for reactivity and regioselectivity remains underexplored and is an active area of research. This article reports a SNAr-based etherification of 2,4-difluoroarylcarboxamides as a model system and shows that the ortho/para regioselectivity spans >500:1 to 1:∼20 simply by varying the reaction conditions via high-throughput experimentation (HTE). An in-depth characterization of the ortho-selective lead conditions is presented, and these insights are used to build a reactivity model that self-consistently accounts for the regioselectivity and reaction scope. This article discusses synthetic implications of condition-dependent magnesium coordination and Schlenk equilibria and demonstrates that consideration of molecular-level stoichiometry and isomerism is an essential prerequisite for rationalizing reactivity and regioselectivity in SNAr.

Computationally Guided Ligand Discovery from Compound Libraries and Discovery of a New Class of Ligands for Ni-Catalyzed Cross-Electrophile Coupling of Challenging Quinoline Halides.

Although screening technology has heavily impacted the fields of metal catalysis and drug discovery, its application to the discovery of new catalyst classes has been limited. The diversity of on- and off-cycle pathways, combined with incomplete mechanistic understanding, means that screens of potential new ligands have thus far been guided by intuitive analysis of the metal binding potential. This has resulted in the discovery of new classes of ligands, but the low hit rates have limited the use of this strategy because large screens require considerable cost and effort. Here, we demonstrate a method to identify promising screening directions via simple and scalable computational and linear regression tools that leads to a substantial improvement in hit rate, enabling the use of smaller screens to find new ligands. The application of this approach to a particular example of Ni-catalyzed cross-electrophile coupling of aryl halides with alkyl halides revealed a previously overlooked trend: reactions with more electron-poor amidine ligands result in a higher yield. Focused screens utilizing this trend were more successful than serendipity-based screening and led to the discovery of two new types of ligands, pyridyl oxadiazoles and pyridyl oximes. These ligands are especially effective for couplings of bromo- and chloroquinolines and isoquinolines, where they are now the state of the art. The simplicity of these models with parameters derived from metal-free ligand structures should make this approach scalable and widely accessible.

Computational Methods Enable the Prediction of Improved Catalysts for Nickel-Catalyzed Cross-Electrophile Coupling.

Cross-electrophile coupling has emerged as an attractive and efficient method for the synthesis of C(sp2)-C(sp3) bonds. These reactions are most often catalyzed by nickel complexes of nitrogenous ligands, especially 2,2'-bipyridines. Precise prediction, selection, and design of optimal ligands remains challenging, despite significant increases in reaction scope and mechanistic understanding. Molecular parameterization and statistical modeling provide a path to the development of improved bipyridine ligands that will enhance the selectivity of existing reactions and broaden the scope of electrophiles that can be coupled. Herein, we describe the generation of a computational ligand library, correlation of observed reaction outcomes with features of the ligands, and the in silico design of improved bipyridine ligands for Ni-catalyzed cross-electrophile coupling. The new nitrogen-substituted ligands display a 5-fold increase in selectivity for product formation versus homodimerization when compared to the current state of the art. This increase in selectivity and yield was general for several cross-electrophile couplings, including the challenging coupling of an aryl chloride with an N-alkylpyridinium salt.

Immunogenicity and cross-reactivity against Mycobacterium tuberculosis of proteoliposomes derived from Mycobacterium bovis BCG.

The only currently available vaccine against tuberculosis (TB) is Mycobacterium bovis Bacille Calmette-Guerin (BCG), which has inconsistent efficacy to protect against the disease in adults. M. tuberculosis (MTB) cell wall components have been implicated in the pathogenicity of TB and therefore have been a prime target for the identification and characterization of cell wall proteins with potential application in vaccine development. In this regard, proteoliposomes (PLs) derived from mycobacteria containing lipids and cell wall proteins could be potential vaccine candidates against TB. In the present study PLs derived from BCG were prepared. These homogeneous population of spherical microparticles was then immunized into Balb/c mice. Sera of immunized animals showed high IgG response and strong cross-reactivity against different MTB antigens.These results showed that BCG PLs could be potential vaccine candidates against TB.

Estado periodontal de niños de 5 a 12 años del internado «Marta Abreu¼, Santa Clara / Periodontal status of children aged 5 to 12 years from" Marta Abreu" boarding school in Santa Clara

RESUMEN Los estudios poblacionales muestran que la gingivitis es frecuente en la niñez; esta afección es más prevalente en la adolescencia y tiende a estabilizarse en edades más avanzadas. Se realizó un estudio descriptivo de corte epidemiológico transversal, en una población de 313 escolares, comprendidos en las edades de 5 a 12 años, pertenecientes al internado «Marta Abreu de Estévez¼, de la ciudad de Santa Clara, de septiembre de 2017 a junio de 2018, para caracterizar su estado periodontal. Prevaleció la gingivitis leve y se estableció la relación ascendente entre higiene bucal y gravedad de la enfermedad periodontal.

ABSTRACT Population studies show that gingivitis is common in childhood; this condition is more prevalent in adolescence and tends to stabilize at older ages. A descriptive, cross-sectional and epidemiological study was carried out in a population of 313 school children aged 5 to 12 years, belonging to "Marta Abreu de Estévez" boarding school, in Santa Clara city, from September 2017 to June of 2018, in order to characterize their periodontal status. Mild gingivitis prevailed and an ascending relationship between oral hygiene and severity of periodontal disease was established.

Relación orto-periodontal / Interrelationship between Orthodontics and Periodontics

RESUMEN El periodonto es el conjunto de tejidos que protegen y soportan los dientes, los cuales están relacionados en su desarrollo, topografía y funciones. Entre ellos se encuentra el ligamento periodontal: estructura de tejido conectivo que rodea la raíz del diente uniéndola al hueso alveolar. El ortodoncista mueve los dientes a expensas de esta estructura, por lo tanto, el éxito de un tratamiento ortodóncico depende en parte de la integridad y la salud de los tejidos periodontales. En esta investigación se presentó una paciente adulta que recibió un tratamiento fruto de la cooperación interdisciplinaria entre especialistas de Periodoncia y Ortodoncia. La paciente tenía diagnósticos establecidos y presentaba factores etiológicos involucrados en afecciones comunes de ambas especialidades. Se estableció una planificación del tratamiento adecuado, según el caso, para garantizar la salud bucal y estética de la paciente.

ABSTRACT The periodontium is the group of tissues that protect and support the teeth, which are related in their development, topography and functions. The periodontal ligament is one of them: that is a structure of connective tissue surrounding the root of the tooth and joining it to the alveolar bone. The orthodontist moves the teeth at the expense of this structure, so the success of orthodontic treatment depends in part on the integrity and health of the periodontal tissues. In this research, we present an adult patient who received treatment as a result of the interdisciplinary cooperation between specialists in Periodontics and Orthodontics. The patient had established diagnoses and presented etiological factors involved in common conditions of both specialties. An adequate treatment planning was established, according to the case, to guarantee her aesthetics and oral health.

Proteoliposomes from Mycobacterium smegmatis induce immune cross-reactivity against Mycobacterium tuberculosis antigens in mice.

Proteoliposomes (PL) obtained from Mycobacterium smegmatis (Ms) were evaluated for their capacity to elicit cross-reactive responses against Mycobacterium tuberculosis (Mtb) antigens in BALB/c mice. Animals immunized with PL adjuvanted with alum (PL-AL) or Freund's Incomplete Adjuvant (PL-IFA) showed significant IgG responses against the PL as well as total Ms lipids. Both groups of animals also showed significant IgG responses against BCG, but only animals immunized with PL-AL produced significant IgG responses against soluble cell wall proteins (SCWP) or whole cell lysate (WCL) of Mtb. Significant DTH responses against WCL were observed in both groups of animals after 24 h, but only PL-AL-immunized mice showed significant DTH responses after 48 h and 72 h. PL-Ms are capable of eliciting cross-reactive humoral and cellular responses against Mtb antigens and thus may be a potential vaccine strategy against tuberculosis.