RESUMEN
Metal-free, visible light-initiated, living cationic polymerization of 4-methoxystyrene using 2,4,6-tri(p-tolyl)pyrylium tetrafluoroborate and methanol is demonstrated. Molecular weight and dispersity are controlled by the concentration of methanol. Initial mechanistic analysis suggests that methanol likely serves to regulate propagation of the cation chain end via reversible chain transfer in a manner analogous to reversible addition-fragmentation chain transfer polymerization.
RESUMEN
The Newman-Kwart rearrangement is perhaps the quintessential method for the synthesis of thiophenols from the corresponding phenol. However, the high thermal conditions required for the rearrangement of the requisite O-aryl carbamothioates often leads to decomposition. Herein, we present a general strategy for catalysis of O-aryl carbamothioates to S-aryl carbamothioates using catalytic quantities of a commercially available organic single-electron photooxidant. Importantly, this reaction is facilitated at ambient temperatures.
RESUMEN
A direct catalytic anti-Markovnikov addition of carboxylic acids to alkenes is reported. The catalyst system is comprised of the Fukuzumi acridinium photooxidant (1) and a substoichiometric quantity of a hydrogen-atom donor. Oxidizable olefins, such as styrenes, trisubstituted aliphatic alkenes, and enamides, can be employed along with a variety of carboxylic acids to afford the anti-Markovnikov addition adducts exclusively. A deuterium-labeling experiment lends insight to the potential mechanism.
Asunto(s)
Acetatos/síntesis química , Alquenos/química , Ácidos Carboxílicos/química , Acetatos/química , Catálisis , Estructura MolecularRESUMEN
4'-Phosphopantetheinyl transferase (PptT) is an essential enzyme for Mycobacterium tuberculosis (Mtb) survival and virulence and therefore an attractive target for a tuberculosis therapeutic. In this work, two modeling-informed approaches toward the isosteric replacement of the amidinourea moiety present in the previously reported PptT inhibitor AU 8918 are reported. Although a designed 3,5-diamino imidazole unexpectedly adopted an undesired tautomeric form and was inactive, replacement of the amidinourea moiety afforded a series of active PptT inhibitors containing 2,6-diaminopyridine scaffolds.
RESUMEN
A newly validated target for tuberculosis treatment is phosphopantetheinyl transferase, an essential enzyme that plays a critical role in the biosynthesis of cellular lipids and virulence factors in Mycobacterium tuberculosis. The structure-activity relationships of a recently disclosed inhibitor, amidinourea (AU) 8918 (1), were explored, focusing on the biochemical potency, determination of whole-cell on-target activity for active compounds, and profiling of selective active congeners. These studies show that the AU moiety in AU 8918 is largely optimized and that potency enhancements are obtained in analogues containing a para-substituted aromatic ring. Preliminary data reveal that while some analogues, including 1, have demonstrated cardiotoxicity (e.g., changes in cardiomyocyte beat rate, amplitude, and peak width) and inhibit Cav1.2 and Nav1.5 ion channels (although not hERG channels), inhibition of the ion channels is largely diminished for some of the para-substituted analogues, such as 5k (p-benzamide) and 5n (p-phenylsulfonamide).
Asunto(s)
Proteínas Bacterianas/metabolismo , Guanidina/análogos & derivados , Mycobacterium tuberculosis/enzimología , Transferasas (Grupos de Otros Fosfatos Sustitutos)/metabolismo , Urea/análogos & derivados , Proteínas Bacterianas/antagonistas & inhibidores , Sitios de Unión , Cristalografía por Rayos X , Guanidina/química , Guanidina/metabolismo , Guanidina/farmacología , Cinética , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Simulación de Dinámica Molecular , Mycobacterium tuberculosis/efectos de los fármacos , Relación Estructura-Actividad , Transferasas (Grupos de Otros Fosfatos Sustitutos)/antagonistas & inhibidores , Urea/química , Urea/metabolismo , Urea/farmacologíaRESUMEN
A systematic study of the stability of a set of cephalosporins in mouse plasma reveals that cephalosporins lacking an acidic moiety at C-2 may be vulnerable to ß-lactam cleavage in mouse plasma.
Asunto(s)
Antibacterianos/sangre , Antibacterianos/química , Cefalosporinas/sangre , Cefalosporinas/química , Animales , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The historical view of ß-lactams as ineffective antimycobacterials has given way to growing interest in the activity of this class against Mycobacterium tuberculosis (Mtb) in the presence of a ß-lactamase inhibitor. However, most antimycobacterial ß-lactams kill Mtb only or best when the bacilli are replicating. Here, a screen of 1904 ß-lactams led to the identification of cephalosporins substituted with a pyrithione moiety at C3' that are active against Mtb under both replicating and nonreplicating conditions, neither activity requiring a ß-lactamase inhibitor. Studies showed that activity against nonreplicating Mtb required the in situ release of the pyrithione, independent of the known class A ß-lactamase, BlaC. In contrast, replicating Mtb could be killed both by released pyrithione and by the parent ß-lactam. Thus, the antimycobacterial activity of pyrithione-containing cephalosporins arises from two mechanisms that kill mycobacteria in different metabolic states.