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We report the high-yielding, large-scale, one-pot synthesis of two versatile building blocks ( 1-Cl and 1 - Br ) for the regioselective synthesis of a variety of 2,3,5-trisubstituted pyridines from inexpensive materials. These molecules are readily derivatized at positions 2, 3, and 5. These building blocks can also be used for the synthesis of fused pyrido-oxazines and for the synthesis of 2,3,4,5-tetrasubstituted pyridines.

Structural optimization of a previously reported agonist of µOR, PZM21 is described resulting in the discovery of a novel series of amides with at least 4-folds enhanced CNS penetration in rat. Furthermore, these efforts yielded compounds with varying levels of efficacy on the receptor ranging from high efficacy agonists such as compound 20 to antagonists, such as 24. The correlation between in vitro activation of µOR and relative activity in models of analgesia for these compounds is discussed. The compelling results obtained in these studies demonstrate the potential utility of these newly discovered compounds in the treatment of pain and opioid use disorder., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 R2M Pharma. Published by Elsevier Ltd.. All rights reserved.)

Nucleoside analogues have excellent records as anti-HBV drugs. Chronic infections require long-term administration ultimately leading to drug resistance. Therefore, the search for nucleosides with novel scaffolds is of high importance. Here we report the synthesis of novel 2'-hydroxy- and 2'-hydroxymethyl-apionucleosides, 4 and 5 , corresponding triphosphates and phosphoramidate prodrugs. Triphosphate 38 of 2'-hydroxymethyl-apionucleoside 5 exhibited potent inhibition of HBV polymerase with an IC 50 value of 120 nM. In an HBV cell-based assay, the phosphoramidate prodrug 39 demonstrated potent activity with an EC 50 value of 7.8 nM.

Densely functionalized cyclopentane derivatives with up to four consecutive stereocenters are assembled by a tandem Michael addition/single-electron transfer oxidation/radical cyclization/oxygenation strategy mediated by ferrocenium hexafluorophosphate, a recyclable, less toxic single-electron transfer oxidant. Ester enolates were coupled with α-benzylidene and α-alkylidene β-dicarbonyl compounds with switchable diastereoselectivity. This pivotal steering element subsequently controls the diastereoselectivity of the radical cyclization step. The substitution pattern of the radical cyclization acceptor enables a switch of the cyclization mode from a 5-exo pattern for terminally substituted olefin units to a 6-endo mode for internally substituted acceptors. The oxidative anionic/radical strategy also allows efficient termination by oxygenation with the free radical 2,2,6,6-tetramethyl-1-piperidinoxyl, and two C-C bonds and one C-O bond are thus formed in the sequence. A stereochemical model is proposed that accounts for all of the experimental results and allows the prediction of the stereochemical outcome. Further transformations of the synthesized cyclopentanes are reported., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Oxidative single-electron transfer-catalyzed tandem reactions consisting of a conjugate addition and a radical cyclization are reported, which incorporate the mandatory terminal oxidant as a functionality into the product., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A new method for alcohol oxidation using TEMPO or AZADO in conjunction with BF3·OEt2 or LiBF4 as precatalysts and tert-butyl nitrite as a stoichiometric oxidant has been developed. The system is based on a NO(+)/NO· pair for nitroxide reoxidation under anaerobic conditions. This allows the simple, high-yielding conversion of various achiral and chiral alcohols to carbonyl compounds without epimerization and no formation of nonvolatile byproducts.

A patient with a borderline small left heart requires difficult clinical decision making during prenatal and neonatal periods. This report describes the unusual natural history of a newborn with prenatally diagnosed hypoplastic left heart structures and early spontaneous postnatal closure of the interatrial communication. Initial deterioration from pulmonary edema and low-cardiac output improved with postnatal intensive care. During the seventh week of life, aortic coarctation was diagnosed and the infant underwent uneventful surgical repair. Despite transient clinical deterioration, early spontaneous closure of the interatrial communication in a newborn with borderline small left heart could be associated with gradual hemodynamic adaptation to postnatal biventricular circulation.

Background: In neonates, left-sided obstructive heart defects are critical diseases requiring early recognition, initial stabilization, and transfer to Cardiac Center., Objectives: To assess management of these neonates in primary care hospitals., Methods: Retrospective analysis of medical records of neonates admitted to Cardiac Intensive Care Unit in whom diagnosis of left-sided obstructive heart defect was established., Results: During 8-year period records of 117 patients were evaluated. Of those, 83 had hypoplastic left heart syndrome, 13 aortic stenosis, 12 coarctation of aorta, and 9 interruption of aortic arch. In 13 (11%) patients diagnosis of heart defect was established prenatally, other neonates presented postnatally with heart failure (28.2%), shock (65.4%) or severe cyanosis (4.8%). Continuous infusion of PGE1 and dopamine was administered in 84.6% and 30.8% patients, respectively. Thirty-two (30.8%) patients were mechanically ventilated and 36 (34.6%) received sodium bicarbonate. In referring hospitals the heart defect was most often diagnosed using echocardiography and diagnosis was established accurately in 55% patients., Conclusion: The study showed that in primary care hospitals neonates with known or suspected left-sided obstructive heart disease need more aggressive resuscitative measures than those used in this patient series. Prenatal diagnosis rate of these heart defects is very low (Tab. 3, Fig. 1, Ref 8). Full Text (Free, PDF) www.bmj.sk.