Lead optimisation of dehydroemetine for repositioned use in malaria

Drug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel anti-malarial treatments. The anti-amoebic compound, emetine dihydrochloride, has been identified as a potent in-vitro inhibitor of the multi-drug resistant strain K1 of Plasmodium falciparum (IC50: 47 nM ± 2.1 nM). Dehydroemetine, a synthetic analogue of emetine dihydrochloride has been reported to have less cardiotoxic effects than emetine. The structures of two diastereomers of dehydroemetine were modelled on the published emetine binding site on cryo-EM structure 3J7A (Pf 80S ribosome in complex with emetine) and it was found that (-)-R,S-dehydroemetine mimicked the bound pose of emetine more closely than (-)-S,S-dehydroisoemetine. (-)-R,S-dehydroemetine (IC50 71.03 ± 6.1 nM) was also found to be highly potent against the multi-drug resistant K1 strain of P. falciparum in comparison with (-)-S,S-dehydroisoemetine (IC50 2.07 ± 0.26 μM), which loses its potency due to the change of configuration at C-1′. In addition to its effect on the asexual erythrocytic stages of P. falciparum, the compounds exhibited gametocidal properties with no cross-resistance against any of the multi-drug resistant strains tested. Drug interaction studies showed (-)-R,S-dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride, and (-)-R,S-dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed activity on the mitochondrial membrane potential indicating a possible multi-modal mechanism of action. [Abstract copyright: Copyright © 2020 Panwar et al.

СЛУЧАЙ УСПЕШНОГО ХИРУРГИЧЕСКОГО ЛЕЧЕНИЯ ТРОМБОЭМБОЛИИ ЛЕГОЧНОЙ АРТЕРИИ У БОЛЬНОЙ НА СРОКЕ БЕРЕМЕННОСТИ 11 НЕДЕЛЬ

Pulmonary embolism in pregnant women is fairly common complication, and it remains to be the one of major causes of maternal mortality in the number of countries. The need to compare risks of the mother and child makes the search for optimal treatment tactics very complicated in this specific case. The experience of the last decades provides evidences for choosing aggressive treatment tactics, accurate diagnostics and early surgical intervention. The authors of this article describe the clinical case of successful treatment of the young woman whose pregnancy course was complicated by pulmonary embolism at the 11th week of gestation. The article describes the results of laboratory and instrumental diagnostics and anasthesiological support technique within available scope of pharmacological and technical means. Also the article reviews the literature data on this problem. The conclusion contains recommendations for intra-operative management of such patients. Тромбоэмболия легочной артерии (ТЭЛА) у беременных женщин является весьма частым осложнением, она остается одной из ведущих причин материнской смертности в ряде стран. Необходимость соотнесения рисков для организма матери и ребенка делает поиск оптимальной тактики лечения в данном случае очень сложной задачей. Опыт последних десятилетий свидетельствует в пользу избрания агрессивной тактики лечения, точной диагностики и раннего оперативного вмешательства. В данной статье авторы представляют случай успешного лечения молодой женщины, течение беременности которой осложнилось ТЭЛА на сроке гестации 11 недель. Описываются результаты проведенной лабораторной и инструментальной диагностики, а также методика анестезиологического пособия в рамках доступного объема фармакологических и технических средств. Приводится анализ данных литературы по этой актуальной проблеме. В заключении даны рекомендации по интраоперационному ведению подобных больных.

Mechanism and Enantioselectivity in Palladium-Catalyzed Conjugate Addition of Arylboronic Acids to β‑Substituted Cyclic Enones: Insights from Computation and Experiment

Enantioselective conjugate additions of arylboronic acids to β-substituted cyclic enones have been previously reported from our laboratories. Air- and moisture-tolerant conditions were achieved with a catalyst derived in situ from palladium(II) trifluoroacetate and the chiral ligand (S)-t-BuPyOx. We now report a combined experimental and computational investigation on the mechanism, the nature of the active catalyst, the origins of the enantioselectivity, and the stereoelectronic effects of the ligand and the substrates of this transformation. Enantioselectivity is controlled primarily by steric repulsions between the t-Bu group of the chiral ligand and the α-methylene hydrogens of the enone substrate in the enantiodetermining carbopalladation step. Computations indicate that the reaction occurs via formation of a cationic arylpalladium(II) species, and subsequent carbopalladation of the enone olefin forms the key carbon–carbon bond. Studies of nonlinear effects and stoichiometric and catalytic reactions of isolated (PyOx)Pd(Ph)I complexes show that a monomeric arylpalladium–ligand complex is the active species in the selectivity-determining step. The addition of water and ammonium hexafluorophosphate synergistically increases the rate of the reaction, corroborating the hypothesis that a cationic palladium species is involved in the reaction pathway. These additives also allow the reaction to be performed at 40 °C and facilitate an expanded substrate scope

History of Political Police in Russia: V.F. Dzunkovsky and Fight against Police Provocation Practice in 1913-1915

The article is devoted to an attempt to limit secret police permissiveness before World War I. Deputy Interior Minister V.F. Dzhunkovsky carried out a number of reforms aimed at limiting provocation in the army, among students of secondary educational institutions, the State Duma deputies. He took measures to put the secret police activities under strict control of legal investigation bodies. The article analyzes these reforms' causes, course, results and estimation

o-Nitroaryl-bis(5-methylfur-2-yl)methanes as Versatile Synthons for the Synthesis of Nitrogen-Containing Heterocycles

2-Nitroaryldifurylmethanes 1a and 1b, readily available by condensation of 2-nitrobenzaldehyde and 6-nitroveratraldehyde with 2-methylfuran, were transformed into indole, cinnoline and benzothiazine-3,1 derivatives. The reduction of 2-nitroaryldifurylmethanes gave the corresponding anilines 2a,b or indole 3 depending on the reaction conditions. A plausible mechanism for the last reaction involving intramolecular heterocyclic addition between a nitroso-group and a furan ring is proposed. Diazotisation of the amine 2b gave a cinnoline derivative - a product of intramolecular oxidative furan ring opening. Treatment of isothiocyanates 7a,b with perchloric acid resulted in a new rearrangement with furan ring migration leading to the 4-Hbenzothiazine-3,1 derivatives

New pyridine N-oxides as chiral organocatalysts in the asymmetric allylation of aromatic aldehydes

Asymmetric allylation of aromatic aldehydes 1 with allyltrichlorosilane (2) can be catalyzed by new terpene-derived bipyridine N,N'-dioxides 12-15 and an axially chiral biisoquinoline dioxide 17b with good enantioselectivities. Dioxides have been found to be more reactive catalysts than their monooxide counterparts. Crown Copyright . All rights reserved

CLINICAL CASE OF SUCCESSFUL SURGICAL TREATMENT OF PULMONARY EMBOLISM IN THE PATIENT WITH 11 WEEK PREGNANCY

Pulmonary embolism in pregnant women is fairly common complication, and it remains to be the one of major causes of maternal mortality in the number of countries. The need to compare risks of the mother and child makes the search for optimal treatment tactics very complicated in this specific case. The experience of the last decades provides evidences for choosing aggressive treatment tactics, accurate diagnostics and early surgical intervention. The authors of this article describe the clinical case of successful treatment of the young woman whose pregnancy course was complicated by pulmonary embolism at the 11th week of gestation. The article describes the results of laboratory and instrumental diagnostics and anasthesiological support technique within available scope of pharmacological and technical means. Also the article reviews the literature data on this problem. The conclusion contains recommendations for intra-operative management of such patients