A Study of Negishi Cross-Coupling Reactions with Benzylzinc Halides To Prepare Original 3-Ethoxypyrazoles

International audienceThe Negishi palladium-catalyzed cross-coupling reaction between 3-ethoxy-4-iodo-1H-pyrazole and various benzylzinc halides was extensively studied. Using simplified, robust, and optimized reaction conditions, a series of electron-poor benzylzinc halides were prepared and used to synthesize 4-benzyl-3-ethoxy-1H-pyrazoles derivatives. From these, iodination on C5 of the pyrazole nucleus led to the corresponding 4-benzyl-3-ethoxy-5-iodo-1H-pyrazoles, these are original building blocks for the preparation of libraries of new chemical entitie

On the reliability of NMR relaxation data analyses: A Markov Chain Monte Carlo approach

none4The analysis of NMR relaxation data is revisited along the lines of a Bayesian approach. Using a Markov Chain Monte Carlo strategy of data fitting, we investigate conditions under which relaxation data can be effectively interpreted in terms of internal dynamics. The limitations to the extraction of kinetic parameters that characterize internal dynamics are analyzed, and we show that extracting characteristic time scales shorter than a few tens of ps is very unlikely. However, using MCMC methods, reliable estimates of the marginal probability distributions and estimators (average, standard deviations, etc.) can still be obtained for subsets of the model parameters. Thus, unlike more conventional strategies of data analysis, the method avoids a model selection process. In addition, it indicates what information may be extracted from the data, but also what cannot.noneDaniel Abergel;Andrea Volpato;Eloi P. Coutant;Antonino PolimenoDaniel, Abergel; Andrea, Volpato; Eloi P., Coutant; Polimeno, Antonin

Synthesis of α-Amino Esters via α-Nitro or α-Oxime Esters: A Review

International audienceThis review is an in-depth survey of the reported synthetic approaches for the preparation of racemic α-amino esters via the reduction of α-nitro or α-oxime ester intermediates. Accordingly, it describes the many pathways that have been designed to prepare such intermediates­. This includes synthesis starting with α-nitroacetates, dialkyl malonates, acetoacetates, diethyl oxalates as well as [2+3] or [2+4] cycloadditions using, respectively, alkyl carbonocyanidate N-oxides or alkyl 2-nitrosoacrylates. This review also contains the description of a myriad of side reactions which can occur when working with α-nitro esters­.1 Introduction2 α-Amino Esters from α-Nitroacetates via Condensation Reactions3 α-Amino Esters via C-Alkylation or C-Arylation of α-Nitroacetates4 α-Amino Esters from α-Nitroacetates Using Other Reactions5 Synthesis of α-Amino Esters via α-Oxime Esters6 Synthesis of α-Amino Esters via [2+3] Cycloadditions7 Synthesis of α-Amino Esters via [2+4] Cycloadditions8 On the Reduction of α-Oxime Esters9 Conclusio

Synthesis of unnatural α-amino esters using ethyl nitroacetate and condensation or cycloaddition reactions

We report here on the use of ethyl nitroacetate as a glycine template to produce α-amino esters. This started with a study of its condensation with various arylacetals to give ethyl 3-aryl-2-nitroacrylates followed by a reduction (NaBH4 and then zinc/HCl) into α-amino esters. The scope of this method was explored as well as an alternative with arylacylals instead. We also focused on various [2 + 3] cycloadditions, one leading to a spiroacetal, which led to the undesired ethyl 5-(benzamidomethyl)isoxazole-3-carboxylate. The addition of ethyl nitroacetate on a 5-methylene-4,5-dihydrooxazole using cerium(IV) ammonium nitrate was also explored and the synthesis of other oxazole-bearing α-amino esters was achieved using gold(I) chemistry

Original 2-(3-Alkoxy-1H-pyrazol-1-yl)azines Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH).

International audienceFollowing our discovery of human dihydroorotate dehydrogenase (DHODH) inhibition by 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidine derivatives as well as 2-(4-benzyl-3-ethoxy-5-methyl-1H-pyrazol-1-yl)-5-methylpyridine, we describe here the syntheses and evaluation of an array of azine-bearing analogues. As in our previous report, the structure−activity study of this series of human DHODH inhibitors was based on a phenotypic assay measuring measles virus replication. Among other inhibitors, this round of syntheses and biological evaluation iteration led to the highly active 5-cyclopropyl-2-(4-(2,6-difluorophenoxy)-3-isopropoxy-5-methyl-1H-pyrazol-1-yl)-3-fluoropyridine. Inhibition of DHODH by this compound was confirmed in an array of in vitro assays, including enzymatic tests and cell-based assays for viral replication and cellular growth. This molecule was found to be more active than the known inhibitors of DHODH, brequinar and teriflunomide, thus opening perspectives for its use as a tool or for the design of an original series of immunosuppressive agent. Moreover, because other series of inhibitors of human DHODH have been found to also affect Plasmodium falciparum DHODH, all the compounds were assayed for their effect on P. falciparum growth. However, the modest in vitro inhibition solely observed for two compounds did not correlate with their inhibition of P. falciparum DHODH

Synthesis and evaluation of original bioisosteres of bacterial type IIA topoisomerases inhibitors

International audienceA recently discovered series of inhibitors of the ATPase function of bacterial type IIA topoisomerases featuring a carboxypyrrole component led us to attempt to replace this group with a potentially bioisosteric carboxypyrazole. Accordingly, synthetic pathways to 2-(4-(1H-pyrazole-5-carboxamido)piperidin-1-yl)thiazole-5-carboxylic acids or 2-(4-(N-methyl-1H-pyrazole- 5-carboxamido)piperidin-1-yl)thiazole-5-carboxylic acids featuring an array of substituents on the pyrazole ring were explored. Unfortunately, none of the analogues made were effective on the ATPase function of Mycobacterium tuberculosis gyrase as well on the DNA supercoiling activity of the whole gyrase of M. tuberculosis and Escherichia coli. However, this work is still providing original insights in chemistry as well as in the structure–activity relationships of this series of inhibitorsUne série récente d’inhibiteurs de la fonction ATP-asique des topoisomérases bactériennes de type IIA comportant un noyau carboxypyrrole nous a conduits à tenter de remplacer celui-ci par un noyau carboxypyrazole bioisostère. Ainsi, des accès aux dérivés d’acide 2-(4-(1H-pyrazole-5-carboxamido)piperidin-1-yl)thiazole-5-carboxylique, comportant une gamme de substituants, ont été explorés. Malheureusement, aucun des analogues préparés n’a eu d’effet, que ce soit sur la fonction ATP-asique de la gyrase de Mycobacterium tuberculosis ou sur l’activité de surenroulement des gyrases de M. tuberculosis ou d’Escherichia coli. Toutefois, ce travail représente une contribution originale en ce qui concerne la chimie ou les relations structure–activité de cette série d’inhibiteurs

Maximizing binary interactome mapping with a minimal number of assays.

Complementary assays are required to comprehensively map complex biological entities such as genomes, proteomes and interactome networks. However, how various assays can be optimally combined to approach completeness while maintaining high precision often remains unclear. Here, we propose a framework for binary protein-protein interaction (PPI) mapping based on optimally combining assays and/or assay versions to maximize detection of true positive interactions, while avoiding detection of random protein pairs. We have engineered a novel NanoLuc two-hybrid (N2H) system that integrates 12 different versions, differing by protein expression systems and tagging configurations. The resulting union of N2H versions recovers as many PPIs as 10 distinct assays combined. Thus, to further improve PPI mapping, developing alternative versions of existing assays might be as productive as designing completely new assays. Our findings should be applicable to systematic mapping of other biological landscapes