Synthesis, characterization and complex evaluation of antibacterial activity and cytotoxicity of new arylmethylidene ketones and pyrimidines with camphane skeletons

The synthesis of 20 arylidenecamphors and 15 pyrimidines with camphane skeleton is described in the current report. A modified method for preparation of sterically hindered 2- aminopyrimidines in two steps was demonstrated. The evaluation of their in vitro activity against Mycobacterium tuberculosis H37Rv showed different MIC values (up to 0.91 μM for ketone 39). Compound 35 demonstrated moderate (8.23 μM), but sustainable activity toward a collection of drug-resistant M. tuberculosis strains. Many of the compounds (especially among 2-aminopyridines 42–56) exhibited good to excellent activity against different strains of pathogenic bacteria and fungi (MIC up to 0.60 μM for compound 50), compared with reference antibiotics. Many of the newly designed compounds possess also in vitro cytotoxicity.This study was supported by: Bulgarian National Science Fund- project KP-06-H39/7 and Spanish Ministry of Science, Innovation and Universities- Grant RTI2018-094629-BI00. MEDINA’s authors disclosed the receipt of financial support from Fundación MEDINA, a public-private partnership of Merck Sharp and Dohme de EspañaS.A./Universidad de Granada/Junta de Andalucía

Hémisynthèses à partir de produits d'origine naturelle

L'obtention de nouveaux synthons chiraux à partir de produits naturels reste l'un des domaines fondamentaux de la chimie organique contemporaine. Donner de nouvelles applications aux substances naturelles constitue un moyen très important de produire de nouvelles structures chimiques. Les produits naturels sont des composés chimiques, produits par des organismes vivants tels que les bactéries, les champignons, les plantes et les animaux. Une grande diversité de substances ayant d'intéressantes propriétés peut être trouvée partout dans la nature. La capacité du vivant à créer des structures chimiques est immense, elle offre un trésor de matériaux pour toutes les branches de l'activité humaine. Les substances naturelles ont toujours suscité un intérêt scientifique considérable dans des domaines scientifiques variés - de la médecine à la chimie industrielle en passant par les sciences pharmaceutiques. La chimie organique de synthèse explore le potentiel des produits naturels, trouve de nouvelles applications et de nouvelles avancées scientifiques et technologiques. Les disciplines s'intéressent à la qualité de la vie, l'allongement de l'espérance de vie, la lutte contre le vieillissement, le cancer, les maladies infectieuses ou tout autres types de maladies, font appel à la nature pour trouver des composés, des idées et de l'inspiration. Parmi la grande variété de produits naturels, ce travail s'articule autour de trois molécules de la famille des terpènes : - L'aucuboside, à partir duquel de nouveaux synthons chiraux ont été obtenus et testés en tant que ligands pour la catalyse asymétrique. - La fenchone, à partir de laquelle une série de dérivés a été produite et examinée pour son activité antituberculeuse. - Le camphre, à partir duquel des dérivés ayant une activité anticancéreuse potentielle ont été synthétisés. Les iridoïdes naturels sont énantiomériquement purs et parfois abondants chez certains végétaux. Non commerciaux, ils ne font pas partie du pool chiral. L'objectif de ce travail était de trouver des conditions efficaces pour convertir l'aucuboside en une série de nouveaux ligands chiraux destinés à la catalyse asymétrique. Les travaux de recherche ont débuté par l'étude de la séquence réactionnelle découverte par Cachet et ses collaborateurs, qui permet de libérer le glucose de l'aucuboside et de convertir l'aglycone en un mélange d'esters (1R,5S,8R)-4-alcoxy-6-pivaloyoxyméthyl, 8- pivaloyloxy-3-oxabicyclo[3.3.0]dec-6-ène-1-carboxyliques. Les quatre 2,4-diastéréoisoromères possibles étant formés, nous avons d'abord cherché les conditions de réaction permettant la formation d'un seul stéréoisomère. Appliquant ensuite une réduction cationique sur le fragment acétal en C (4) et une double addition du réactifs de Grignard à l'ester carboxylique, six nouveaux alcools tertiaires diastéréoisomériquement purs ont été obtenus et leur potentiel en tant que ligands chiraux lors de l'ajout de diéthylzinc à du benzaldéhyde a été exploré. Bien que nos résultats préliminaires concernant l'induction asymétrique soient médiocres, nos études ont permis de limiter le nombre de voies mécanistes de formation des esters (1R, 5S, 8R) -4-alcoxy-6-pivaloyoxyméthyle, 8-pivaloyloxy-3-oxabicyclo] [3.3.0] dec-6-ène-1-carboxyliques et suggèrent de nouvelles alternatives pour la valorisation de l'aucuboside. La (-) - fenchone commerciale a été utilisée comme produit de départ pour une synthèse facile de 31 nouveaux dérivés diastéréoisomériquement purs, portant une partie cinnamique. Tous les composés nouvellement synthétisés ont été évalués pour leur activité in vitro contre Mycobacterium tuberculosis H37Rv. La série dans son ensemble a démontré une activité antituberculeuse significative.The obtaining of new chiral synthons from natural products remains one of the fundamental fields of the contemporary organic chemistry. Giving natural substances new applications constitutes a very significant way of producing new chemical structures. Natural products are chemical compounds, produced by living organisms such as bacteria, fungi, plants and animals. A great variety of substances with all kinds of fascinating properties can be found everywhere in nature. Life's abilities to create chemical structures are immense and this natural process creates a treasure-trove of materials, applicable in every branch of human activity. Natural products have always attracted interest from different scientific fields - medicine, industrial chemistry, and the pharmaceutical sciences. Synthetic organic chemistry explores the potential of the natural products and finds newer and more advanced scientific and technologic applications for them. Disciplines like quality of life, expanding the lifespan, anti-aging, as well as the struggle against cancer, infectious disease and other kinds of human illness, they all look to nature for materials, ideas and inspiration. Out of the great variety of natural products, this work is focused on three representatives of the terpene family: - Aucubin, from which new chiral synthons to be obtained and tested as ligands for asymmetric catalysis. - Fenchone, from which a series of derivatives to be produced and examined for their antitubercular activity. - Camphor, which to be chemically modified into derivatives with potential anticancer activity. Natural iridoids are enantiomerically pure and sometimes abundant in certain plants. They are not commercially available and are not part of the chiral pool. The objective of this work was to find efficient routes converting aucubin into a library of new enantiomerically pure ligands for their application in asymmetric catalysis. The search started with the application of a sequence of reactions presented first by Cachet and co-workers that permits the liberation of the aglycon of aucubin and its conversion into mixtures of (1R,5S,8R)-4-alkoxy-6-pivaloyoxymethyl, 8- pivaloyloxy-3-oxabicyclo[3.3.0]dec-6-ene-1-carboxylic esters, the 4 possible 2,4-diasteoisoromers being formed. We first have searched for reaction conditions that would provide one of these stereoisomers selectively. Applying then a sequence of cationic reduction to the acetal moiety at C(4) and double additions of Grignard reagents to the carboxylic ester, six new diastereoisomerically pure tertiary alcohols have been obtained and their potential as chiral ligands in the addition of diethylzinc to benzaldehyde has been explored. Although our preliminary results concerning the asymmetric induction are mediocre, our studies have permitted to limit the number of mechanistic ways of the formation of (1R,5S,8R)-4-alkoxy-6-pivaloyoxymethyl, 8-pivaloyloxy-3- oxabicyclo [3.3.0]dec-6-ene-1-carboxylic esters: they suggest new alternatives for the valorization of aucubin. The commercial (-)-fenchone was used as a starting material for the facile synthesis of 31 new diastereoisomerically pure derivatives, bearing a cinnamic moiety. All of the newly synthetized compounds were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv. The series as a whole demonstrated significant antitubercular activity, with 4 compounds matching or exceeding the potency of the referent ethambutol

Base-promoted direct amidation of esters : beyond the current scope and practical applications

The base-promoted direct amidation of unactivated esters is among the most useful reactions for amide bond formation in contemporary organic chemistry. The intensive research in this area has led to the development of a number of new methods to achive this transformation. However, to date, the existing literature is more methodological and in many instances lacks practical directions. Therefore, the full potential of this transformation is yet to be revealed by broadening the substrate scope. In a search for new practical applications of the amidation reaction, herein we present a comprehensive study of a number of base-promoted direct amidations that encompass a wide range of amines and esters. Furthermore, we applied our findings in the synthesis of phosphoramidates and several industrially relevant products.peerReviewe

In Vitro Anticancer Activity of Two Ferrocene-Containing Camphor Sulfonamides as Promising Agents against Lung Cancer Cells

The successful design of antitumour drugs often combines in one molecule different biologically active subunits that can affect various regulatory pathways in the cell and thus achieve higher efficacy. Two ferrocene derivatives, DK-164 and CC-78, with different residues were tested for cytotoxic potential on non-small lung cancer cell lines, A549 and H1299, and non-cancerous MRC5. DK-164 demonstrated remarkable selectivity toward cancer cells and more pronounced cytotoxicity against A549. The cytotoxicity of CC-78 toward H1299 was even higher than that of the well-established anticancer drugs cisplatin and tamoxifen, but it did not reveal any noticeable selective effect. DK-164 showed predominantly pro-apoptotic activity in non-small cell lung carcinoma (NSCLC) cells, while CC-78 caused accidental cell death with features characteristic of necrosis. The level of induced autophagy was similar for both substances in cancer cells. DK-164 treatment of A549, H1299, and MRC5 cells for 48 h significantly increased the fluorescence signal of the NFkB (nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells) protein in the nucleus in all three cell lines, while CC-78 did not provoke NFkB translocation in any of the tested cell lines. Both compounds caused a significant transfer of the p53 protein in the nucleus of A549 cells but not in non-cancerous MRC5 cells. In A549, DK-164 generated oxidative stress close to the positive control after 48 h, while CC-78 had a moderate effect on the cellular redox status. In the non-cancerous cells, MRC5, both compounds produced ROS similar to the positive control for the same incubation period. The different results related to the cytotoxic potential of DK-164 and CC-78 associated with the examined cellular mechanisms induced in lung cancer cells might be used to conclude the specific functions of the various functional groups in the ferrocene compounds, which can offer new perspectives for the design of antitumour drugs

Structure and Conformational Mobility of OLED-Relevant 1,3,5-Triazine Derivatives

A series of OLED-relevant compounds, consisting of 1,3,5-triazine core linked to various aromatic arms by amino group, has been synthesized and characterized. The studied compounds exist in solution as a mixture of two conformers, a symmetric propeller and asymmetric conformer, in which one of the aromatic arms is rotated around the C-N bond. At temperatures below −40 °C, the VT NMR spectra in DMF-d7 are in a slow exchange regime, and the signals of two conformers can be elucidated. At temperatures above 100 °C, the VT NMR spectra in DMSO-d6 are in a fast exchange regime, and the averaged spectra can be measured. The ratio of symmetric and asymmetric conformers in DMF-d7 varies from 14:86 to 50:50 depending on the substituents. The rotational barriers of symmetric and asymmetric conformers in DMF-d7 were measured for all compounds and are in the interval from 11.7 to 14.7 kcal/mol. The ground-state energy landscapes of the studied compounds, obtained by DFT calculations, show good agreement with the experimental rotational barriers. The DFT calculations reveal that the observed chemical exchange occurs by the rotation around the C(1,3,5-triazine)-N bond. Although some of the compounds are potentially tautomeric, the measured absorption and emission spectra do not indicate proton transfer neither in the ground nor in the excited state

Structure and Conformational Mobility of OLED-Relevant 1,3,5-Triazine Derivatives

A series of OLED-relevant compounds, consisting of 1,3,5-triazine core linked to various aromatic arms by amino group, has been synthesized and characterized. The studied compounds exist in solution as a mixture of two conformers, a symmetric propeller and asymmetric conformer, in which one of the aromatic arms is rotated around the C-N bond. At temperatures below −40 °C, the VT NMR spectra in DMF-d7 are in a slow exchange regime, and the signals of two conformers can be elucidated. At temperatures above 100 °C, the VT NMR spectra in DMSO-d6 are in a fast exchange regime, and the averaged spectra can be measured. The ratio of symmetric and asymmetric conformers in DMF-d7 varies from 14:86 to 50:50 depending on the substituents. The rotational barriers of symmetric and asymmetric conformers in DMF-d7 were measured for all compounds and are in the interval from 11.7 to 14.7 kcal/mol. The ground-state energy landscapes of the studied compounds, obtained by DFT calculations, show good agreement with the experimental rotational barriers. The DFT calculations reveal that the observed chemical exchange occurs by the rotation around the C(1,3,5-triazine)-N bond. Although some of the compounds are potentially tautomeric, the measured absorption and emission spectra do not indicate proton transfer neither in the ground nor in the excited state

Molecular Insight into Mycobacterium tuberculosis Resistance to Nitrofuranyl Amides Gained through Metagenomics-like Analysis of Spontaneous Mutants

We performed synthesis of new nitrofuranyl amides and investigated their anti-TB activity and primary genetic response of mycobacteria through whole-genome sequencing (WGS) of spontaneous resistant mutants. The in vitro activity was assessed on reference strain Mycobacterium tuberculosis H37Rv. The most active compound 11 was used for in vitro selection of spontaneous resistant mutants. The same mutations in six genes were detected in bacterial cultures grown under increased concentrations of 11 (2×, 4×, 8× MIC). The mutant positions were presented as mixed wild type and mutant alleles while increasing the concentration of the compound led to the semi-proportional and significant increase in mutant alleles. The identified genes belong to different categories and pathways. Some of them were previously reported as mediating drug resistance or drug tolerance, and counteracting oxidative and nitrosative stress, in particular: Rv0224c, fbiC, iniA, and Rv1592c. Gene-set interaction analysis revealed a certain weak interaction for gene pairs Rv1592–Rv1639c and Rv1592–Rv0224c. To conclude, this study experimentally demonstrated a multifaceted primary genetic response of M. tuberculosis to the action of nitrofurans. All three 11-treated subcultures independently presented the same six SNPs, which suggests their non-random occurrence and likely causative relationship between compound action and possible resistance mechanism.This study was supported by Scientific Research Program of Rospotrebnadzor, Russia (topic AAAA-A21-121021600206-5 to I.M.), Russian Science Foundation (grant 19-15-00028 to A.V., N.S.), Bulgarian National Science Fund (grants KP-06-N39/7 to G.M.D. and KP-06-N41/3 to V.V.). Work at the Bacterial Pathogenomics and Drug Resistance Laboratory at the Research Institute for Medicines was supported in part by UID/DTP/04138/2019 from Fundação para a Ciência e Tecnologia (FCT), Portugal. J.P. is supported by Fundação para a Ciência e Tecnologia through Estímulo Individual ao Emprego Científico, Portugal [CEECIND/00394/2017].info:eu-repo/semantics/publishedVersio

The genomic history of southeastern Europe

Farming was first introduced to Europe in the mid-seventh millennium bc, and was associated with migrants from Anatolia who settled in the southeast before spreading throughout Europe. Here, to understand the dynamics of this process, we analysed genome-wide ancient DNA data from 225 individuals who lived in southeastern Europe and surrounding regions between 12000 and 500 bc. We document a west-east cline of ancestry in indigenous hunter-gatherers and, in eastern Europe, the early stages in the formation of Bronze Age steppe ancestry. We show that the first farmers of northern and western Europe dispersed through southeastern Europe with limited hunter-gatherer admixture, but that some early groups in the southeast mixed extensively with hunter-gatherers without the sex-biased admixture that prevailed later in the north and west. We also show that southeastern Europe continued to be a nexus between east and west after the arrival of farmers, with intermittent genetic contact with steppe populations occurring up to 2,000 years earlier than the migrations from the steppe that ultimately replaced much of the population of northern Europe.Iain Mathieson … Wolfgang Haak … David Reic