Crystal structure of {2-[4-(4-chlorophenyl)-4-hydroxy-l-piperidinylmethyl] cyclopentyl}-(4-fluorophenyl)-methanone, C24H27CIFNO2

Abstract C24H27ClFNO2, triclinic, P1̅̅̅̅ (No. 2), a = 9.494(2) Å, b = 10.769(2) Å, c = 11.377(3)Å, α = 87.18(3)°, β = 67.27(3)°, γ = 88.01(3)°, V = 1071.4 Å3, Z = 2, Rgt(F) = 0.076, wRobs(F2) = 0.302, T = 293 K

Skin Sensitisation (Q)SARs/Expert Systems: from Past, Present to Future

This review describes the state of the art of available (Q)SARs/expert systems for skin sensitisation and evaluates their utility for potential regulatory use. There is a strong mechanistic understanding with respect to skin sensitisation which has facilitated the development of different models. Most existing models fall into one of two main categories either they are local in nature, usually specific to a chemical class or reaction chemical mechanism or else they are global in form, derived empirically using statistical methods. Some of the published global QSARs available have been recently characterised and evaluated elsewhere in accordance with the OECD principles. An overview of expert systems capable of predicting skin sensitisation is also provided. Recently, a new perspective regarding the development of mechanistic skin sensitisation QSARs so-called Quantitative Mechanistic Modelling (QMM) has been proposed, where reactivity and hydrophobicity, are used as the key parameters in mathematically modelling skin sensitisation. Whilst hydrophobicity can be conveniently modelled using log P, the octanol-water partition coefficient; reactivity is less readily determined from chemical structure. Initiatives are in progress to generate reactivity data for reactions relevant to skin sensitisation but more resources are required to realise a comprehensive set of reactivity data. This is a fundamental and necessary requirement for the future assessment of skin sensitisation.JRC.I.3-Toxicology and chemical substance

Predicting Proteome-Early Drug Induced Cardiac Toxicity Relationships (Pro-EDICToRs) with Node Overlapping Parameters (NOPs) of a new class of Blood Mass-Spectra graphs

The 11th International Electronic Conference on Synthetic Organic Chemistry session Computational ChemistryBlood Serum Proteome-Mass Spectra (SP-MS) may allow detecting Proteome-Early Drug Induced Cardiac Toxicity Relationships (called here Pro-EDICToRs). However, due to the thousands of proteins in the SP identifying general Pro-EDICToRs patterns instead of a single protein marker may represents a more realistic alternative. In this sense, first we introduced a novel Cartesian 2D spectrum graph for SP-MS. Next, we introduced the graph node-overlapping parameters (nopk) to numerically characterize SP-MS using them as inputs to seek a Quantitative Proteome-Toxicity Relationship (QPTR) classifier for Pro-EDICToRs with accuracy higher than 80%. Principal Component Analysis (PCA) on the nopk values present in the QPTR model explains with one factor (F1) the 82.7% of variance. Next, these nopk values were used to construct by the first time a Pro-EDICToRs Complex Network having nodes (samples) linked by edges (similarity between two samples). We compared the topology of two sub-networks (cardiac toxicity and control samples); finding extreme relative differences for the re-linking (P) and Zagreb (M2) indices (9.5 and 54.2 % respectively) out of 11 parameters. We also compared subnetworks with well known ideal random networks including Barabasi-Albert, Kleinberg Small World, Erdos-Renyi, and Epsstein Power Law models. Finally, we proposed Partial Order (PO) schemes of the 115 samples based on LDA-probabilities, F1-scores and/or network node degrees. PCA-CN and LDA-PCA based POs with Tanimoto’s coefficients equal or higher than 0.75 are promising for the study of Pro-EDICToRs. These results shows that simple QPTRs models based on MS graph numerical parameters are an interesting tool for proteome researchThe authors thank projects funded by the Xunta de Galicia (PXIB20304PR and BTF20302PR) and the Ministerio de Sanidad y Consumo (PI061457). González-Díaz H. acknowledges tenure track research position funded by the Program Isidro Parga Pondal, Xunta de Galici

QSAR Study for Macromolecular RNA Folded Secondary Structures of Mycobacterial Promoters with Low Sequence Homology

The 9th International Electronic Conference on Synthetic Organic Chemistry session Computational ChemistryThe general belief is that quantitative structure-activity relationships (QSAR) techniques work only for small molecules and, proteins sequences or, more recently, DNA sequences. However, with non-branched graph for proteins and DNA sequences the QSAR often have to be based on powerful non-linear techniques such as support vector machines. In our opinion linear QSAR models based in RNA could be useful to assign biological activity when alignment techniques fail due to low sequence homology. The idea bases in the high level of branching for the RNA graph. This work introduces the so called Markov electrostatic potentials k?M as a new class of RNA 2D-structure descriptors. Subsequently, we validate these molecular descriptors solving a QSAR classification problem for mycobacterial promoter sequences (mps), which constitute a very low sequence homology problem. The model developed (mps = –4.664·0cM + 0.991·1cM – 2.432) was intended to predict whether a naturally occurring sequence is an mps or not on the basis of the calculated kcM value for the corresponding RNA secondary structure. The RNAQSAR approach recognises 115/135 mps (85.2%) and 100% of control sequences. Average predictability and robustness were greater than 95%. A previous non-linear model predicts mps with slightly higher accuracy (97%) but uses a very large parameter space for DNA sequences. Conversely, the kcM-based RNA-QSAR encodes more structural information and needs only two variablesGonzález-Díaz, H. thanks the Xunta de Galicia (BTF20301PR) for partial financial suppor

Coumarin-Chalcone Hybrids as new scaffolds in drug discovery

The 13th International Electronic Conference on Synthetic Organic Chemistry session General Organic SynthesisThe first hydroxilated series of coumarin-chalcone derivatives has been synthesize starting from the corresponding salicyl aldehyde and β-ketoester precursors by a Knoevenagel reaction in order to obtain the methoxy derivatives which have been further hydrolyzed with a Lewis aci

Alcaloides de especies chilenas del género Rhodophiala C. Presl (Amaryllidaceae) y su importancia quimiotaxonómica

The family Amaryllidaceae is widely distributed from temperate to tropical regions. Amaryllidaceae species from thesubfamily Amaryllidoideae can biosynthesize alkaloids with important physiological effects. Rhodophiala C. Presl isone of the native genera of Amaryllidoideae of Chile, Argentina, Paraguay, Uruguay and Brazil. However, despite thediversity of this genus in Chile, their alkaloids have only been studied previously in one species of this country. The presentwork aims to analyze the alkaloid profi les and chemotaxonomically compare three other Chilean species of Rhodophiala:Rhodophiala bagnoldii (Herb.) Traub, Rhodophiala pratensis (Poepp.) Traub and Rhodophiala volckmannii Phil. Bulbextracts were analyzed by means of gas chromatography-mass spectrometry (GC-MS) and alkaloids were characterizedaccording to retention time and fragmentation pattern. The skeleton type alkaloids detected were lycorine, crinine,galanthamine, homolycorine, tazettine and montanine. All analyzed species showed different alkaloid profi les, indicatingthese compounds can be used as a chemotaxonomic tool. Furthermore, the alkaloid types detected in this genus havemultiple reported biological properties and these species can constitute new sources of important medicinal products.La familia Amaryllidaceae está ampliamente distribuida desde regiones templadas a tropicales. Las especies de la subfamiliaAmaryllidoideae biosintetizan alcaloides con importantes efectos fi siológicos. Rhodophiala C. Presl es uno de los génerosnativos de Amaryllidoideae de Chile, Argentina, Paraguay, Uruguay y Brasil. Sin embargo, a pesar de la diversidad deeste género en Chile, sólo se han estudiado los alcaloides de una especie de este país. En este trabajo se analiza el perfi lalcaloideo y se comparan quimiotaxonómicamente otras tres especies chilenas del género Rhodophiala: Rhodophialabagnoldii (Herb.) Traub, Rhodophiala pratensis (Poepp.) Traub y Rhodophiala volckmannii Phil. Se analizaron extractosde bulbos mediante cromatografía de gases-espectrometría de masas (CG-EM). Los alcaloides fueron caracterizados por sutiempo de retención y patrón de fragmentación. Los tipos de esqueletos de los alcaloides detectados fueron licorina, crinina,galantamina, homolicorina, tazetina y montanina. Todas las especies analizadas presentaron diferentes perfi les alcaloideos,por lo que estos compuestos pueden ser usados como una herramienta quimiotaxonómica. Además, los tipos de alcaloidesdetectados en este género tienen múltiples propiedades biológicas reportadas en literatura y estas especies pueden constituirnuevas fuentes de productos de importancia medicinal

Synthesis and electrochemical study of new 3-(hydroxyphenyl)benzo[f]coumarins

New hydroxyl substituted 3-arylbenzo[f]coumarins (compounds 6–10) have been designed and synthesized. Their electrochemical redox mechanisms, and the influence of one or two hydroxyl groups, in different positions on the coumarin scaffold, was investigated by cyclic, differential pulse and square wave voltammetry, at a glassy carbon electrode, at different pHs, and a comparative study was performed. The structural information obtained enabled a better understanding of the structure/electrochemical relationship of hydroxyl substituted 3-arylbenzo[f]coumarins, compounds with important antioxidant properties

Exploring the Multi-Target Performance of Mitochondriotropic Antioxidants against the Pivotal Alzheimer’s Disease Pathophysiological Hallmarks

Alzheimer disease (AD) is the most common neurodegenerative disease featuring progressive and degenerative neurological impairments resulting in memory loss and cognitive decline. The specific mechanisms underlying AD are still poorly understood, but it is suggested that a deficiency in the brain neurotransmitter acetylcholine, the deposition of insoluble aggregates of fibrillar β-amyloid 1–42 (Aβ42), and iron and glutamate accumulation play an important role in the disease progress. Despite the existence of approved cholinergic drugs, none of them demonstrated effectiveness in modifying disease progression. Accordingly, the development of new chemical entities acting on more than one target is attracting progressively more attention as they can tackle intricate network targets and modulate their effects. Within this endeavor, a series of mitochondriotropic antioxidants inspired on hydroxycinnamic (HCA’s) scaffold were synthesized, screened toward cholinesterases and evaluated as neuroprotectors in a differentiated human SH-SY5Y cell line. From the series, compounds 7 and 11 with a 10-carbon chain can be viewed as multi-target leads for the treatment of AD, as they act as dual and bifunctional cholinesterase inhibitors and prevent the neuronal damage caused by diverse aggressors related to protein misfolding and aggregation, iron accumulation and excitotoxicityThis work was funded by FEDER funds through the Operational Programme Competitiveness Factors-COMPETE and national funds by FCT-Foundation for Science and Technology under research grants (UID/QUI/00081, NORTE-01-0145-FEDER-000028, PTDC/DTP-FTO/2433/2014, PTDC/BIA-MOL/28607/2017, POCI-01-0145-FEDER-028607). S. Benfeito and C. Fernandes grants are supported by FCT, POPH and QREN. The authors also thank the COST action CA15135 for supportS

edición, notas y comentarios de Gabriel María Verd Conradi, S. I.

Se sabía que el gran especialista en bibliografía de la Compañía de Jesús, particularmente de la española, el jesuita José Eugenio de Uriarte (1842-1909), había dejado inédito un estudio sobre el célebre soneto "No me mueve, mi Dios, para quererte". En su importante Catálogo razonado de obras anónimas y seudónimas de autores de la Compañía de Jesús pertenecientes á la antigua Asistencia española, al tratar del "No me mueve", se nos informa póstumamente que «El Autor tenía en preparación un estudio, acerca del famoso Soneto, que dejó por terminar». Y en el último volumen, dentro de la relación de las obras del P. Uriarte, en la Breve noticia bio-bibliográfica del P. José Eugenio de Uriarte y Basterrechea, S.J. (sin firma, pero al parecer del P. Mariano Lecina), se menciona lo siguiente: «48. Apuntamientos y extractos para una disertación sobre el Soneto “No me mueve, mi Dios, para quererte”. En 4.º, de 25 fols. y además varias anotaciones en papeles sueltos»