Synthesis of 3-amino-2-ethoxycarbonyl pyrido[1,2-a]thieno-[2,3-d]-4-pyrimidone derivatives and their antimalarial and cytotoxic activities in vitro

A series of 3-amino-2-ethoxycarbonyl pyrido[1,2-a]thieno[2,3-d]-4-pyrimidone 10-13 were prepared in order to investigate their cytotoxicity and antimalarial activities. Some of the them showed a promising activity. The detailed synthesis, spectroscopic, computational and biological data are described.Fil: Charris, Jaime. Universidad Central de Venezuela; VenezuelaFil: Domínguez, José. Universidad Central de Venezuela; VenezuelaFil: Cordero, Mary. Universidad Central de Venezuela; VenezuelaFil: Orfila, Luz. Universidad Central de Venezuela; VenezuelaFil: Riggione, Flavia. Universidad Central de Venezuela; VenezuelaFil: López, Simón E.. Universidad Simon Bolivar. Departamento de Quimica.; VenezuelaFil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Suviere, Fernando. Universidad Nacional de San Luis. Facultad de Ciencias Físico- Matemáticas y Naturales; Argentin

[(7-chloroquinolin-4-yl)amino]acetophenones and their copper(II) derivatives

The synthesis of the compounds [(7-chloroquinolin-4-yl)amino]acetophenones (4, 5) and their copper(II) complexes (4a, 5a) is reported. The compounds were characterized using a wide range of spectroscopic and spectrometric techniques, such as FTIR, UV-vis, NMR, EPR, ESI-CID-MS2. The spectral results suggested that the ligand acted as chelating species coordinating the metal through the endocyclic nitrogen of the quinoline ring in both complexes, with general formulae ex pressed in two ways, according to the phase in which they are: [Cu(L)2Cl2] for solid phase and [Cu(L)2][2Cl] for liquid phase. The EPR study of the Cu (II) complexes indicated a probable distorted tetrahedral coordination geometry. This result was confirmed by the calculated optimized structures at the DFT/B3LYP method with the 6-31G (d,p) basis set. The characterization of the fragmentation pattern of protonated free ligands was extended here to fragments as low as m/z 43, while for coordination complexes it extends to fragments at m/z 80 and m/z 111. The antimalarial activity of the compounds was determined through three different tests: inhibitory activity against in vitro growth of Plasmodium falciparum (W2), inhibition of hemozoin formation (β-hematin) and in vitro inhibitory activity against recombinant falcipain-2, where compound 5 showed considerable activity. However, the activity of free ligands against P. falciparum was increased by complexing with the Cu (II) metal ion. The values of the HOMO-LUMO energy gap of 3.847 eV (4a) and 3.932 eV (5a) were interpreted with high chemical activity and thus, could influence on biological activity. In both compounds, the total electron density surface mapped with electrostatic po tential clearly revealed the presence of high negative charge on the Cu atom. Also, this study reported the molecular docking of free ligands (4, 5) using software package ArgusLab 4.0.1. The results revealed the importance of water molecules as interaction bridges through hydrogen bonds between free ligands and β-hematin; at the same time, the hypothesis that π–π interaction between quinoline derivatives and the electronic system of hematin governs the formation of adducts was confirmed

(2E)-2-(2,4-Dichloro­phenyl­sulfon­yl)-3-(4-methyl­anilino)-3-(methyl­sulfan­yl)acrylonitrile

The title compound, C17H14Cl2N2O2S2, and the 3-methoxy­anilino analogue reported in the preceding paper have been used as starting materials to develop benzothia­zine derivatives with anti­malarial activity. The mol­ecule displays an E (trans) configuration about the central double bond. Due to conjugation in the C=C—C N group, the putative single bond shows a significant shortening [1.418 (3) Å]. The mol­ecule has a six-membered ring involving an intra­molecular N—H⋯O(sulfon­yl) bond, which is an example of resonance-assisted hydrogen bonding. In the crystal structure, bonds of the C—H⋯O(sulfon­yl) and C—H⋯N(cyano) types form double layers of mol­ecules parallel to (01). Within these layers there are π–π inter­actions between benzene rings of pairs of centrosymmetrically related mol­ecules, with distances of 3.7969 (12) Å between centroids. C—H⋯π interactions are also present

Synthesis and preliminary pharmacological evaluation of methoxilated indoles with possible dopaminergic central action

Compounds 5-7 were synthesized from 4-tetralones with o-iodoanilines by a radical nucleophilic substitution or SRN1 reaction, and were pharmacologically evaluated in order to establish their possible antagonistic action on the central dopaminergic receptors. Behavioural parameters, such as stereotypy in rats were measured after intracerebroventricular administration of these compounds at doses of 10 μg/5 μL. Our results demonstrate that compounds 5-7 do not affect stereotypy behaviour. However, they inhibit the apomorphine-induced stereotypy behaviour, suggesting the involvement of the central dopaminergic system. Also we observe that there is a concordance between the behavioural profiles induced by our compounds and those reported for clozapine 8 and ziprasidone 9. It is plausible to suggest that compounds 5-7 could be acting as potential atypical antipsychotic agents. Quantum calculations performed on the basis of a comparative conformational study of their structures indicate a stereoelectronic similarity between the basic nuclei of compounds 4 and 5-7. In addition Molecular Dynamics (MD) simulations performed on compounds 5-7 at the binding site of dopamine D2 receptor suggest that these compounds could interact with the human D2 dopamine receptors.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Synthesis of 6-carbomethoxy-3-Phenyl-5-(4-dimethylaminophenyl)-cyclohexenone

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