Browsing by Author "Kouznetsov, Vladimir V."
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Publication Análisis de los cambios fenotípicos del pez Cebra (Danio rerio) producidos por nuevas moléculas tetrahidroquinolínicas en busca de potentes y selectivos moduladores genéticos.(2016-03-28) Kouznetsov, Vladimir V.; Universidad Industria de Santander (Bucaramanga, Colombia); COL0011189 - Grupo de Estudios en Biodiversidad; COL0058247 - Laboratorio de Química Orgánica y BiomolecularEn el presente proyecto se propone utilizar los embriones del pez Cebra (Danio rerio) como objetos de estudio biológico y las nuevas tetrahidroquinolinas 3,4,5-trimetoxifenil sustituidas (THQs), estructuralmente diversas como sondas químicas capaces de inducir cambios morfológicos durante la organogénesis del pez. Estas expresiones (fenotipos), causadas por las THQs, permitirá identificar nuevos moduladores de redes genéticas que esten involucrados en el desarrollo temprano de los vertebrados. La identificación de nuevas moléculas (moduladores) que alteren (estimulen o inhiban) los eventos de desarrollo de un organismo vivo, con una especificidad cercana a la mutación genética, es fundamental para la comprensión y diseño de tratamientos selectivos para las enfermedades humanas. Este enfoque ''genética química hacia adelante'' (desde del fenotipo a la proteína) del pez Cebra es rápido, económico y no requiere la cría a largo plazo. Más importante aún, las moléculas-moduladoras identificadas hacen un control instantáneo y distinguible visualmente de una posible función proteíca que este influyendo el desarrollo normal del embrión. La realización de esta investigación no es posible sin disponer de librerías de nuevas y diversas moléculas. Por tal motivo, y en primer lugar, se planea la preparación de diferentes librerías de compuestos heterocíclicos, basados en el esqueleto de las THQs, ampliamente repartidos en la naturaleza como metabolitos secundarios. Es importante resaltar que las librerías de moléculas, parecidas a los productos naturales, son más exitosas en la búsqueda de agentes farmacológicamente activos. Para generar estas moléculas, inicalmente, se plantea desarrollar nuevos métodos preparativos de síntesis, acordes con los principios de la química verde, de moléculas heterocíclicas analogas a productos naturales, empleando las multi-reacciones de cicloadición. Adicionalmente, teniendo experiencia exitosa en la estandarización de métodos de imino Diels-Alder de tres componentes, en este proyecto se propone combinar los elementos estructurales de THQs con los de un terpenoide natural, llamado combretastatina A-4 (CA-4), un agente citotóxico reconocido que actúa como inhibidor de la polimerización de la tubulina, lo que se presume ofrecerá nuevas entidades químicas con propiedades farmacodinámicas y farmacocinéticas diferentes. Una vez se tengan las bibliotecas químicas, se planea implementar el método de alto contenido (el screening en microplacas de 96 pocillos) para el modelo del pez Cebra en estado embrionario. Al analizar los cambios fenotípicos en órganos, inducidos por las THQs obtenidas y por la CA-4 u otras moléculas-inhibidoras de la polimerización de la tubulina (colchicina y podofilotoxina), se piensa encontrar las similitudes y dierencias de los cambios morfológicos producidos por las THQs y los inhibidores microtubulares naturales y así identificar nuevos moduladores como posibles agentes antimitóticos. La idea principal de esta propuesta se basa en los siguientes hechos confirmados: a. La proliferación de las células cancerosas se parece mucho al crecimiento normal de embriones del pez Cebra (ambos procesos son fenómenos rápidos); b. La alta homología genética entre el pez Cebra y los humanos (se comparte más del 80 % del genoma) permite extrapolar los resultados biológicos obtenidos con este modelo al ser humano; c. Los productos naturales son reconocidos andamios privilegiados porque fueron moldeados y reajustados específicamente con el propósito universal de llegar a interactuar con las macromoléculas biológicas, en especial con los productos de genes (las proteínas); d. Las THQs a estudiar en este proyecto, se asemejan claramente en su estructura a los metabolitos secundarios (alcaloides tetrahidroquinolínicos y terpenoides con función de 3,4,5-trimetoxifenilo) presentes en la naturaleza; e. El 90% de moléculas con una actividad biológica prominente in vitro son descartadas en las etapas posteri.Publication Anti-leishmanial evaluation of C2-aryl quinolines: Mechanistic insight on bioenergetics and sterol biosynthetic pathway of Leishmania braziliensis(2013-05-09) Bompart, Daznia; Núñez Durán, Jorge; Rodríguez, Daniel; Kouznetsov, Vladimir V.; Meléndez Gómez, Carlos M.; Sojo, Felipe; Arvelo, Francisco; Visbal, Gonzalo; Álvarez, Álvaro; Serrano Martín, Xenón; García Marchán, YaelA series of diverse simple C2-aryl quinolines was synthesized de novo via a straightforward synthesis based on the acid-catalyzed multicomponent imino Diels–Alder reactions. Seven selected quinolines were evaluated at different stages of Leishmania braziliensis parasite. Among them, the 6-ethyl-2-phenylquinoline 5f was able to inhibit the growth of promastigotes of this parasite without affecting the mammalian cells viability and decreasing the number of intracellular L. braziliensis amastigotes on BMDM macrophages. The mechanism of action studied for the selected compound consisted in: (1) alteration of parasite bioenergetics, by disrupting mitochondrial electrochemical potential and alkalinisation of acidocalcisomes, and (2) inhibition of ergosterol biosynthetic pathway in promastigote forms. These results validate the efficiency of quinoline molecules as leishmanicide compounds.Publication Aqueous SDS micelle-promoted acid-catalyzed domino ABB’ imino Diels-Alder reaction: a mild and efficient synthesis of privileged 2-methyltetrahydroquinoline(2013) Merchan Arenas, Diego Rolando; Martínez Bonilla, Carlos A.; Kouznetsov, Vladimir V.New green protocol for the efficient synthesis of pharmacologically relevant 4-amidyl-2-methyl-1,2,3,4-tetrahydroquinolines (THQs) through the domino type ABB’ imino Diels–Alder reaction in acidified water in the presence of sodium dodecyl sulphate (SDS) surfactant was developed for the first time. The influence of the SDS micelles and their different concentrations (5.0, 8.2 and 12.0 mM) on reactivity of the imino Diels–Alder reaction was studied. It was found that the best THQ yields (70–99%) are achieved above the critical micellar concentration (12 mM) using pH 1.0–2.5. This procedure resulted in a general and clean environmentally benign protocol to obtain the privileged diastereospecific cis 2,4-disubstituted THQ molecules of highest biological interest.Publication Cantharidin-Based Small Molecules as Potential Therapeutic Agents(2013) Puerto Galvis, Carlos Eduardo; Vargas Méndez, Leonor Yamile; Kouznetsov, Vladimir V.Chemical and pharmacological information on cantharidin-based small molecules was analyzed. The review summarizes new facts about blister beetles’ metabolites for the period 2006–2012. General synthetic approaches to cantharidin-based small molecules as well as their chemical transformations and biological activities related to cantharidin, norcantharidin, cantharidimide, and norcantharimide analogs, especially their inhibitory activity of phosphoprotein phosphatases in cancer treatment, were discussed in this mini review, which could help to design new small molecule modulators for other biological models.Publication Design, synthesis, acetylcholinesterase inhibition and larvicidal activity of girgensohnine analogs on Aedes aegypti, vector of dengue fever(2014-03) Carreño Otero, Aurora L.; Vargas Méndez, Leonor Yamile; Duque L., Jonny Edward; Kouznetsov, Vladimir V.Girgensohnine alkaloid was used as a natural model in the design and generation of new alkaloid-like α-aminonitrilea series that was completed by the use of SSA-catalyzed Strecker reaction between commercial and inexpensive substituted benzaldehydes, piperidine (pyrrolidine, morpholine and N-methylpiperazine) and acetone cyanohydrin. Calculated ADMETox parameters of the designed analogs revealed their good pharmacokinetic profiles indicating lipophilic characteristics. In vitro AChE enzyme test showed that obtained a-aminonitriles could be considered as AChEIs with micromolar IC50 values ranging from 42.0 to 478.0 mM (10.3e124.0 mg/mL). Among this series, the best AChE inhibitor was the pyrrolidine a-aminonitrile 3 (IC50 ¼ 42 mM), followed by the piperidine a-aminonitriles 2 and 6 (IC50 ¼ 45 mM and IC50 ¼ 51 mM, respectively), and the compound 7 (IC50 ¼ 51 mM). In vivo insecticidal activity of more active AChEIs against Aedes aegypti larvae was also performed showing a good larvicidal activity at concentrations less than 140 ppm, highlighting products 2 and 7 that could serve as lead compounds to develop new potent and selective insecticides.Publication Diastereoselective Synthesis of Dihydroisoindolo[2,1‑a]quinolin-11- ones by Solvent-Free AMCell-SO3H‑Catalyzed Imino Diels−Alder/Intramolecular Amide Cyclization Cascade Reactions(2014-04-30) Merchan Arenas, Diego Rolando; Kouznetsov, Vladimir V.Nineteen bioactive highly functionalized 6,6a-dihydroisoindolo[2,1-a]quinolin-11(5H)-one derivatives were easily prepared in good yield without solvent using catalytic amorphous milled cellulose sulfonic acid (AMCell-SO3H), substituted anilines, propenyl-phenols, and phthaldehydic acid. The cascade reaction gave high regioselectivity and diastereoselectivity.Publication First Girgensohnine Analogs Prepared Through InCl3-catalyzed Strecker Reaction and their Bioprospection(2013) Vargas Méndez, Leonor Yamile; Kouznetsov, Vladimir V.An efficient preparation of the girgensohnine and its close analogs with α-aminonitrile structure, and their spectral characterization were reported for the first time. The piperidine α-aminonitriles were obtained through 5 mol% InCl3-catalyzed one-pot Strecker reaction and tested for antioxidant activity and AChE inhibitory properties. It was found that girgensohnine possesses a moderate AChE inhibitory property while its spiroanalog shows good antioxidant capacityPublication Gd(OTf)3-catalyzed synthesis of geranyl esters for the intramolecular radical cyclization of their epoxides mediated by titanocene (III)(2015) García Santos, William H.; Puerto Galvis, Carlos Eduardo; Kouznetsov, Vladimir V.A selective and mild method for the esterification of a variety of carboxylic acids with geraniol is developed. We demonstrated that the use of triphenylphosphine, I2, 2-methylimidazole or imidazole and a catalytic amount of Gd(OTf)3 resulted to be more active than the previous protocols, providing a 16-membered library of geranyl esters in higher yields and in shorter reaction times. The use of essential oil of palmarosa (Cymbopogon martinii), enriched with geraniol, as a raw material for the synthesis of the target compounds complemented and proved how sustainable and eco-friendly this protocol is. Finally, the selective 6,7-epoxidation of the obtained geranyl esters led us to study their regio-controlled radical cyclization mediated by titanocene(III) for the synthesis of novel (8-hydroxy-9,9-dimethyl-5-methylene cyclohexyl)methyl esters in moderate yields and with excellent stereoselectivities.Publication In vitro phenotypic screening of 7-chloro-4-amino(oxy)quinoline derivatives as putative anti-Trypanosoma cruzi agents(2014) Kouznetsov, Vladimir V.; Gómez Barrio, Alicia; Escario, José A.; Rojas Ruiz, Fernando A.; Fonseca Berzal, CristinaIn this study, a series of 22 pre-synthesized 7-chloro-4-mino(oxy)quinoline derivatives was assayed in vitro as potential antichagasic agents. A primary screening against Trypanosoma cruzi epimastigotes and a non-specific cytotoxicity assay on murine fibroblasts were simultaneously performed, resulting quinolines 3, 7 and 12 with great selectivity (SI) on the extracellular parasite (SI7, SI3 , SI12 and SIBZ >9.44). Therefore, the activity of these derivatives was evaluated on intracellular amastigotes, achieving derivative 7 the best SI (SI = 12.73). These results, supported by the in silico prediction of a good oral bioavailability and a suitable risk profile, propose the 4-amino-7-chloroquinoline scaffold as a potential template for designing trypanocidal prototypes.Publication Programa: Bioprospección y desarrollo de ingredientes naturales para las industrias cosmética, farmacéutica y de productos de aseo con base en la biodiversidad colombiana(2018) Stashenko, Elena E.; Martínez Morales, Jairo René; Kouznetsov, Vladimir V.; Fuentes Lorenzo, Jorge Luis; Ocazionez, Raquel Elvira; Duque, Jonny Edward; Villa Holguín, Aída Luz; Olivero Vebel, Jesús; Sepúlveda, Juan Carlos; Muños Acevedo, Amner; Gutíerrez De Aguas, Ricardo Gonzalo; Jiménez, Ruben Alberto; Cotes Oyaga, Sandra Beatriz; Tafurt García, Geovanna; Gonzáles Mina, Robert Tulio; Vargas Méndez, Leonor Yamile; Cervantes Díaz, Martha; Rozo Correa, Ciro Eduardo; Martínez Pérez, Francisco José; Méndez Sánchez, Stelia Carolina; Ramírez Sanabria, Fernando; Angulo Silva, Víctor Manuel; González Rodríguez, Lina María; Alarcón Durango, Edwin Alexis; Veloza Castiblanco, Luz Angela; Ramírez Aristizábal, Luz Stella; Orrego Agudelo, Gloria Amparo; Almeyda Parra, Gloria; Santamaria Bueno, Óscar EliecerPublication Selective activity of 2,4-diaryl-1,2,3,4-tetrahydroquinolines on Trypanosoma cruzi epimastigotes and amastigotes expressing β-galactosidase(2013-07) Fonseca Berzal, Cristina; Merchan Arenas, Diego Rolando; Romero Bohórquez, Arnold R.; Escario, José A.; Kouznetsov, Vladimir V.; Gómez Barrio, AliciaThe growth inhibitory effect on Trypanosoma cruzi epimastigotes and the unspecific cytotoxicity over NCTC-929 fibroblasts of two series of previously synthesized 2,4-diaryl-1,2,3,4-tetrahydroquinolines (THQ), have been studied in vitro and compared with those of benznidazole (BZ). Derivatives AR39, AR40, AR41, AR91 and DM15 achieved outstanding selectivity indexes (SI) on the extracellular form (SITHQ > SIBZ > 9.44) and thus, were tested in a more specific in vitro assay against amastigotes, showing less effectiveness than the reference drug (SIBZ > 320) but also accomplishing great selectivity on the intracellular stage (SITHQ > 25). These promising results, supported by the in-silico prediction of high bioavailability and less potential risk than benznidazole, reveal several tetrahydroquinolines as prototypes of potential antichagasic drugs.Publication Yb(OTf)3-Catalyzed Bromination Reactions of Natural Product-like N-Benzyl Cinnamamides: A Facile Route to Diverse N-Substituted Amides of Pharmacological Interest(2013) Puerto Galvis, Carlos Eduardo; Hernandez Barajas, José G.; Kouznetsov, Vladimir V.Diverse natural product-like N-benzyl cinnamamides were prepared by condensation of trans-cinnamic acid with substituted benzylamines in the presence of boric acid as catalyst. The further evaluation of this amides as a substrates of the bromo-arylation reaction, in the presence of N-bromosuccinimide (NBS) as the halogen source and under the catalysis of Yb(OTf)3, generate a different types of N-substituted amides: N-aryl 2,3-dibromopropanamides, N-(2-bromobenzyl) cinnamamides and tetrahydro-2-benzazepin-3-one as a new molecules. Here we discuss the formation of these main products on the basis of the electronic nature of the substituents present in the N-benzyl aromatic ring of the prepared cinnamamides.