Examinando por Autor "Aguilar, Luis F."

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    Combined 3D-QSAR and docking analysis for the design and synthesis of chalcones as potent and selective monoamine oxidase B inhibitors
    (Elsevier, 2021) Mellado, Marco; González, César; Mella, Jaime; Aguilar, Luis F.; Viña, Dolores; Uriarte, Eugenio; Cuellar, Mauricio; Matos, Maria J.
    Monoamine oxidases (MAOs) are important targets in medicinal chemistry, as their inhibition may change the levels of different neurotransmitters in the brain, and also the production of oxidative stress species. New chemical entities able to interact selectively with one of the MAO isoforms are being extensively studied, and chalcones proved to be promising molecules. In the current work, we focused our attention on the understanding of theoretical models that may predict the MAO-B activity and selectivity of new chalcones. 3D-QSAR models, in particular CoMFA and CoMSIA, and docking simulations analysis have been carried out, and their successful implementation was corroborated by studying twenty-three synthetized chalcones (151–173) based on the generated information. All the synthetized molecules proved to inhibit MAO-B, being ten out of them MAO-B potent and selective inhibitors, with IC50 against this isoform in the nanomolar range, being (E)-3-(4-hydroxyphenyl)-1-(2,2-dimethylchroman-6-yl)prop-2-en-1-one (152) the best MAO-B inhibitor (IC50 of 170 nM). Docking simulations on both MAO-A and MAO-B binding pockets, using compound 152, were carried out. Calculated affinity energy for the MAO-A was +2.3 Kcal/mol, and for the MAO-B was −10.3 Kcal/mol, justifying the MAO-B high selectivity of these compounds. Both theoretical and experimental structure–activity relationship studies were performed, and substitution patterns were established to increase MAO-B selectivity and inhibitory efficacy. Therefore, we proved that both 3D-QSAR models and molecular docking approaches enhance the probability of finding new potent and selective MAO-B inhibitors, avoiding time-consuming and costly synthesis and biological evaluations.
  • Miniatura
    Ítem
    Inhibition of Caco-2 and MCF-7 cancer cells using chalcones: synthesis, biological evaluation and computational study
    (Taylor & Francis, 2021) Mellado, Marco; Reyna-Jeldes, Mauricio; Weinstein-Oppenheimer, Caroline; Coddou, Claudio; Jara-Gutierrez, Carlos; Villena, Joan; Aguilar, Luis F.
    Cancer is the second death cause worldwide, with breast and colon cancer among the most prevalent types. Traditional treatment strategies have several side effects that inspire the development of novel anticancer agents derived from natural sources, like chalcone derivatives. For this investigation, twenty-three chalcones (4a-w) were synthesized and evaluated as antiproliferative agents against MCF-7 and Caco-2 cells, finding three and two compounds with similar or higher antiproliferative activity than daunorubicin, while only two chalcones showed better selectivity indexes than daunorubicin on MCF-7. From these results, we developed good-performance QSAR models (r> 0.850, q2 >0.650), finding several structural features that could modify chalcone activity and selectivity. According to these models, chalcones 4w and 4t have high potency and selectivity against Caco-2 and MCF-7, respectively, which make them attractive candidates for hit-to-lead development of ROS-independent pro apoptotic agents.