Browsing by Author "Duarte, Yorley"

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    Direct Oral FXa Inhibitors Binding to Human Serum Albumin: Spectroscopic, Calorimetric, and Computational Studies
    (2023) Mariño Ocampo, Nory Johana; Rodríguez Sánchez, Diego Fernando; Daniel Sebastian, Guerra Diaz; Zúñiga Núñez, Daniel; Duarte, Yorley; Fuentealba Patiño, Denis Alberto; Zacconi, Flavia C. M.
    Direct FXa inhibitors are an important class of bioactive molecules (rivaroxaban, apixaban,edoxaban, and betrixaban) applied for thromboprophylaxis in diverse cardiovascular pathologies.The interaction of active compounds with human serum albumin (HSA), the most abundant protein inblood plasma, is a key research area and provides crucial information about drugs’ pharmacokineticsand pharmacodynamic properties. This research focuses on the study of the interactions betweenHSA and four commercially available direct oral FXa inhibitors, applying methodologies includingsteady-state and time-resolved fluorescence, isothermal titration calorimetry (ITC), and moleculardynamics. The HSA complexation of FXa inhibitors was found to occur via static quenching, and thecomplex formation in the ground states affects the fluorescence of HSA, with a moderate bindingconstant of 104 M−1. However, the ITC studies reported significantly different binding constants (103 M−1) compared with the results obtained through spectrophotometric methods. The suspectedbinding mode is supported by molecular dynamics simulations, where the predominant interactionswere hydrogen bonds and hydrophobic interactions (mainly π–π stacking interactions between thephenyl ring of FXa inhibitors and the indole moiety of Trp214). Finally, the possible implications ofthe obtained results regarding pathologies such as hypoalbuminemia are briefly discussed.
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    Green by Design: Convergent Synthesis, Computational Analyses, and Activity Evaluation of New FXa Inhibitors Bearing Peptide Triazole Linking Units
    (2022) Rodriguez, Diego F.; Duran Osorio, Francisca; Duarte, Yorley; Olivares, Pedro; Moglie, Yanina; Dua, Kamal; Zacconi, Flavia C. M.
    Green chemistry implementation has led to promising results in waste reduction in the pharmaceutical industry. However, the early sustainable development of pharmaceutically active compounds and ingredients remains a considerable challenge. Herein, we wish to report a green synthesis of new pharmaceutically active peptide triazoles as potent factor Xa inhibitors, an important drug target associated with the treatment of diverse cardiovascular diseases. The new inhibitors were synthesized in three steps, featuring cycloaddition reactions (high atom economy), microwave-assisted organic synthesis (energy efficiency), and copper nanoparticle catalysis, thus featuring Earth-abundant metals. The molecules obtained showed FXa inhibition, with IC50-values as low as 17.2 mu M and no associated cytotoxicity in HEK293 and HeLa cells. These results showcase the environmental potential and chemical implications of the applied methodologies for the development of new molecules with pharmacological potential.
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    Microwave-mediated synthesis of N-allyl/propargyl derivatives : enzymatic analysis as a potential factor Xa (FXa) inhibitor, theoretical and computational molecular docking
    (2020) Santana Romo, Fabián Mauricio; Duarte, Yorley; Castillo Suzarte, Francisco Javier; Maestro, Miguel A.; Zacconi, Flavia C. M.
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    Toward the cholinesterase inhibition potential of TADDOL derivatives: Seminal biological and computational studies
    (2022) Constantino, Andrea R.; Charbe, Nitin Bharat; Duarte, Yorley; Gutierrez, Margarita; Giordano Villatoro, Ady; Prasher, Parteek; Dua, Kamal; Mandolesi, Sandra; Zacconi, Flavia C. M.
    Alzheimer's disease (AD) is a degenerative neurological disease characterized by gradual loss of cognitive skills and memory. The exact pathogenesis involved still remains unrevealed, but several studies indicate the involvement of an array of different enzymes, underlining the multifactorial character of the disease. Inhibition of these enzymes is therefore a powerful approach in the development of AD treatments, with promising candidates, including acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidase. Interestingly, AChE is the target of a major pesticide family (organophosphates), with several reports indicating an intersection between the pesticide's activity and AD. In this study, various TADDOL derivatives were synthesized and their in vitro activities as AChE/BuChE inhibitors as well as their antioxidant activities were studied. Molecular modeling studies revealed the capability of TADDOL derivatives to bind to AChE and induce inhibition, especially compounds 2b and 3c furnishing IC50 values of 36.78 +/- 8.97 and 59.23 +/- 5.31 mu M, respectively. Experimental biological activities and molecular modeling studies clearly demonstrate that TADDOL derivatives with specific stereochemistry have an interesting potential for the design of potent AChE inhibitors. The encouraging results for compounds 2b and 3c indicate them as promising scaffolds for selective and potent AChE inhibitors.