Structure-activity relationship of new antimalarial 1-aryl-3-susbtituted propanol derivatives : synthesis, preliminary toxicity profiling, parasite life cycle stage studies, target exploration, and targeted delivery
| Autor: | Diego A. Nieto-Aco, Xavier Fernàndez-Busquets, Isabelle Fabing, Eric Deharo, Leonardo Bonilla-Ramirez, Ariane Vettorazzi, Giovanny Garavito, Juan C. Pizarro, Adriana Pabón, Kim Y. Fong, Ernest Moles, David W. Wright, Miguel Quiliano, Ignacio Aldana, Silvia Galiano, Adela López de Cerain |
|---|---|
| Přispěvatelé: | Instituto de Salud Tropical, Universidad de Navarra (Pamplona), Universidad de Antioquia = University of Antioquia [Medellín, Colombia], University of Barcelona, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Vanderbilt University [Nashville], Tulane University School of Public Health and Tropical Medicine [New Orleans, LA, USA], Clínica Universidad de Navarra [Pamplona], Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Universidad Nacional de Colombia [Bogotà] (UNAL), Department of Endocrinology and Nutrition, Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cell Survival Plasmodium berghei Propanols In silico Plasmodium falciparum 030106 microbiology Antimalarial Hsp90 Parasitemia Antiplasmodial Propanol Antimalarials Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Drug Delivery Systems Parasitic Sensitivity Tests In vivo parasitic diseases Drug Discovery Multi-stage activity [CHIM]Chemical Sciences Animals Humans Structure–activity relationship Cytotoxicity Pharmacology Dose-Response Relationship Drug Molecular Structure biology Chemistry Organic Chemistry Hep G2 Cells General Medicine biology.organism_classification In vitro Arylamino alcohol 3. Good health 030104 developmental biology Biochemistry Enantiomer separation |
| Zdroj: | European Journal of Medicinal Chemistry European Journal of Medicinal Chemistry, Elsevier, 2018, 152, pp.489-514. ⟨10.1016/j.ejmech.2018.04.038⟩ European Journal of Medicinal Chemistry, 2018, 152, pp.489-514. ⟨10.1016/j.ejmech.2018.04.038⟩ |
| ISSN: | 0223-5234 1768-3254 |
| DOI: | 10.1016/j.ejmech.2018.04.038⟩ |
| Popis: | International audience; Design, synthesis, structure-activity relationship, cytotoxicity studies, in silico drug-likeness, genotoxicity screening, and in vivo studies of new 1-aryl-3-substituted propanol derivatives led to the identification of nine compounds with promising in vitro (55, 56, 61, 64, 66, and 70-73) and in vivo (66 and 72) antimalarial profiles against Plasmodium falciparum and Plasmodium berghei. Compounds 55, 56, 61, 64, 66 and 70-73 exhibited potent antiplasmodial activity against chloroquine-resistant strain FCR-3 (IC50s < 0.28 μM), and compounds 55, 56, 64, 70, 71, and 72 showed potent biological activity in chloroquine-sensitive and multidrug-resistant strains (IC50s < 0.7 μM for 3D7, D6, FCR-3 and C235). All of these compounds share appropriate drug-likeness profiles and adequate selectivity indexes (77 < SI < 184) as well as lack genotoxicity. In vivo efficacy tests in a mouse model showed compounds 66 and 72 to be promising candidates as they exhibited significant parasitemia reductions of 96.4% and 80.4%, respectively. Additional studies such as liver stage and sporogony inhibition, target exploration of heat shock protein 90 of P. falciparum, targeted delivery by immunoliposomes, and enantiomer characterization were performed and strongly reinforce the hypothesis of 1-aryl-3-substituted propanol derivatives as promising antimalarial compounds. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect