title: Exploring the scope of new arylamino alcohol derivatives: Synthesis, antimalarial evaluation, toxicological studies, and target exploration.
abstract: Synthesis of new 1-aryl-3-substituted propanol derivatives followed by structure-activity relationship, in silico drug-likeness, cytotoxicity, genotoxicity, in silico metabolism, in silico pharmacophore modeling, and in vivo studies led to the identification of compounds 22 and 23 with significant in vitro antiplasmodial activity against drug sensitive (D6 IC50≤ 0.19 μM) and multidrug resistant (FCR-3 IC50≤ 0.40 μM and C235 IC50≤ 0.28 μM) strains of Plasmodium falciparum. Adequate selectivity index and absence of genotoxicity was also observed. Notably, compound 22 displays excellent parasitemia reduction (98 ± 1%), and complete cure with all treated mice surviving through the entire period with no signs of toxicity. One important factor is the agreement between in vitro potency and in vivo studies. Target exploration was performed; this chemotype series exhibits an alternative antimalarial mechanism.
authors.affiliation: Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy and Nutrition, University of Navarra, Pamplona, 31008, Spain; Institute of Tropical Health (ISTUN), University of Navarra, Pamplona, 31008, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Quiliano
authors.affiliation: Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy and Nutrition, University of Navarra, Pamplona, 31008, Spain.
authors.forename: Adela
authors.initials: A
authors.lastname: Mendoza
authors.affiliation: Department of Chemistry, Vanderbilt University, Station B 351822, Nashville, TN 37235, USA.
authors.forename: Kim Y
authors.initials: KY
authors.lastname: Fong
authors.affiliation: Grupo Malaria, Universidad de Antioquía, Medellín, Colombia.
authors.forename: Adriana
authors.initials: A
authors.lastname: Pabón
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, USA.
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Goldfarb
authors.affiliation: Laboratoire de Synthèse et Physicochimie de Molécules d'Intérêt Biologique SPCMIB - UMR5068, CNRS - Université Paul Sabatier, 118, route de Narbonne, 31062, Toulouse Cedex 09, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Fabing
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy and Nutrition, University of Navarra, Pamplona, 31008, Spain.
authors.forename: Ariane
authors.initials: A
authors.lastname: Vettorazzi
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy and Nutrition, University of Navarra, Pamplona, 31008, Spain.
authors.forename: Adela
authors.initials: A
authors.lastname: López de Cerain
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, USA.
authors.forename: Ben M
authors.initials: BM
authors.lastname: Dunn
authors.affiliation: Universidad Nacional de Colombia, Sede Bogotá, Facultad de Ciencias, Departamento de Farmacia (DFUNC), Grupo de investigación FaMeTra (Farmacología de la Medicina tradicional y popular), Carrera 30 45-03, Bogotá D.C., Colombia.
authors.forename: Giovanny
authors.initials: G
authors.lastname: Garavito
authors.affiliation: Department of Chemistry, Vanderbilt University, Station B 351822, Nashville, TN 37235, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Wright
authors.affiliation: UMR 152 PHARMA-DEV, Université Toulouse, IRD, UPS, 31062, Toulouse, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Deharo
authors.affiliation: Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy and Nutrition, University of Navarra, Pamplona, 31008, Spain; Institute of Tropical Health (ISTUN), University of Navarra, Pamplona, 31008, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pérez-Silanes
authors.affiliation: Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy and Nutrition, University of Navarra, Pamplona, 31008, Spain; Institute of Tropical Health (ISTUN), University of Navarra, Pamplona, 31008, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Aldana
authors.affiliation: Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy and Nutrition, University of Navarra, Pamplona, 31008, Spain; Institute of Tropical Health (ISTUN), University of Navarra, Pamplona, 31008, Spain. Electronic address: sgaliano@unav.es.
authors.forename: Silvia
authors.initials: S
authors.lastname: Galiano
mesh_terms: D000605:Amino Alcohols / Q000009:adverse effects / Q000302:isolation & purification* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000962:Antimalarials / Q000009:adverse effects / Q000302:isolation & purification* / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D020128:Inhibitory Concentration 50; D016778:Malaria, Falciparum / Q000188:drug therapy; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000605:Amino Alcohols; D000962:Antimalarials
keywords: Antimalarial; Antiplasmodial; Arylamino alcohol; Hemozoin inhibition; Mannich reaction; Plasmepsin II enzyme