title: Design and exploratory data analysis of a second generation of dendrimer prodrugs potentially antichagasic and leishmanicide.
abstract: Chagas disease and leishmaniasis are neglected tropical diseases, considered as a serious public health. Also, the drugs available for their treatment are toxic and exhibit questionable efficacy. Consequently, the discovery and development of new drug candidates are currently necessary. Dendrimers are highly branched molecules with extremely controlled structure. Those molecular systems display several biological applications (i.e., drug carriers), especially when the focus is prodrug design. Herein, a second generation of dendrimer prodrugs was planned to obtain potentially antichagasic and leishmanicide delivery systems. These dendrimers were composed by myo-inositol (core), L-malic acid (spacer), and three bioactive agents [hydroxymethylnitrofurazone (NFOH), quercetin, 3-hydroxyflavone]. The major aim of this study was to investigate the molecular properties (thermodynamics, steric, steric/electronic, electronic, and hydrophobic) to further describe intersamples relationships through either similarity indices or linear combinations of the original variables. Then, an exploratory data analysis, which comprises hierarchical cluster analysis (HCA) and principal components analysis (PCA), was carried out. Complementary findings were observed for PCA and HCA. Steric, intrinsic/steric, steric/electronic, steric/hydrophobic, hydrophobic, and electronic properties influenced the discrimination process. In addition, these molecular properties can also contribute to enzymatic hydrolysis mechanism elucidation, which depends upon the approximation and a subsequent nucleophilic attack to release the drug from the dendrimer prodrugs.
authors.affiliation: LAPEN, Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo (USP), Av. Prof. Lineu Prestes, 580-Bloco 13 sup., Cidade Universitária, São Paulo, SP, 05508-900, Brazil, jeanineg@usp.br.
authors.forename: Jeanine
authors.initials: J
authors.lastname: Giarolla
authors.forename: Kerly Fernanda Mesquita
authors.initials: KF
authors.lastname: Pasqualoto
authors.forename: Elizabeth I
authors.initials: EI
authors.lastname: Ferreira
mesh_terms: D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000737:chemistry*; D014355:Chagas Disease / Q000188:drug therapy; D050091:Dendrimers / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D007891:Leishmania / Q000187:drug effects; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D050091:Dendrimers; D011355:Prodrugs