Molecular modeling study on the disassembly of dendrimers designed as potential antichagasic and antileishmanial prodrugs

Abstract

A molecular modeling study was carried out to investigate the most likely enzymatic disassembly mechanism of dendrimers that were designed as potential antichagasic and antileishmanial prodrugs. The models contained myo-inositol (core), L-malic acid (spacer), and active agents such as 3-hydroxyflavone, quercetin, and hydroxymethylnitrofurazone (NFOH). A theoretical approach that considered one, two, or three branches has already been performed and reported by our research group; the work described herein focused on four (models A and B), five, or six branches, and considered their physicochemical properties, such as spatial hindrance, electrostatic potential mapping, and the lowest unoccupied molecular orbital energy (E(LUMO)). The findings suggest that the carbonyl group next to the myo-inositol is the most promising ester breaking point.

Flavonoids as efficient scaffolds: Recent trends for malaria, leishmaniasis, Chagas disease, and dengue

“…However, 3‐hydroxyflavone was only active in vitro but not in vivo , probably because of bioavailability failures. Trying to solve this problem, Giarolla, Pasqualoto and Ferreira (); Giarolla, Pasqualoto, Rando, Zaim and Ferreira () have developed in silico studies of dendrimer prodrug derivatives of this flavone. Flavonoids of the aerial parts of Ageratum conyzoides L. (eupalestin [ 110 ]; 5,6,7,5′‐tetramethoxy‐3′,4′‐methylenedioxyflavone [ 111 ]; 5′‐methoxynobiletin [ 112 ]; 5,6,7,3′,4′,5′‐hexamethoxyflavone [ 113 ]; and ageconyflavone C [ 114 ]) were evaluated against axenic amastigotes of L. donovani .…”

Drug Design for Chagas'Disease: Advances and Challenges

“…83 Pró-fármacos dendriméricos ou fármacos dirigidos dendriméricos, cujo dêndron é constituído de ácido málico, composto bioativo (composto 36, dentre outros) e inositol como centro (Figura 22) vêm sendo sintetizados e a liberação estudada por meio de modelagem molecular. 84,85 Registro de patente envolvendo forma diferenciada de dendrímeros nos quais o centro é o inositol e os dêndrons são constituídos de unidades de repetição, no caso ácido málico e composto bioativo 86 encontrase em análise no INPI.…”

Leishmanicidas potenciais: estudo da síntese de fármacos dirigidos dendriméricos de primeira geração com hidroximetilnitrofural

“…The dendrimers were designed with myo-inositol (core and directing group), D-mannose (directing group), malic L-acid (spacer and branch) and NFOH (bioactive agent) [19,20]. D-mannose, as dendrimer external groups, can provide a selective action to macrophages, since these cells contain mannose receptors on their surface.…”

“…The computational methodologies were carried out as previously reported by Giarolla and coworkers [19,20]. Briefly, the three-dimensional (3D) molecular models of each dendrimer containing one, two and three branches with NFOH (bioactive agent) and directing groups (myo-inositol or D-mannose) in their neutral forms were built up, without any constrains, in MM+ force field [23] using the HyperChem 7.51 software [24].…”

“…A modelagem molecular foi aplicada para predição da liberação dos compostos ativos a partir do fármaco dirigido proposto, a exemplo do trabalho realizado por Giarolla et al (2010Giarolla et al ( , 2012 (TROSSINI et al, 2010b).…”