Jeanine Giarolla

Prodrugs for the Treatment of Neglected Diseases

Recently, World Health Organization (WHO) and Medicins San Frontieres (MSF) proposed a classification of diseases as global, neglected and extremely neglected. Global diseases, such as cancer, cardiovascular and mental (CNS) diseases represent the targets of the majority of the R&D efforts of pharmaceutical companies. Neglected diseases affect millions of people in the world yet existing drug therapy is limited and often inappropriate. Furthermore, extremely neglected diseases affect people living under miserable conditions who barely have access to the bare necessities for survival. Most of these diseases are excluded from the goals of the R&D programs in the pharmaceutical industry and therefore fall outside the pharmaceutical market. About 14 million people, mainly in developing countries, die each year from infectious diseases. From 1975 to 1999, 1393 new drugs were approved yet only 1% were for the treatment of neglected diseases [3]. These numbers have not changed until now, so in those countries there is an urgent need for the design and synthesis of new drugs and in this area the prodrug approach is a very interesting field. It provides, among other effects, activity improvements and toxicity decreases for current and new drugs, improving market availability. It is worth noting that it is essential in drug design to save time and money, and prodrug approaches can be considered of high interest in this respect. The present review covers 20 years of research on the design of prodrugs for the treatment of neglected and extremely neglected diseases such as Chagas’ disease (American trypanosomiasis), sleeping sickness (African trypanosomiasis), malaria, sickle cell disease, tuberculosis, leishmaniasis and schistosomiasis.

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

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 (ELUMO). The findings suggest that the carbonyl group next to the myo-inositol is the most promising ester breaking point.

Drug Design for Neglected Disease in Brazil

Neglected tropical diseases (NTD) are a group of 17 diseases transmitted by virus, protozoa, helminthes and bacteria. These illnesses are responsible for millions of deaths per year, affecting mainly the poorest populations in the world. The therapeutic drugs available are obsolete, toxic, have questionable efficacy and there are reports of resistance. Therefore, the discovery of new, safe, effective and affordable active molecules is urgently needed. Considering that, the main purpose of this mini-review is to show the current scenario concerning drug design for neglected disease in Brazil. NTD are a very broad topic. Thus, we selected four infections for discussion: Chagas disease, leishmaniasis, malaria and tuberculosis. According to CNPq (National Counsel of Technological and Scientific Development) directories, there are many Brazilian groups studying these respective diseases. The papers published possess high quality and some of them, the most recent, are briefly discussed here. Medicinal chemistry approaches such as synthesis of novel series of molecules and biological activity evaluation, studies of structure-activity relationships (qualitative and quantitative), molecular modeling calculations and electrochemistry are some of the tools applied in the design of the compounds.

Design and exploratory data analysis of a second generation of dendrimer prodrugs potentially antichagasic and leishmanicide

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.

Molecular modelling as a tool for studying the disassembly of potentially leishmanicide-targeted dendrimer

Molecular modelling studies were carried out to analyse which carbonyl group is the most vulnerable to the disassembly of potentially leishmanicide-targeted dendrimer. The dendrimers were designed using myo-inositol (core and directing group), d-mannose (directing group), l-malic acid (spacer and dendron) and hydroxymethylnitrofurazone (NFOH) as a bioactive agent. The molecular models were built containing one, two and three branches. For this preliminary analysis, physicochemical properties, such as electronic density distribution and steric hindrance regarding the carbonyl groups were evaluated, and the carbon atoms in the following carbonyl groups were considered: near the core (C1), close to the directing group (C2), in l-malic acid (C3) and near the bioactive agent (C4). The most probable targeted dendrimers showed the carbonyl close to the core as the most susceptible to a nucleophilic attack, except those molecular systems containing two branches with d-mannose as the directing group, which displayed the carbonyl group near NFOH as the most likely ester breaking point.

Chalcones and N-acylhydrazones: direct analogues? Exploratory data analysis applied to potential novel antileishmanial agents

As leishmanioses sao importantes problemas sociais e de saude publica para os quais a terapia farmacologica atual e, ainda, limitada. Chalconas e N-acilidrazonas tem sido estudadas como promissores agentes leishmanicidas tanto em ensaios in vitro quanto em ensaios de inibicao de cisteino-proteases importantes para o parasito. Uma vez que estas classes de compostos apresentam similaridade bidimensional, seria interessante estudar se estes compostos guardariam relacao de analogia direta entre si. Analise exploratoria de dados foi aplicada, entao, a biblioteca de chalconas e N-acilidrazonas nitradas ensaiadas contra Leishmania donovani para investigar suas relacoes de similaridade. Os resultados mostraram que, ao menos sob as condicoes consideradas neste estudo, as duas classes de compostos nao apresentam analogia estrutural e funcional simultaneamente, embora elas apresentem alguma similaridade estrutural.

In silico study to analyse the disassembly of quercetin-targeted dendrimers potentially leishmanicide

Molecular modelling methods were previously applied to obtain information regarding the disassembly of the first generation quercetin-targeted dendrimers potentially leishmanicide. Dendrimers containing one to three branches were designed, and their three-dimensional molecular models were built up. They were constituted by myo-inositol (core and directing group), d-mannose (directing group), l-malic acid (spacer) and quercetin (bioactive agent). Physicochemical properties, such as spatial hindrance, electrostatic potential mapping and the lowest unoccupied molecular orbital energy, were evaluated. Hence, the main purpose of this study was to identify which carbonyl group was the most vulnerable to undergo chemical or enzymatic action. The carbonyl groups were named according to their positions in dendrimer systems as follows: C1, close to the core group; C2, near the directing group; C3 in the l-malic acid; and, C4 nearby the bioactive agent. C4 seemed to be the most promising carbonyl group to suffer hydrolysis. However, regarding larger molecular systems, such as targeted dendrimers with three branches, C4 carbonyl group is the most sterically hindered impairing any enzymatic approximation. For this kind of molecular systems, C1 has presented more spatial accessibility as well as lower electronic density distribution, which are features needed to dendrimer enzymatic disassembly, though.