Elizabeth Igne Ferreira

Leishmaniasis phytotherapy. Nature's leadership against an ancient disease

The use of phytotherapy to treat human diseases has its roots in pre-historical times. Despite the modern advances achieved in the field of synthetic chemistry, the most efficient drugs available have their genesis directly or indirectly related with the vegetal kingdom. Indigenous communities have long used plant extracts to treat illnesses. Many of these extracts have shown effective action, with new bioactive compounds being extracted and screened every year. These extracts have also proven to be good sources of therapeutic agents to the treatment of Leishmaniasis. This work highlights some of these agents, while trying to emphasize the importance of plants as a source of new and powerful drugs against this widespread disease.

Advances in prodrug design.

The background of prodrug design is presented herein as the basis for introducing new and advanced latent systems, taking into account mainly the versatility of polymers and other macromolecules as carriers. PDEPT (Polymer-Directed Enzyme Prodrug Therapy); PELT (Polymer-Enzyme Liposome Therapy); CDS (Chemical Delivery System); ADEPT(Antibody-Directed Enzyme Prodrug Therapy); GDEPT/VDEPT (Gene-Directed Enzyme Prodrug Therapy/Virus-Directed Enzyme Prodrug Therapy); ODDS (Osteotropic Drug Delivery System) and LEAPT (Lectin-directed enzyme-activated prodrug therapy) are briefly described and some examples are given.

Quitosana: derivados hidrossolúveis, aplicações farmacêuticas e avanços

Chitin and chitosan are copolymers build from N-acetyl-D-glucosamine and D-glucosamine. The former is widely found in nature and yields the latter on deacetylation. The copolymers are being used for several purposes. Since 1977, when the First International Conference on Chitin and Chitosan was held in Boston, USA, the interest on chitin and chitosan has remarkably increased. This review emphasizes pharmaceutical applications of chitosan and its derivatives, and presents recent advances. Some therapeutical applications of these polymers are also discussed.

4D-QSAR: Perspectives in Drug Design

Drug design is a process driven by innovation and technological breakthroughs involving a combination of advanced experimental and computational methods. A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the optimization of leads into drug candidates. The quantitative structure–activity relationship (QSAR) formalisms are among the most important strategies that can be applied for the successful design new molecules. This review provides a comprehensive review on the evolution and current status of 4D-QSAR, highlighting present challenges and new opportunities in drug design.

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.

Antileishmanial activity screening of 5-nitro-2-heterocyclic benzylidene hydrazides

A series of 53 nitro derivatives rationally designed were obtained by parallel synthesis and screened against Leishmania donovani. Six compounds exhibited IC(50) values lower than standard drugs. Brief SAR analysis revealed that substitution is important to the activity. Nitrothiophene analogues were more potent than the nitrofuran ones. This was attributed to the ability of sulfur atoms in accommodating electrons from nitro group, which facilitate its reduction and therefore the formation of free radicals lethal to parasites.

Quantitative structure-activity relationships for a series of inhibitors of cruzain from Trypanosoma cruzi: molecular modeling, CoMFA and CoMSIA studies.

Human parasitic diseases are the foremost threat to human health and welfare around the world. Trypanosomiasis is a very serious infectious disease against which the currently available drugs are limited and not effective. Therefore, there is an urgent need for new chemotherapeutic agents. One attractive drug target is the major cysteine protease from Trypanosoma cruzi, cruzain. In the present work, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies were conducted on a series of thiosemicarbazone and semicarbazone derivatives as inhibitors of cruzain. Molecular modeling studies were performed in order to identify the preferred binding mode of the inhibitors into the enzyme active site, and to generate structural alignments for the three-dimensional quantitative structure-activity relationship (3D QSAR) investigations. Statistically significant models were obtained (CoMFA, r2=0.96 and q2=0.78; CoMSIA, r2=0.91 and q2=0.73), indicating their predictive ability for untested compounds. The models were externally validated employing a test set, and the predicted values were in good agreement with the experimental results. The final QSAR models and the information gathered from the 3D CoMFA and CoMSIA contour maps provided important insights into the chemical and structural basis involved in the molecular recognition process of this family of cruzain inhibitors, and should be useful for the design of new structurally related analogs with improved potency.

Potential Tuberculostatic Agents: Micelle‐Forming Copolymer Poly(ethylene glycol)‐Poly(aspartic acid) Prodrug with Isoniazid

With the objective of obtaining slow‐acting isoniazid derivatives, of potential use as chemoprophylactics or chemotherapeutics in tuberculosis, the micelle‐forming copolymer of poly(ethylene glycol)‐ poly(aspartic acid) prodrug with isoniazid was synthesized. The derivative obtained was found to be active in Mycobacterium tuberculosis culture, with a minimal inhibitory concentration (MIC) 5.6 times lower than that of the tuberculostatic drug.

Leishmaniasis. What do we know about its chemotherapy

With the objective to evaluate the desorption of phosphorus by silicon in surface layers of a Dark-Red Latosol (Oxisol) under cerrado vegetation and Cambisol (Inceptisol), under open cerrado vegetation at Campos das Vertentes physiographical region State Minas Gerais, experiments were carried out under greenhouse conditions at the Soil Science Department of the Federal University of Lavras, Minas Gerais state, Brazil, from August 1997 to May 1998. Each soil was submitted to three sequential incubations: (a) CaCO3 + MgCO3 to maintain the pH around 6.0; (b) basic fertilization, including phosphorus in one dose calculated to maintain 0.2 mg L-1 of P in soil solution; and (c) six silicon (CaSiO3) doses defined with basis on phosphorus dose. Seedlings of Eucalyptus grandis were cultivated during 120 days in pots with 3 dm3 of soil. Dry matter production and dry matter P content were evaluated at 60, 90 and 120 days after seedling transplanting to the pots. Response surfaces of these variables were adjusted as a function of Si doses and times. The desorbed P contributed with 15.25% of the content of this nutrient in dry matter of plants cultivated in the Cambisol (higher content of kaolinite).

Cruzain inhibition by hydroxymethylnitrofurazone and nitrofurazone: investigation of a new target in Trypanosoma cruzi

Nitrofurazone (NF) and its derivative, hydroxymethylnitrofurazone (NFOH), have presented antichagasic activity. NFOH has higher activity and lower mutagenicity. The aim of this work was to assess whether NF and its derivative NFOH would also be inhibitors of cruzain, besides their trypanothione reductase inhibitory activity. In vitro cruzain inhibition tests were performed for both compounds, and the 50% inhibitory concentration (IC50) for NF and NFOH presented values of 22.83 ± 1.2 μM and 10.55 ± 0.81 μM, respectively. AM1 semi-empirical molecular modeling studies were performed to understand the activity of the compounds, corroborating the observed cruzain inhibitory activity.