Malaria and tuberculosis are no longer considered to be neglected diseases by the World Health Organization. However, both are huge challenges and public health problems in the world, which affect poor people, today referred to as neglected populations. In addition, malaria and tuberculosis present the same difficulties regarding the treatment, such as toxicity and the microbial resistance. The increase of Plasmodium resistance to the available drugs along with the insurgence of multidrug- and particularly tuberculosis drug-resistant strains are enough to justify efforts towards the development of novel medicines for both diseases. This literature review provides an overview of the state of the art of antimalarial and antituberculosis chemotherapies, emphasising novel drugs introduced in the pharmaceutical market and the advances in research of new candidates for these diseases, and including some aspects of their mechanism/sites of action.

Teaching classes and events regarding the molecular aspects of drug-receptor interactions is not an easy task. The ligand stereochemistry and the spatial arrangement of the macromolecular targets highly increase the complexity of the process. In this context, the use of alternative and more playful approaches could allow students to gain a more thorough understanding of this important topic in medicinal chemistry. Herein, we describe a practical teaching approach that uses computational strategies as a tool for drug-receptor interaction studies performed for angiotencsin converting enzyme inhibitors (ACEi). Firstly, the students learn how to find the crystallographic structure (enzyme-ligand complex). Then, they proceed to the treatment of crude crystallographic data. Thereafter, they learn how to analyze the positioning of the drug on the active site of the enzyme, looking for regions related to the molecular recognition. At the end of the study, students can summarize the molecular requirements for the interaction and the structure-activity relationships of the studied drugs.

Hidroximetilnitrofural (NFOH) é um novo composto que possui atividade leishmanicida e tripanomicida potencial. Um método apropriado foi desenvolvido e validado para a determinação de NFOH em nanopartículas de poli(n-butil cianoacrilato) (PBCA). A separação cromatográfica foi obtida usando uma coluna C18 (5 µm de tamanho de partícula, 4,6 mm de diâmetro e 150 mm de comprimento), mantida a 25 °C, fase móvel composta de água e acetonitrila 80:20 (v/v), fluxo de 1,2 mL min- 1 e detecção por UV a 265 nm. Investigaram-se os seguintes parâmetros de validação: seletividade, linearidade, exatidão, precisão e robustez (mudanças na temperatura de coluna, proporção da fase móvel e fluxo). O método mostrou-se específico, o pico de NFOH não apresentou interferência dos picos provenientes dos excipientes das nanopartículas e separado do principal produto de degradação (nitrofural). A linearidade foi obtida na faixa de 0,94-13,11 μg mL- 1 (r2=0,999). O método mostrou exatidão (recuperação de 100,7%, DPR de 0,4 %) e precisão (intra-dia e inter-dia, 9,98-9,99 μg mL- 1 e DPR 0,3% a 0,5%, respectivamente). A robustez provou que o método pode resistir às mudanças propostas. Aplicação do método otimizado revelou eficiência de encapsulação de 64,4% (n=3). Portanto, o método foi desenvolvido e validado com sucesso para a determinação da eficiência de encapsulação de nanopartículas de NFOH-PBCA.

Hydroxymethylnitrofurazone (NFOH) is a new compound with potential leishmanicidal and trypanocidal activity. Despite its effectiveness, the formulators have to overcome its poor aqueous solubility. Recently, polymeric nano-scale drug delivery systems have proposed for the treatment of neglected diseases. As several studies have confirmed the advantages of such formulations, and this approach provides new analytical challenges, including the need to detect trace amounts of the drug. A suitable method was developed and validated for NFOH determination bound to poly (n-butylcyanoacrylate) (PBCA) nanoparticles. The chromatographic separation was achieved using a C18 column maintained at 25 ºC and an isocratic mobile phase consisting of water and acetonitrile: 80:20 (v/v) at a flow rate of 1.2 mL min-1 and UV-detection at 265 nm. Investigated validation parameters included selectivity, linearity, accuracy, precision and robustness (changes in column temperature, mobile phase composition and flow). The method was specific, the peak of NFOH had no interference with any nanoparticle excipients and no co-elution with main degradation product (nitrofurazone). Linearity was over the range of 0.94 13.11 μg mL-1 (r2=0.999). The method was accurate and precise, recovery of 100.7%, RSD of 0.4%; intra-day and inter-day RSD range 9.98-9.99 μg mL-1 and 0.3% to 0.5%, respectively. Robustness confirmed that method could resist the applied changes. Application of the optimized method revealed an encapsulation efficiency of 64.4% (n=3). Therefore, the method was successfully developed and validated for the determination of the encapsulation efficiency of NFOH-PBCA nanoparticles.

A compreensão do mecanismo de redução de compostos com potencial atividade antichagásica pode contribuir para o melhor entendimento de sua ação biológica. Com este objetivo, a redução eletroquímica de nitrofural (nitrofurazona, NF) e seus análogos, nitrofurfurilideno tiossemicarbazona (NFS), nitrotiofeno semicarbazona (NT), nitrotiofeno tiossemicarbazona (NTS), foi estudada pelas voltametrias de pulso diferencial, cíclica e cronoamperometria em meio aquoso, utilizando eletrodo de carbono vítreo. Esses três análogos sintéticos apresentam átomos de oxigênio e de enxofre distribuídos no anel heterocíclico (furano e tiofeno, respectivamente) e no grupo carbonila (semicarbazona e tiossemicarbazona, respectivamente). A hidroxilamina é o principal produto formado em meio ácido, sendo sua formação linearmente dependente do pH. A cronoamperometria mostrou que esta redução envolve 4 elétrons. Entretanto, em meio alcalino, esta onda de redução é desdobrada e um pico reversível a potencial mais positivo foi registrado, correspondendo à formação nitro ânion radical. O nitro ânion radical sofre desproporcionamento e sua estabilidade cinética foi avaliada aplicando a razão de corrente correspondente ao par reversível R - NO2/R - NO2• - e as constantes de segunda ordem (k2) foram determinadas. A partir dos valores de k2 observou-se que o análogo NTS registrou a maior estabilidade.

The biological action of drugs with potential antichagasic activities can be better understood by knowing their reduction mechanism. For this proposal, the electrochemical reduction of nitrofurazone (NF) and its analogues, nitrofurfurilidene thiosemicarbazone (NFS), nitrothiophene semicarbazone (NT), nitrothiophene thiosemicarbazone (NTS), was studied by differential pulse and cyclic voltammetries and chronoamperometry in aqueous medium by using a glassy carbon electrode. Those three synthetic analogues have oxygen and sulfur atoms arranged between the nitroheterocyclic ring (furan and thiophene, respectively) and the carbonyl group (semicarbazone and thiosemicarbazone, respectively). The respective hydroxylamine derivatives are the main products formed in acidic medium, being its formation linearly pH dependent. Although chronoamperometric data show that this reduction involves 4 electrons, its corresponding reduction voltammetric wave, in alkaline medium, is unfolded and a reversible reduction peak at a more positive potential appears. This peak is characterized as a nitro anion radical formation, whose decay is caused by a disproportionation reaction. Its kinetic stability was studied by the current ratio values of the R - NO2/R - NO2• - redox couple and the second-order constant (k2) was determined, being NTS the analogue that registered the highest stability.

O objetivo do trabalho foi ressaltar a importância do planejamento de pró-fármacos para a terapia, por meio de exemplos disponíveis no mercado farmacêutico brasileiro. Os princípios da latenciação são sucintamente discutidos. Apresentam-se exemplos de pró-fármacos de muitas classes terapêuticas importantes e as vantagens relativas aos fármacos dos quais derivam são, também, discutidas. Considerando-se a importância dessas classes terapêuticas, tanto do aspecto terapêutico quanto do econômico, o planejamento de pró-fármacos representa aspecto de grande valor na busca de novos fármacos e na indústria farmacêutica como um todo.

The aim of this paper was to emphasize the importance of prodrug design to therapy, by examining examples available on the Brazilian pharmaceutical market. The principles of prodrug design are briefly discussed herein. Examples of prodrugs from many important therapeutic classes are shown and their advantages relative to the drugs they are derived from are also discussed. Considering the importance of these therapeutic classes, from both therapy and economic standpoints, prodrug design is a very valuable aspect in the research of new drugs and for the pharmaceutical industry as a whole.

As leishmanioses são importantes problemas sociais e de saúde pública para os quais a terapia farmacológica atual é, ainda, limitada. Chalconas e N-acilidrazonas têm sido estudadas como promissores agentes leishmanicidas tanto em ensaios in vitro quanto em ensaios de inibição de cisteíno-proteases importantes para o parasito. Uma vez que estas classes de compostos apresentam similaridade bidimensional, seria interessante estudar se estes compostos guardariam relação de analogia direta entre si. Análise exploratória de dados foi aplicada, então, à biblioteca de chalconas e N-acilidrazonas nitradas ensaiadas contra Leishmania donovani para investigar suas relações de similaridade. Os resultados mostraram que, ao menos sob as condições consideradas neste estudo, as duas classes de compostos não apresentam analogia estrutural e funcional simultaneamente, embora elas apresentem alguma similaridade estrutural.

Leishmaniasis is an important health and social problem for which there is limited effective therapy. Chalcones and N-acylhydrazones have been studied as promising antileishmanial agents in enzymatic inhibition and in vitro assays. Since these chemical classes of compounds also resemble each other structurally, it would be useful to investigate whether they share direct analogy. Exploratory data analysis was applied to a library of chalcones and nitrated N-acylhydrazones assayed against Leishmania donovani to investigate their similarity. Under the conditions applied in the present study, the two classes did not present functional or structural analogy.