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These are all the trajectories used to study CRD4 conformational stability under normal (pH = 7) and acid (pH = 5) environments, as well as in complex with the auxiliary Ca II, a-mannose and a-mannose-1,2-a-mannose.

Background: Tuberculosis (TB) has been a challenging disease worldwide, especially for the neglected poor populations. Presently, there are approximately 2 billion people infected with TB worldwide and 10 million people in the world fell ill with active TB, leading to 1.5 million deaths. Introduction: The classic treatment is extensive and the drug- and multi-drug resistance of Mycobacterium tuberculosis has been a threat to the efficacy of the drugs currently used. Therefore, the rational design of new anti-TB candidates is urgently needed. Methods: With the aim of contributing to face this challenge, 78 compounds have been proposed based on SBDD (Structure-Based Drug Design) strategies applied to target the M. tuberculosis phosphopantetheine adenylyltransferase (MtPPAT) enzyme. Ligand-Based Drug Design (LBDD) strategies were also used for establishing Structure-Activity Relationships (SAR) and for optimizing the structures. MtPPAT is important for the biosynthesis of coenzyme A (CoA) and it has been studied recently toward the discovery of new inhibitors. Results: After docking simulations and enthalpy calculations, the interaction of selected compounds with MtPPAT was found to be energetically favorable. The most promising compounds were then synthesized and submitted to anti-M. tuberculosis and MtPPAT inhibition assays. Conclusion: One of the compounds synthesized (MCP163), showed the highest activity in both of these assays.

Background: Parasitic infections are diseases transmitted by parasites usually found in contaminated food, water, or insect bites. Generally classified as neglected tropical diseases, malaria and trypanosomiases are some of the most prominent parasitic diseases that cause significant loss of life annually. In 2020, an estimated 241 million malaria cases were reported, with 627,000 deaths worldwide. An estimated 6 to 7 million people are infected with Trypanosoma cruzi worldwide, whereas an estimated 1000 global cases of African human trypanosomiasis were reported in 2020. Flavanones are a group of compounds that belong to the flavonoid family and are chemically obtained by direct cyclization of chalcones. Recent pharmacological studies have demonstrated the effectiveness of plant flavanones in inhibiting the growth of the parasites responsible for malaria and trypanosomiases. Objective: The present work aims to summarize up-to-date and comprehensive literature information on plant flavanones with antimalarial and antitrypanosomal activities. The mechanisms of action of the antiparasitic flavanones are also discussed. Method: A literature search was performed for naturally occurring flavanones and antimalarial and antitrypanosomal activities by referencing textbooks and scientific databases (SciFinder, Wiley, American Chemical Society, Science Direct, National Library of Medicine, Scientific Electronic Library Online, Web of Science, etc.) from their inception until April 2022. Results: Based on in vitro experiments, more than sixty flavanones were reported to exhibit antimalarial, anti-T. cruzi, and anti-T. brucei activities. Previous studies demonstrated that these compounds bind to PGP-like transporters of P. falciparum to reverse the parasite’s resistance. Other reports pinpointed the direct effect of these compounds on the mitochondria of the malaria parasite. Moreover, flavanones have shown strong docking to several validated T. cruzi and T. brucei protein targets, including adenosine kinase, pteridine reductase 1, dihydrofolate reductase, and trypanothione reductase, among others. Conclusion: Flavanones, isolated and characterized from diverse plant parts, were reported to exhibit moderate to high activity against P. falciparum, T. cruzi, and T. brucei in in vitro studies. These potentially active flavanones can be used as scaffolds for the development of new antiparasitic agents. However, more studies on the cytotoxicity, pharmacokinetics, and mechanisms of action of potent flavanones should be performed.

Neglected tropical diseases (NTDs) are highly prevalent communicable diseases in tropical and subtropical countries, generally not economically attractive for drug development and related to poverty. In Brazil, more specifically, socioeconomic inequalities and health indicators are strongly influenced by skin color, race, and ethnicity, due to the historical process of slavery. In this context, it is important to understand the concept of systemic racism: a form of indirect racial discrimination present in many institutions, which determines the process of illness and death of the black population, the ethnic group most affected by these diseases. The main objective of this paper was to carry out a literature review on the socioeconomic aspects of these diseases, relating them to institutional racism, and to encourage reflection on the influence of this type of racism in the NTDs context. Therefore, we present a paper that brings a evident correlation between racism versus neglected populations, which are affected by equally neglected diseases. A more humane and comprehensive view is needed to realize that these illnesses affect neglected and vulnerable populations, who require decent living conditions, health, and social justice. We hope to provide, with this paper, enough, but not exhaust, knowledge to initiate the discussion about neglected diseases, their socioeconomic aspects and institutional racism.

Background: Dysphania ambrosioides (L.) Mosyakin & Clemants is an aromatic herb native to South America but also distributed widely throughout Africa and Europe. This plant is traditionally used to treat various ailments including pain and swellings, flu, parasitic diseases and is used as an analgesic, antipyretic, and wound healing. Phytochemical analyses of D. ambrosioides revealed the presence of terpenoids, flavonoids, coumarins, fatty acids, and miscellaneous compounds, among others, which might be responsible for its modern pharmacological actions. Objective: The present work summarizes recent developments on phytochemistry, ethnomedicinal use, pharmacology, and toxicity of D. ambrosioides. A critical assessment of the literature information of D. ambrosioides is also presented. Methods: The available information on D. ambrosioides was collected through libraries and electronic databases [Scifinder, ACS, Scielo, Science direct, Pubmed (National Library of Medicine), Wiley, Springer, PROTA, Web of Science, Google Web, Yahoo search and Google scholar] from respective inception until January 2021. Results: More than 150 compounds, including terpenoids, flavonoids, coumarins, fatty acids, and miscellaneous compounds, etc., were identified from D. ambrosioides. D. ambrosioides exhibited a wide range of pharmacological activities, including antimalarial, anti-inflammatory, antiparasitic, anticancer, insecticidal, antigiardial, among others. Metal nanoparticles synthesized from D. ambrosioides extracts presented enhanced pharmacological activities as compared to the crude plant extracts counterparts. Conclusion: D. ambrosioides is a promising medicinal plant, however, more in vivo experiments, cytotoxicity tests, and mechanisms of actions of its extracts and compounds are recommended to transubstantiate the ethnomedicinal claims of this plant into scientific rationale-based information.

Background: Chagas disease is a potentially life-threatening illness caused by the protozoan parasite Trypanosoma cruzi and is transmitted to humans through the excreta of infected blood-sucking triatomine bugs. According to the World Health Organization, 6 to 7 million people are infected with T. cruzi worldwide, mainly in Latin America, with more than 10000 deaths annually. Aim of the Study: The present study aims to provide comprehensive literature information on the importance of triazole-containing heterocycles in developing anti-Chagas disease agents. Methodology: The embodied information was acquired without date limitation by December 2020 using various electronic databases including, SciFinder, PubMed (National Library of Medicine), Science Direct, Wiley, ACS (American Chemical Society), SciELO (Scientific Electronic Library Online), Google Scholar, Springer, Scopus, and Web of Science. Results: Upon in vitro studies, more than 100 triazole-containing heterocycles have been predicted as active compounds against the pathogen responsible for the American trypanosomiasis. However, less is known about their in vivo activity in animal models and their clinical studies in humans. Moreover, the pharmacokinetic studies of these bioactive compounds are still pending. Despite the variety of mechanisms of action attributed to most of these molecules, the exact mechanism involved is still controversial. Thus, in vivo experiments, followed by pharmacokinetics, and the mechanism of action of the most active compounds, should be the subject of future investigation. Conclusion: All in all, recent studies have demonstrated the importance of triazole-containing heterocycles in search of potential candidates for drug development against Chagas disease. Nonetheless, the use of new catalysts and chemical transformations is expected to provide avenues for the synthesis of unexplored triazole derivatives, leading to the development of triazole-containing compounds with new properties and trypanocidal activity.

Endemic in 149 tropical and subtropical countries, neglected tropical diseases (NTDs) affect more than 1 billion people annually with over 500,000 deaths. Among the NTDs, some of the most severe consist of leishmaniasis, Chagas disease, and dengue. The impact of the combined NTDs closely rivals that of malaria. According to the World Health Organization, 216 million cases of malaria were reported in 2016 with 445,000 deaths. Current treatment options are associated with various limitations including widespread drug resistance, severe adverse effects, lengthy treatment duration, unfavorable toxicity profiles, and complicated drug administration procedures. Flavonoids are a class of compounds that has been the subject of considerable scientific interest. New developments of flavonoids have made promising advances for the potential treatment of malaria, leishmaniasis, Chagas disease, and dengue, with less toxicity, high efficacy, and improved bioavailability. This review summarizes the current standings of the use of flavonoids to treat malaria and neglected diseases such as leishmaniasis, Chagas disease, and dengue. Natural and synthetic flavonoids are leading compounds that can be used for developing antiprotozoal and antiviral agents. However, detailed studies on toxicity, pharmacokinetics, and mechanisms of action of these compounds are required to confirm the in vitro pharmacological claims of flavonoids for pharmaceutical applications. HIGHLIGHTS: In the current review, we have tried to compile recent discoveries on natural and synthetic flavonoids as well as their implication in the treatment of malaria, leishmaniasis, Chagas disease, and dengue. A total of 373 (220 natural and 153 synthetic) flavonoids have been evaluated for antimalarial, antileishmanial, antichagasic, and antidengue activities. Most of these flavonoids showed promising results against the above diseases. Reports on molecular modeling of flavonoid compounds to the disease target indicated encouraging results. Flavonoids can be prospected as potential leads for drug development; however, more rigorously designed studies on toxicity and pharmacokinetics, as well as the quantitative structure-activity relationship studies of these compounds, need to be addressed.

Neglected tropical diseases (NTDs) are responsible for over 500,000 deaths annually and are characterized by multiple disabilities. Leishmaniasis and Chagas diseases are among the most severe NTDs, and are caused by the Leishmania sp and Trypanosoma cruzi, respectively. Glucantime, pentamidine, and miltefosine are commonly used to treat leishmaniasis, whereas nifurtimox, benznidazole are current treatments for Chagas disease. However, these treatments are associated with drug resistance and severe side effects. Hence, the development of synthetic products, especially those containing N02, F, or Cl, are known to improve biological activity. The present work summarizes the information on the antileishmanial and antitrypanosomal activity of nitro-, chloro-, and fluorosynthetic derivatives. Scientific publications referring to halogenated derivatives in relation to antileishmanial and antitrypanosomal activities were hand-searched in databases such as SciFinder, Wiley, Science Direct, PubMed, ACS, Springer, Scielo, and so on. According to the literature information, more than 90 compounds were predicted as lead molecules with reference to their IC50/EC50 values in in vitro studies. It is worth mentioning that only active compounds with known cytotoxic effects against mammalian cells were considered in the present study. The observed activity was attributed to the presence of nitro-, fluoro-, and chloro-groups in the compound backbone. All in all, nitro and halogenated derivatives are active antileishmanial and antitrypanosomal compounds and can serve as the baseline for the development of new drugs against leishmaniasis and Chagas disease. However, efforts in in vitro and in vivo toxicity studies of the active synthetic compounds is still needed. Pharmacokinetic studies and the mechanism of action of the promising compounds need to be explored. The use of new catalysts and chemical transformation can afford unexplored halogenated compounds with improved antileishmanial and antitrypanosomal activity.

Cancer represents a major global health concern, showing high number of new cases and deaths annually worldwide. The treatment, in its turn, proves to be extremely toxic, presenting high incidence of adverse events. Therefore, designing new therapeutic approaches is an urgent need. In this context, dendrimers have been commonly applied as drug carriers, improving the pharmaceutical, pharmacokinetic, and pharmacodynamic properties of the prototype. The bioactive compound can be adsorbed on the dendrimeric structure or attached to the surface. Additionally, targeted groups can be used to promote the selective action of the drug in the human body. Hence, this chapter demonstrated the dendrimers state of art potentially directed to cancer therapy, as well as difficulties in clinical translation.

Made available in DSpace on 2022-04-29T08:45:33Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-07-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Hydroxymethylnitrofurazone (NFOH) is a therapeutic candidate for Chagas disease (CD). It has negligible hepatotoxicity in a murine model compared to the front-line drug benznidazole (BZN). Here, using Trypanosoma cruzi strains that express bioluminescent and/or fluorescent reporter proteins, we further investigated the in vitro and in vivo activity of NFOH to define whether the compound is trypanocidal or trypanostatic. The in vitro activity was assessed by exploiting the fluorescent reporter strain using wash-out assays and real-time microscopy. For animal experi-mentation, BALB/c mice were inoculated with the bioluminescent reporter strain and assessed by highly sensitive in vivo and ex vivo imaging. Cyclophosphamide treatment was used to promote parasite relapse in the chronic stage of infection. Our data show that NFOH acts by a trypanostatic mechanism, and that it is more active than BZN in vitro against the infectious trypomastigote form of Trypanosoma cruzi. We also found that it is more effective at curing experimental infections in the chronic stage, compared with the acute stage, a feature that it shares with BZN. Therefore, given its reduced toxicity, enhanced anti-trypomastigote activity, and curative properties, NFOH can be considered as a potential therapeutic option for Chagas disease, perhaps in combination with other trypanocidal agents. School of Pharmaceutical Sciences Sao Paulo State University (UNESP) Department of Infection Biology Faculty of Infectious and Tropical Diseases London School of Hygiene and Tropical Medicine, Keppel Street LAPEN—Laboratory of Design and Synthesis of Chemotherapeutic Agents Potentially Active on Neglected Diseases Department of Pharmacy School of Pharmaceutical Sciences University of Sao Paulo (USP) Advanced Research Center in Medicine School of Medicine Union of the Colleges of the Great Lakes (UNILAGO) School of Pharmaceutical Sciences Sao Paulo State University (UNESP) FAPESP: 2016/10847-9

The electrochemical reduction mechanism of two isomers of position drug leaders against Chagas disease, p-nitrosulfonylhydrazine derivative (p-NSF), and m-nitrosulfonylhydrazine derivative (m-NSF), was investigated in aqueous media and in the absence of oxygen using voltammetric techniques. The main reduction process was attributed to the reduction of the nitro group (Epc (p-NSF) = −0.58 V and Epc (m-NSF) = −0.62 V), generating nitroso derivative in intermediate and higher values of pH and hydroxylamine in lower values of pH. Another reduction process in a less negative potential value was only observed for p-NSF and attributed to the generation of the nitro radical anion. The difference in the reduction potentials between both compounds and the presence of another reduction process for p-NSF was associated with the position of the nitro group, due to the distinct stabilization of the reduction intermediates by the aromatic ring. A catalytic response for the reduction process of the nitro anion radical was observed for p-NSF in the presence of oxygen, given that its magnitude of current increased when increasing the oxygen availability. Also, for m-NSF, this reduction process could be detected, even though it was not observed in the voltammograms in the absence of oxygen. This further confirmed the generation of the nitro radical anion, since it reacts with molecular oxygen and regenerates the initial nitro compound. The interaction with cysteine was also evaluated, which favored the reduction process towards the generation of the nitroso derivative due to adduct formation, destabilizing the reduction process regarding the nitro radical anion. Therefore, electrochemical experiments can evaluate how different isomers of position and other coupled functional groups affect the reduction of the nitro group and, consequently aid in the design of new classes of antichagasic pharmaceuticals, with improved stability of reactive intermediates that are often correlated with the degree of injury towards the parasite.

Chagas disease is a potentially life-threatening illness caused by the protozoan parasite Trypanosoma cruzi and is transmitted to humans through the excreta of infected blood-sucking triatomine bugs. According to the World Health Organization, 6 to 7 million people are infected with T. cruzi worldwide, mainly in Latin America, with more than 10000 deaths annually.The present study aims to provide comprehensive literature information on the importance of triazole-containing heterocycles in developing anti-Chagas disease agents.The embodied information was acquired without date limitation by December 2020 using various electronic databases including, SciFinder, PubMed (National Library of Medicine), Science Direct, Wiley, ACS (American Chemical Society), SciELO (Scientific Electronic Library Online), Google Scholar, Springer, Scopus, and Web of Science.Upon in vitro studies, more than 100 triazole-containing heterocycles have been predicted as active compounds against the pathogen responsible for the American trypanosomiasis. However, less is known about their in vivo activity in animal models and their clinical studies in humans. Moreover, the pharmacokinetic studies of these bioactive compounds are still pending. Despite the variety of mechanisms of action attributed to most of these molecules, the exact mechanism involved is still controversial. Thus, in vivo experiments, followed by pharmacokinetics, and the mechanism of action of the most active compounds, should be the subject of future investigation.All in all, recent studies have demonstrated the importance of triazole-containing heterocycles in search of potential candidates for drug development against Chagas disease. Nonetheless, the use of new catalysts and chemical transformations is expected to provide avenues for the synthesis of unexplored triazole derivatives, leading to the development of triazole-containing compounds with new properties and trypanocidal activity.

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.

Self-immolative drug delivery system is one of the delivery systems, which have drawn attention, in recent research, highlighting the improvement they generate in drug selectivity and efficacy. Self-immolative linkers, or spacers, are covalent groups, which have the role of cleavaging two bonds between a protector group and a drug, in the case of drug delivery systems, after a stimuli.The cascade of reactions allows to control the release of the drug. The choice of the adequate self-immolative linker is essential and depend on many variables and goals as well. Many approaches can be explored when designing a system adequate for achieving these goals, especially prodrugs. Some of the most used stimuli-responses for self-immolative drugs - enzyme triggers, chemical triggers, as pH, redox system, 1,4-, 1,6-, 1,8-eliminations, photodegradable triggers, multiple triggers, among others - are described in this ten-year review, along with their application as theranostic agents. We intend that the examples presented in this review inspire researchers working on drug delivery systems to further explore their application.

This chapter introduces the recent advances in the antituberculosis properties of natural and synthetic flavonoids, covering from the inception of the database till 2018. It explains the potential of natural and synthetic flavonoids to treat tuberculosis. By the end of the chapter, reports that deal with the antitubercular activity of flavonoids are explained. The emphasis will be placed on isolated flavonoids, plant parts and species from which the flavonoid compounds were identified together with the relevant antimycobacterial significance. The synthetic studies of flavonoids and their antituberculosis activity will be included. A critical assessment of the reported information will be discussed.

Multi-walled carbon nanotubes (MWCNTs) have structures characterized by remarkable mechanical and electronic properties. However, their applications can be hindered because of their hydrophobic nature, lack of homogeneity due to impurities, and their variable sizes. Thus, MWCNT was treated by acidic oxidation (H2SO4 3:1 HNO3), seeking out to evaluate the influence of this functionalization on the electrochemical reduction behavior of nitrofurazone applying cyclic voltammetry, the glassy carbon surface having been modified as working electrode. The MWCNT functionalization was characterized by using scanning electron microscopy, infrared and Raman spectroscopies, thermogravimetric analysis, and potentiometric titration. Differences between non-functionalized and functionalized MWCNT were observed, suggesting that carboxylic groups were introduced in the carbon nanotube walls. Moreover, the glassy carbon surface modification was also studied concerning the dispersing agents for functionalized MWCNT. Several solvents of different natures, hydrophilic and lipophilic, were evaluated. The best dispersion associated with electrochemical response of nitrofurazone was obtained with 1,3-dioxolane as dispersing agent, which presented higher affinity with MWCNT than the other solvents. The electrochemical response of the glassy carbon electrode modified with MWCNT was evaluated by nitrofurazone voltammetric behavior with emphasis on the $$ \mathrm{R}-\mathrm{N}{\mathrm{O}}_2/\mathrm{R}-\mathrm{N}{\mathrm{O}}_2^{\cdotp -} $$ couple generation and its kinetic stability.

In the preceding two chapters in Section I, different strategies used to characterize the properties and performance of a drug, which can be either a free drug or a drug that has been loaded into a carrier, have been discussed. From Section II onward, selected strategies to enhance systemic drug delivery will be presented. As the first chapter in this section, we will introduce the concept of prodrug design. In fact, prodrugs have been very important to solve many problems with leads and drugs. The optimization of leads can overcome the “valley of death,” allowing the drug candidate to reach clinical phases. On the other hand, drugs can be optimized even though they have been launched in the therapeutics, improving their usage and patient adherence. Pharmaceutical, pharmacokinetics, and, indirectly, pharmacodynamic problems of leads and drugs can be managed by prodrug design. In this chapter, we will present some classical and recent examples related to bioavailability, prolonged action, reduction of toxicity and, mainly, selectivity of action, and will also introduce some of the drugs approved by FDA to illustrate the use of prodrug design in reality.

As doenças cardiovasculares são as principais causas de morte no Brasil e no mundo e constituem problema de saúde médico-social, de grande impacto econômico. As alterações no perfil lipídico e hematológico são fundamentais na formação da aterosclerose, considerando que o LDL (do inglês Low-Density Lipoprotein) e a agregação plaquetária estão envolvidos na formação dos trombos e, consequentemente, em eventos vaso-oclusivos. Entre os fármacos utilizados, encontram-se as estatinas. A rosuvastatina, um dos fármacos utilizados, é inibidora da hidroximetilglutaril coenzima A (HMG CoA) redutase e possui melhor perfil farmacodinâmico entre as estatinas, com maior potência e seletividade. O ácido acetilsalicílico, anti-inflamatório não-esteroide com atividade antiplaquetária mais difundido na terapia, é utilizado, por esse efeito, em associação com estatinas. Fatores limitantes para o uso da rosuvastatina e o ácido acetilsalicílico são: a baixa permeabilidade da rosuvastatina cálcica, e consequente baixa biodisponibilidade (biodisponibilidade absoluta 20%), e tempo de meia-vida do ácido acetilsalicílico de 6-7 h, o que leva à necessidade de elevadas doses e maior frequência de administração de ambos os fármacos. Visto que a associação das estatinas e do ácido acetilsalicílico promove melhor eficácia na prevenção e tratamento de doenças cardiovasculares, o objetivo foi aumentar a solubilidade da estatina e, consequentemente, a sua biodisponibilidade, e a meia-vida do ácido acetilsalicílico, juntamente com a diminuição da toxicidade desse último.. Por outro lado, considerando-se a importância dos dendrímeros como transportadores de fármacos na latenciação, propôs-se o planejamento e a síntese de pró-fármacos dendriméricos, potencialmente cardiovasculares, derivados da associação de rosuvastatina e ácido acetilsalicílico, utilizando etilenoglicol e pentaeritritol como núcleos e ácido L(-)-málico, ácido 2,2-bis(hidroximetil)propiônico e etilenoglicol, como espaçantes.. Obtiveram-se dois pró-fármacos, que se constituem em dendrons como parte dos dendrímeros planejados. O primeiro foi sintetizado pelo método convergente em duplo estágio e faz parte do bloco da camada externa do dendrímero I e o segundo, pela abordagem convergente clássica, sendo este o dendron do dendrímero II. Parte limitante na obtenção desses dendrímeros, além das etapas de purificação, são as etapas de desproteção. Cardiovascular diseases have been the main causes of death in Brazil and in the world and are medical-social health problem with great economic impact. Alterations in the lipid hematological profiles are essentials in atherosclerosis, as LDL (Low-Density Lipoprotein) and the platelet aggregation are involved in the thrombus formation and, consequently, in occlusive vessel events. Among the drugs used to overcome those alterations are the statins. Rosuvastatin, one of the drugs used, is a hydroxymethylglutaryl coenzine A (HMG CoA) reductase inhibitor and it has the best pharmacodynamics profile among the statins, with higher potency and selectivity. Acetylsalicylic acid, a non-steroid anti-inflammatory agent with antiplatelet activity most disseminated in therapeutics, has been used in combination with statins due to this effect. Limited factors for the use of rosuvastatin and acetylsalycilic acid are the low permeability of the former, and consequently a low bioavailability (20% absolute bioavailability), and a 6 to 7 h half-life time of acetylsalycilic acid. Those factors lead to the need of high doses and higher frequency of administration of both drugs. Considering the combination of statins and acetylsalycilic acid promotes a better efficacy in either prevention or in the treatment of cardiovascular diseases, the objective of this work was to increase the rosuvastatin solubility and, consequently, its bioavailability, and the half-life time of acetylsalicylic acid, together with the decrease of its toxicity. On the other hand, considering the importance of dendrimers as drug carriers in prodrug approach, the design and synthesis of potentially cardiovascular dendrimer prodrugs derived from de combination of rosuvastatin and acetylsalicylic acid was proposed. With this goal, ethylene glycol and pentaerytritol were used as core and L(-)malic acid, 2,2-bis(hydroxymethyl)propionic acid and ethylene glycol were used as spacer groups. Two prodrug dendrons were obtained as part of the designed dendrimers. The first one was synthesized by two-step convergent method and it is part of the external layer block of dendrimer I. The second was obtained through classical convergent synthesis as the dendron of dendrimer II. The purification and deprotection steps showed to be the greatest obstacles for obtaining the proposed compounds.

Dendrimers are versatile hyperbranched molecules, which have deserved attention especially for their potential in many applications, including biological. Peptide dendrimers comprise interesting classes of dendrimers, and their use has been emphasized as a drug/bioactive compound delivery system, mostly in the antineoplastic area. The bioactive molecules can be covalently linked or entrapped inside the peptide derivative. Self-assembled nanocarriers are a recent trend in the design of potential delivery systems, and pH-sensitive carriers, one of their methods, have been designed to control their systems. In addition, the use of targeting peptides or other specific groups that direct the drug/bioactive compounds to specific organs is an important trend in the search for better drug delivery systems. Recent examples have been given in the literature, showing that gene delivery as another important peptide dendrimer application. It is worth emphasizing that some peptide dendrimers show activity per se, without bioactive compounds. Immune compounds and vaccines are presented herein, as well as uses of other peptide dendrimers are briefly discussed in this review, which encompasses around 10 years of work.

Chagas disease is a very important neglected disease and millions of people live in endemic areas at the risk of acquiring the infection. Due to scarce and ineffective current chemotherapy, the introduction of new drugs on therapeutics is highly necessary. Bioisoster hybrids derivatives were previously designed, synthesized, and assayed in terms of trypanocidal activity and permeability. Structure activity-relationships were performed with a set of N-acylhydrazone and furoxan derivatives aiming at identifying if the enzyme cruzain might be the target of the system. In addition, lowest unoccupied molecular orbital analysis and docking studies of the two most promising compounds were carried out with the purpose of elucidating the key properties and interactions between the ligands and cruzain. The analysis of cruzain inhibition tests showed that the position of the nitro group is important for the compounds inhibitory activity. The results lead to the conclusion that cruzain may not be the only target. This hypothesis was advanced because the most active in Trypanosoma cruzi, compound 6, is not the most effective in cruzain tests. Notwithstanding, this compound was considered the most promising hit for further in vivo studies, as it did not show toxicity in cycle cell tests.

Dendrimers are nanoscopic compounds, which are monodispersed, and they are generally considered as homogeneous. PAMAM (polyamidoamine) was introduced in 1985, by Donald A. Tomalia, as a new class of polymers, named ‘starburst polymers’. This important contribution of Professor Tomalia opened a new research field involving nanotechnological approaches. From then on, many groups have been using PAMAM for diverse applications in many areas, including biomedical applications. The possibility of either linking drugs and bioactive compounds, or entrapping them into the dendrimer frame can improve many relevant biological properties, such as bioavailability, solubility, and selectivity. Directing groups to reach selective delivery in a specific organ is one of the advanced applications of PAMAM. In this review, structural and safety aspects of PAMAM and its derivatives are discussed, and some relevant applications are briefly presented. Emphasis has been given to gene delivery and targeting drugs, as advanced delivery systems using PAMAM and an incentive for its use on neglected diseases are briefly mentioned.