1,3-Thiazole derivatives as privileged structures for anti-Trypanosoma cruzi activity: Rational design, synthesis, in silico and in vitro studies.

Chagas disease is a deadly and centenary neglected disease that is recently surging as a potential global threat. Approximately 30% of infected individuals develop chronic Chagas cardiomyopathy and current treatment with the reference benznidazole (BZN) is ineffective for this stage. We presently report the structural planning, synthesis, characterization, molecular docking prediction, cytotoxicity, in vitro bioactivity and mechanistic studies on the anti-T. cruzi activity of a series of 16 novel 1,3-thiazoles (2-17) derived from thiosemicarbazones (1a, 1b) in a two-step and reproducible Hantzsch-based synthesis approach. The anti-T. cruzi activity was evaluated in vitro against the epimastigote, amastigote and trypomastigote forms of the parasite. In the bioactivity assays, all thiazoles were more potent than BZN against epimastigotes. We found that the compounds presented an overall increased anti-tripomastigote selectivity (Cpd 8 was 24-fold more selective) than BZN, and they mostly presented anti-amastigote activity at very low doses (from 3.65 µM, cpd 15). Mechanistic studies on cell death suggested that the series of 1,3-thiazole compounds herein reported cause parasite cell death through apoptosis, but without compromising the mitochondrial membrane potential. In silico prediction of physicochemical properties and pharmacokinetic parameters showed promising drug-like results, being all the reported compounds in compliance with Lipinski and Veber rules. In summary, our work contributes towards a more rational design of potent and selective antitripanosomal drugs, using affordable methodology to yield industrially viable drug candidates.

Thiazole, isatin and phthalimide derivatives tested in vivo against cancer models: a literature review of the last six years.

BACKGROUND: Cancer is a disease characterized by the abnormal multiplication of cells and is the second leading cause of death in the world. The search for new effective and safe anticancer compounds is ongoing due to factors such as low selectivity, high toxicity, and multidrug resistance. Thus, heterocyclic compounds derived from isatin, thiazole and phthalimide that have achieved promising in vitro anticancer activity have been tested in vivo and in clinical trials. OBJECTIVE: This review focused on the compilation of promising data from thiazole, isatin, and phthalimide derivatives, reported in the literature between 2015 and 2022, with in vivo anticancer activity and clinical trials. METHOD: A bibliographic search was carried out in the PUBMED, MEDLINE, ELSEVIER, and CAPES PERIODIC databases, selecting relevant works for each pharmacophoric group with in vivo antitumor activity in the last 6 years. RESULTS: In our study, 68 articles that fit the scope were selected and critically analyzed. These articles were organized considering the type of antitumor activity and their year of publication. Some compounds reported here demonstrated potent antitumor activity against several tumor types. CONCLUSION: This review allowed us to highlight works that reported promising structures for the treatment of various cancer types and also demonstrated that the privileged structures thiazole, isatin and phthalimide are important in the design of new syntheses and molecular optimization of compounds with antitumor activity.

Identification of Novel Zika Virus Inhibitors: A Screening using Thiosemicarbazones and Thiazoles Templates.

BACKGROUND: Zika virus (ZIKV) remains an important cause of congenital infection, fetal microcephaly, and Guillain-Barré syndrome in the population. In 2016, WHO declared a cluster of microcephaly cases and other neurological disorders reported as a global public health emergency in Brazil. There is still no specific treatment for Zika virus fever, only palliative care. Therefore, there is a need for new therapies against this disease. According to the literature, thiosemicarbazone, phthalimide and thiazole are privileged structures with several biological activities, including antiviral activity against various viruses. OBJECTIVE: Based on this, this work presents an antiviral screening using previously synthesized compounds derived from thiosemicarbazone, phthalimide, and thiazole as new hits active against ZIKV. METHODS: After synthesis and characterization, all compounds were submitted to Cytotoxicity by MTT and Antiviral activity against ZIKV assays. RESULTS: Compounds 63, 64, 65, and 73 exhibited major reductions in the ZIKV title from this evaluation. Compounds 63 (99.74%), 64 (99.77%), 65 (99.92%), and 73 (99.21%) showed a higher inhibition than the standard 6MMPr (98.74%) at the CC20 dose. These results revealed new chemical entities with anti-ZIKV activity. CONCLUSION: These derivatives are promising candidates for further assays. In addition, the current approach brings a new privileged scaffolding, which may drive future drug discovery for ZIKV.

Outlining the Molecules Tested In Vivo for Chagas Disease, Malaria, and Schistosomiasis Over the Last Six Years - A Literature Review Focused on New Synthetic Drug Identities and Repurposing Strategies.

BACKGROUND: COVID-19 disrupted NTD programs in 60% of countries, impairing public health goals. Thus, boosting NTD's research knowledge is demanding, and in vivo screening of candidates allows for the prospect of promising options based on their overall profile. OBJECTIVE: In this work, we highlighted the relevant research done between 2015-2021 in the fields of synthetic and repurposed drugs that were tested in vivo for Chagas disease, malaria, and schistosomiasis. METHODS: MEDLINE, PUBMED, CAPES PERIODIC, and ELSEVIER databases were used for a comprehensive literature review of the last 6 years of research on each area/disease. RESULTS: Overall, research focused on nitro heterocyclic, aromatic nitro, nucleoside, and metal-based scaffolds for analogue-based drug generation. Repurposing was widely assessed, mainly with heterocyclic drugs, their analogues, and in combinations with current treatments. Several drug targets were aimed for Chagas treatment, specific ones such as iron superoxide dismutase, and more general ones, such as mitochondrial dysfunction. For malaria, hemozoin is still popular, and for schistosomiasis, more general structural damage and/or reproduction impairment were aimed at in vitro analysis of the mechanism of action. CONCLUSION: Latest in vivo results outlined trends for each disease - for Chagas Disease, heterocyclics as thiazoles were successfully explored; for Malaria, quinoline derivatives are still relevant, and for schistosomiasis, repurposed drugs from different classes outstood in comparison to synthetic compounds. This study uprises the continuous development of Chagas disease, malaria, and schistosomiasis drugs, providing researchers with tools and information to address such unmet therapeutic needs.

The prophylactic and anti-fibrotic activity of phthalimido-thiazole derivatives in schistosomiasis mansoni.

Schistosomiasis mansoni is considered a serious public health problem. As praziquantel is the only drug recommended by the World Health Organization for the treatment and control of schistosomiasis, the development of new drugs is of great significance. In this work, we present the antischistosomal activity of a small set of phthalimido-thiazole derivatives against Schistosoma mansoni. The effects of those derivatives on the viability of larvae juveniles and adult parasites, production and development of eggs, mortality of schistosomules in vitro by counting worms, and stages of eggs of infected animals in acute and chronic phases were evaluated, resulting in the identification of new multistage antischistosomal compounds. Additionally, a study of liver fibrogenesis was released. The phthalimido-thiazole derivatives, compounds 2b-d, 2h-j, had shown activity on schistosomules, achieving 100% mortality even at 5 mg/mL, in the first 24 h. In the chronic phase of schistosomiasis infection, compound 2i promoted a reduction in the number of immature eggs, an increase in the number of non-viable parasite eggs, a reduction in the average number of eggs in the liver and intestine, decrease in the levels of hydroxyproline in the liver, and a reduction in the areas of hepatic fibrosis. This compound also promoted an increase of IL-10 and a reduction in the level of TNF-α in the liver. Accordingly, the phthalimide-thiazole scaffold is a new starting point for the development of multistage compounds that affect S. mansoni viability, egg formation, and production.

Immobilization of fibrinolytic protease from Mucor subtilissimus UCP 1262 in magnetic nanoparticles.

This work reports the immobilization of a fibrinolytic protease (FP) from Mucor subtilissimus UCP 1262 on Fe3O4 magnetic nanoparticles (MNPs) produced by precipitation of FeCl3·6H2O and FeCl2·4H2O, coated with polyaniline and activated with glutaraldehyde. The FP was obtained by solid state fermentation, precipitated with 40-60% ammonium sulfate, and purified by DEAE-Sephadex A50 ion exchange chromatography. The FP immobilization procedure allowed for an enzyme retention of 52.13%. The fibrinolytic protease immobilized on magnetic nanoparticles (MNPs/FP) maintained more than 60% of activity at a temperature of 40 to 60 °C and at pH 7 to 10, when compared to the non-immobilized enzyme. MNPs and MNPs/FP did not show any cytotoxicity against HEK-293 and J774A.1 cells. MNPs/FP was not hemolytic and reduced the hemolysis induced by MNPs from 2.07% to 1.37%. Thrombus degradation by MNPs/FP demonstrated that the immobilization process guaranteed the thrombolytic activity of the enzyme. MNPs/FP showed a total degradation of the γ chain of human fibrinogen within 90 min. These results suggest that MNPs/FP may be used as an alternative strategy to treat cardiovascular diseases with a targeted release through an external magnetic field.

PA-Int5: An isatin-thiosemicarbazone derivative that exhibits anti-nociceptive and anti-inflammatory effects in Swiss mice.

Pain and inflammation are symptoms of various diseases, and they can be modulated by different pathways, thus highlighting the importance of investigating the therapeutic effects of novel compounds. Previous studies have shown that isatin-thiosemicarbazone exhibits antitumor, antifungal antibacterial and other biological properties. Based on the wide range of biological effects of these compounds, the aim of the present study was to investigate the central nervous system (CNS) performance, and the anti-nociceptive and anti-inflammatory activity of (Z)-2-(5-nitro-2-oxoindolin-3-ilidene)-N-hydroazinecarbothioamide (PA-Int5) in treated mice. Three doses of PA-Int5 were tested orally (1.0, 2.5 and 5.0 mg/kg) in the nociceptive and inflammatory animal models. Additionally, the potential sedative effects of PA-Int5 (5 mg/kg, oral gavage) were investigated using an open field and rotarod tests, to exclude any possible unspecific effects of the nociceptive assays. Anti-nociceptive activity was assessed using the acetic acid-induced abdominal contortion and formalin tests, whereas anti-inflammatory activity was assessed using a carrageenan-induced paw edema and zymosan-induced air-pouch models. PA-Int5 (5 mg/kg) induced anti-nociceptive activity in the abdominal contortion model. In the formalin test, PA-Int5 (at 2.5 and 5 mg/kg) reduced nociception in the second phase. At the higher dose tested, PA-Int5 did not affect spontaneous locomotion or motor coordination. The data revealed that at all doses tested, the compound significantly reduced paw edema following carrageenan administration. In the zymosan-induced air-pouch model, PA-Int5 potently inhibited leukocyte migration and protein levels at the site of inflammation. When combined, the results revealed, for the first time, that PA-Int5 exhibited anti-nociceptive and anti-inflammatory activities, and highlights its potential, as well that of other derivatives, as novel candidates for pain relief.

Structural improvement of new thiazolyl-isatin derivatives produces potent and selective trypanocidal and leishmanicidal compounds.

Neglected diseases are a group of transmissible diseases that occur mostly in countries in tropical climates. Among this group, Chagas disease and leishmaniasis stand out, considered threats to global health. Treatment for these diseases is limited. Therefore, there is a need for new therapies against these diseases. In this sense, our proposal consisted of developing two series of compounds, using a molecular hybridization of the heterocyclic isatin and thiazole. The isatin and thiazole ring are important scaffold for several biological disorders, including antiparasitic ones. Herein, thiazolyl-isatin has been synthesized from respective thiosemicarbazone or phenyl-thiosemicarbazone, being some of these new thiazolyl-isatin toxic for trypomastigotes without affecting macrophages viability. From this series, compounds 2e (IC50 = 4.43 µM), 2j (IC50 = 2.05 µM), 2l (IC50 = 4.12 µM) and 2m (1.72 µM) showed the best anti-T. cruzi activity for trypomastigote form presenting a selectivity index higher than Benznidazole (BZN). Compounds 2j, 2l and 2m were able to induce a significantly labelling compatible with necrosis in trypomastigotes. Analysis by scanning electron microscopy showed that T. cruzi trypomastigote cells treated with the compound 2m from IC50 concentrations, promoted changes in the shape, flagella and surface of body causing of the parasite dead. Concerning leishmanicidal evaluation against L. amazonensis and L. infantum, compounds 2l (IC50 = 7.36 and 7.97 µM, respectively) and 2m (6.17 and 6.04 µM, respectively) showed the best activity for promastigote form, besides showed a higher selectivity than Miltefosine. Thus, compounds 2l and 2m showed dual in vitro trypanosomicidal and leishmanicidal activities. A structural activity relationship study showed that thiazolyl-isatin derivatives from phenyl-thiosemicarbazone (2a-m) were, in general, more active than thiazolyl-isatin derivatives from thiosemicarbazone (1a-g). Crystallography studies revealed a different configuration between series 1a-g and 2a-m. The configuration and spatial arrangement divergent between the two sub-series could explain the improved biological activity profile of 2a-m sub-series.

Structural design, synthesis and anti-Trypanosoma cruzi profile of the second generation of 4-thiazolidinones chlorine derivatives.

Chagas disease causes more deaths in the Americas than any other parasitic disease. Initially confined to the American continent, it is increasingly becoming a global health problem. In fact, it is considered to be an "exotic" disease in Europe, being virtually undiagnosed. Benznidazole, the only drug approved for treatment, effectively treats acute-stage Chagas disease, but its effectiveness for treating indeterminate and chronic stages remains uncertain. Previously, our research group demonstrated that 4-thiazolidinones presented anti-T. cruzi activity including in the in vivo assays in mice, making this fragment appealing for drug development. The present work reports the synthesis and anti-T. cruzi activities of a novel series of 4-thiazolidinones derivatives that resulted in an increased anti-T. cruzi activity in comparison to thiosemicarbazones intermediates. Compounds 2c, 2e, and 3a showed potent inhibition of the trypomastigote form of the parasite at low cytotoxicity concentrations in mouse splenocytes. Besides, all the 2c, 2e, and 3a tested concentrations showed no cytotoxic activity on macrophages cell viability. When macrophages were submitted to T. cruzi infection and treated with 2c and 3a, compounds reduced the release of trypomastigote forms. Results also showed that the increased trypanocidal activity induced by 2c and 3a is independent of nitric oxide release. Flow cytometry assay showed that compound 2e was able to induce necrosis and apoptosis in trypomastigotes. Parasites treated with the compounds 2e, 3a, and 3c presented flagellum shortening, retraction and curvature of the parasite body, and extravasation of the internal content. Together, these data revealed a novel series of 4-thiazolidinones fragment-based compounds with potential effects against T. cruzi and lead-like characteristics.

Study of acute oral toxicity of the thiazole derivative N-(1-methyl-2-methyl-pyridine)-N-(p-bromophenylthiazol-2-yl)-hydrazine in a Syrian hamster.

The thiazole derivative N-1-methyl-2-methyl-pyridine)-N-(p-bromophenylthiazol-2-yl)-hydrazine was used to evaluate the acute oral toxicity in Syrian hamsters. The concentration of the doses (300 mg/kg and 2000 mg/kg) were based on the "Class Acute Toxicity Method" displayed in the OECD-423 guide. In addition, renal and liver biochemical tests were performed, as well as histopathological analysis. Our results showed that the compound's lethal dose (LD50) was 1000 mg/kg and classified as category 4 according to the criteria adopted in the experiment's protocol. Biochemical analysis of the liver function's parameters showed that the LD50 values in all animals were higher than the reference values. However, the analyze of the kidney injury parameters showed an increase in the urea's dosage but a decrease in the albumin's dosage in all animals when compared to the reference values. Kidney biochemical analysis also showed that creatinine's level was only higher than the reference values in one animal. Massive damages in the liver were observed, such as hypertrophy and hyperplasia of the hepatocyte, coagulation necrosis, the presence of mononuclear cells in the sinusoidal capillaries, steatosis, cholestasis, and congestion of sinusoidal capillaries and central-lobular veins. The animals presented renal injuries related to congestion of glomerular and interstitial capillaries, nephrosis of contorted proximal and distal tubules and congestion in the medullary region. In conclusion, the thiazole derivative was well tolerated although it caused acute liver and kidney damages. Therefore, these results showed the need of further investigation of this compound in vivo to evaluate the potential therapeutic effects with chronic models.

An Overview of the Compounds Tested In Vivo for Leishmania spp. of the Last 5 Years.

BACKGROUND: Leishmaniasis, a still important public health problem, exhibits environmental risk factors such as massive migrations, urbanization, and deforestation. WHO research for Leishmaniasis is mainly focused on the development of new tools, such as diagnostic tests, drugs, and vaccines. During the drug development strategy, only a few compounds were promising and call for further study after the in vitro and in vivo preclinical tests. OBJECTIVE: In this review, our group aimed to highlight the utmost research done during 2014 to 2019 in the fields of natural and synthetic compounds, as well as repurposed drugs and new formulations tested in vivo for Leishmania spp. METHOD: Based on the literature search, we used the databases MEDLINE, PUBMED, CAPES PERIODIC and ELSEVIER to delineate an interval of the last 5 years of research on each field. RESULTS: Among the natural compounds tested, allicin and a fraction of potato tuber extract showed the most promising antileishmanial activity. Concerning synthetic compounds, quinolines, bornyl ester, thymol, benzoxaborole and nitroimidazole derivatives exhibited encouraging results. Moreover, repositioned alternatives involved combinations with known drugs and monotherapy protocols as well. In these years, new formulations were widely assessed as drug delivery systems, such as nanoparticles, micelles and liposomes in polymer conjugations. CONCLUSION: Drug repurposing and new formulations of already-known drugs are worthwhile approaches to promptly introduce new treatment schemes to Leishmaniasis. Nevertheless, the interest in new synthetic compounds and new formulations brings light to new treatment proposals and are notable lines of research.

Dual Parasiticidal Activities of Phthalimides: Synthesis and Biological Profile against Trypanosoma cruzi and Plasmodium falciparum.

Chagas disease and malaria are two neglected tropical diseases (NTDs) that prevail in tropical and subtropical regions in 149 countries. Chagas is also present in Europe, the US and Australia due to immigration of asymptomatic infected individuals. In the absence of an effective vaccine, the control of both diseases relies on chemotherapy. However, the emergence of parasite drug resistance is rendering currently available drugs obsolete. Hence, it is crucial to develop new molecules. Phthalimides, thiosemicarbazones, and 1,3-thiazoles have been used as scaffolds to obtain antiplasmodial and anti-Trypanosoma cruzi agents. Herein we present the synthesis of 24 phthalimido-thiosemicarbazones (3 a-x) and 14 phthalimido-thiazoles (4 a-n) and the corresponding biological activity against T. cruzi, Plasmodium falciparum, and cytotoxicity against mammalian cell lines. Some of these compounds showed potent inhibition of T. cruzi at low cytotoxic concentrations in RAW 264.7 cells. The most active compounds, 3 t (IC50 =3.60 µM), 3 h (IC50 =3.75 µM), and 4 j (IC50 =4.48 µM), were more active than the control drug benznidazole (IC50 =14.6 µM). Overall, the phthalimido-thiosemicarbazone derivatives were more potent than phthalimido-thiazole derivatives against T. cruzi. Flow cytometry assay data showed that compound 4 j was able to induce necrosis and apoptosis in trypomastigotes. Analysis by scanning electron microscopy showed that T. cruzi trypomastigote cells treated with compounds 3 h, 3 t, and 4 j at IC50 concentrations promoted changes in the shape, flagella, and surface of the parasite body similar to those observed in benznidazole-treated cells. The compounds with the highest antimalarial activity were the phthalimido-thiazoles 4 l (IC50 =1.2 µM), 4 m (IC50 =1.7 µM), and 4 n (IC50 =2.4 µM). Together, these data revealed that phthalimido derivatives possess a dual antiparasitic profile with potential effects against T. cruzi and lead-like characteristics.

Effect of acute exposure in swiss mice (Mus musculus) to a fibrinolytic protease produced by Mucor subtilissimus UCP 1262: An histomorphometric, genotoxic and cytological approach.

The fibrinolytic enzyme produced by Mucor subtilissimus UCP 1262 was obtained by solid fermentation and purified by ion exchange chromatography using DEAE-Sephadex A50. The enzyme toxicity was evaluated using mammalian cell lineages: HEK-293, J774.A1, Sarcoma-180 and PBMCs which appeared to be viable at a level of 80%. The biochemical parameters of the mice treated with an acute dose of enzyme (2000 mg/mL) identified alterations of AST and ALT and the histomorphometric analysis of the liver showed a loss of endothelial cells (P < 0.001). However, these changes are considered minimal to affirm that there was a significant degree of hepatotoxicity. The comet assay and the micronucleus test did not identify damage in the DNA of the erythrocytes of the animals treated. The protease did not degrade the Aα and Bß chains of human and bovine fibrinogens, thus indicating that it does not act as anticoagulant, but rather as a fibrinolytic agent. The assay performed to assess blood biocompatibility shows that at dose of 0.3-5 mg/mL the hemolytic grade is considered insignificant. Moreover, the enzyme did not prolong bleeding time in mice when dosed with 1 mg/kg. These results indicate that this enzyme produced is a potential competitor for developing novel antithrombotic drugs.

Structural design, synthesis and pharmacological evaluation of 4-thiazolidinones against Trypanosoma cruzi.

Chagas disease is an infection caused by protozoan Trypanosoma cruzi, which affects approximately 8-10million people worldwide. Benznidazole is the only drug approved for treatment during the acute and asymptomatic chronic phases of Chagas disease; however, it has poor efficacy during the symptomatic chronic phase. Therefore, the development of new pharmaceuticals is needed. Here, we employed the bioisosterism to modify a potent antiparasitic and cruzain-inhibitor aryl thiosemicarbazone (4) into 4-thiazolidinones (7-21). Compounds (7-21) were prepared by using a straightforward synthesis and enabled good to excellent yields. As a chemical elucidation tool, X-ray diffraction of compound (10) revealed the geometry and conformation of this class compounds. The screening against cruzain showed that 4-thiazolidinones were less active than thiosemicarbazone (4). However, the antiparasitic activity in Y strain trypomastigotes and host cell cytotoxicity in J774 macrophages revealed that compounds (10 and 18-21) are stronger and more selective antiparasitic agents than thiosemicarbazone (4). Specifically, compounds (18-20), which carry a phenyl at position N3 of heterocyclic ring, were the most active ones, suggesting that this is a structural determinant for activity. In infected macrophages, compounds (18-20) reduced intracellular amastigotes, whereas Benznidazole did not. In T. cruzi-infected mice treated orally with 100mg/kg of compound (20), a decreased of parasitemia was observed. In conclusion, we demonstrated that the conversation of thiosemicarbazones into 4-thiazolidinones retains pharmacological property while enhances selectivity.

A study of photostability and compatibility of the anti-chagas drug Benznidazole with pharmaceutics excipients.

UNLABELLED: Abstract Context: Benznidazole (BNZ) is an antiparasitic with trypanocidal properties for the etiological treatment of Chagas disease since 1973. Monitoring the stability of this drug is one of the most effective methods of assessment, forecasting and prevention of problems related to quality product. OBJECTIVE: To investigate the direct and indirect photodegradation of BNZ and to evaluate the interference of the excipients used in the forms dosage solid as well as to shed light on the chemical structure of the degradation products obtained. MATERIALS AND METHODS: To perform this work we adopted the "ICH Harmonised Tripartite Guideline: Photostability Testing of New Drug Substances and Products Q1B" (Guideline Q1B). We used benzonidazole (BNZ) (N-benzil-2-(2-nitroimidazol-1-il) acetamide) (LAFEPE®, Recife, Brazil) and various excipients; beyond high-performance liquid chromatography (HPLC), differential scanning calorimetry (DSC), infrared spectroscopy (IR) and mass spectrometry/mass spectrometry (MS/MS). The indirect photodegradation of BNZ was carried out using physical mixtures with 13 pharmaceutical excipients commonly used in the preparation of solid dosage forms. RESULTS: HPLC and MS/MS techniques were selected for the identification of two photoproducts (PPs) and photoreactions found in direct and indirect tests with the microcrystalline cellulose, considered a critical excipient. DISCUSSION: Despite variations in the infrared spectrometry, differential scanning calorimetry and differential thermogravimetry curves, these techniques are not conclusive since the study of photodegradation of the drug caused decay of 30%, according to the ICH. CONCLUSIONS: The results show that BNZ only undergoes direct photodegradation, since no new PPs were found for a combination of the drug and excipients.

Synthesis of 4'-(2-ferrocenyl)-2,2':6'2''-terpyridine: characterization and antiprotozoal activity of Mn(II), Co(II), Ni(II), Cu(II) and Zn(II) complexes.

A terpyridine ligand Fctpy was reacted with divalent metals (Cu, Co, Mn, Ni and Zn), yielding five complexes of general formula [Metal(Fctpy)2][PF6]2. The structure of Fctpy was determined by single crystal X-ray diffraction studies. The complexes characterized using various spectroscopic techniques suggested an octahedral geometry around the central metal ion. These complexes were screened for their antiamoebic, trypanocidal and antimalarial activities. It was found that, complexes 2 and 3 showed better IC50 values than metronidazole against HM1:IMSS strain of Entamoeba histolytica. A substantial parasitic inhibition was not observed for the trypanocidal activity. However, for the erythrocytic stage of W2 strain of Plasmodium falciparum, the complexes inhibited ß-hematin formation. At the concentration of 10 µg/mL, these complexes did not display toxicity.

Synthesis and antitumour evaluation of peptidyl-like derivatives containing the 1,3-benzodioxole system.

In the scope of a research program aiming at the synthesis and pharmacological evaluation of novel possible antitumour prototype compounds, we described in this paper the synthesis of peptidyl-like derivatives containing the 1,3-benzodioxole system. The proliferation inhibitors tested against tumour cell lines identified the derivatives tyrosine (4f) and lysine (4 g) as the most active among them, presenting IC(50) values in micromolar range and are more active than Safrole. For the study on the embryonic development, Safrole did not show any selectivity in this latter assay, which indicates that Safrole acts as a 'cell cycle-nonspecific' inhibitory agent. However, compound 4f presented a fair antimitotic effect, mainly on third cleavage and blastulae stages (38% and 1.7% of normal development, at 10 microg/mL), suggesting a time-dependent activity and a 'cell cycle-specific' agent action. Neither derivatives revealed hemolytic action in assay with mouse erythrocytes.

Synthesis of aminoacyl thiaolidones as potential antitumour agents.

In the scope of a research program aiming to perform the synthesis and pharmacological evaluation of novel possible antitumour prototype compounds, we report in this paper the synthesis of new peptidyl derivatives from 4-thiazolidone nucleus. The synthesis reactions have been performed based in peptide synthesis as strategies. The characterisation of this new class of compounds was performed with IR and (1)H-NMR spectroscopy. In vivo, antitumour activity tests showed that some of these compounds were able to inhibit significantly sarcoma S-180 tumour growth in mice, revealing itself as a new potential class of drugs in cancer chemotherapy.