Study of nitrogen heterocycles as DNA/HSA binder, topoisomerase inhibitors and toxicological safety.

Four new nitrogen-containing heterocyclic derivatives (acridine, quinoline, indole, pyridine) were synthesized and their biological properties were evaluated. The compounds showed affinity for DNA and HSA, with CAIC and CAAC displaying higher binding constants (Kb) of 9.54 × 104 and 1.06 × 106, respectively. The fluorescence quenching assay (Ksv) revealed suppression values ranging from 0.34 to 0.64 × 103 M-1 for ethidium bromide (EB) and 0.1 to 0.34 × 103 M-1 for acridine orange (AO). Molecular docking confirmed the competition of the derivatives with intercalation probes at the same binding site. At 10 µM concentrations, the derivatives inhibited topoisomerase IIα activity. In the antiproliferative assays, the compounds demonstrated activity against MCF-7 and T47-D tumor cells and nonhemolytic profile. Regarding toxicity, no acute effects were observed in the embryos. However, some compounds caused enzymatic and cardiac changes, particularly the CAIC, which increased SOD activity and altered heart rate compared to the control. These findings suggest potential antitumor action of the derivatives and indicate that substituting the acridine core with different cores does not interfere with their interaction and topoisomerase inhibition. Further investigations are required to assess possible toxicological effects, including reactive oxygen species generation.

Development and evaluation of the in vitro schistosomicidal activity of solid dispersions based on 2-(-5-bromo-1-H-indole-3-yl-methylene)-N-(naphthalene-1-ylhydrazine-carbothiamide.

Among all the neglected diseases, schistosomiasis is considered the second most important parasitic infection after malaria. Praziquantel is the most widely used drug for this disease, but its exclusive use may result in the development of drug-resistant schistosomiasis. To increase the control of the disease, new drugs have been developed as alternative treatments, among them 2-(-5-bromo-1-h-indole-3-yl-methylene)-N-(naphthalene-1-ylhydrazine-carbothiamide (LQIT/LT-50), which showed promising schistosomicidal activity in nonclinical studies. However, LQIT/LT-50 presents low solubility in water, resulting in reduced bioavailability. To overcome this solubility problem, the present study aimed to develop LQIT/LT-50 solid dispersions for the treatment of schistosomiasis. Solid dispersions were prepared through the solvent method using Soluplus©, polyethylene glycol (PEG) or polyvinylpyrrolidone (PVP K-30) as hydrophilic carriers. The formulations with the best results in the compatibility tests, aqueous solubility and preliminary stability studies have undergone solubility tests and physicochemical characterizations by Fourier-transform infrared spectroscopy (FTIR), x-ray diffractometry (XRD), exploratory differential calorimetry (DSC), thermogravimetry (TG) and Raman spectroscopy. Finally, the schistosomicidal activity was evaluated in vitro. The phycochemical analyzes showed that when using PVP K-30, there was an interaction between the PVP K-30 and LQIT/LT-50, proving the successful development of the solid dispersion. Furthermore, an increase in the solubility of the new system was observed (LQIT/LT-50:PVP K-30) in addition to the improvement in the in vitro shistosomidal activity at 1:4 (w/w) molar ratio (i.e., 20% drug loading) when compared to LQIT/LT-50 alone. The development of the LQIT/LT-50:PVP K-30 1:4 solid dispersion is encouraging for the future development of new pharmaceutical solid formulations, aiming the schistosomicidal treatment.

In silico ADMET prediction, evaluation of cytotoxicity in mouse splenocytes and preliminary evaluation of in vitro antimalarial activity of 4-(4-chlorophenyl)thiazole compounds.

In this work, an in silico study and evaluation of the cytotoxicity of 4-(4-chlorophenyl)thiazole compounds against mouse splenocytes and the chloroquine-sensitive Plasmodium falciparum 3D7 strain are reported. The in silico results showed that the compounds have important pharmacokinetic properties for compounds with potential drug candidates. Regarding cytotoxicity assays against splenocytes, the compounds have low cytotoxicity. In addition, they were able to promote activation of these cells by increasing nitric oxide production without promoting cell death. Finally, they were able to promote cell proliferation. Regarding the in vitro anti-P. falciparum activity assays, it was observed that the compounds were able to inhibit the parasite's growth, presenting IC50 values ​​ranging from 0.79 to greater than 10 µM. These results are promising when compared to chloroquine. Therefore, this study showed that 4-(4-chlorophenyl)thiazole compounds are promising candidates for antimalarials.

Synthesis of 4-(4-chlorophenyl)thiazole compounds: in silico and in vitro evaluations as leishmanicidal and trypanocidal agents.

Neglected tropical diseases are a diverse group of communicable pathologies that mainly prevail in tropical and subtropical regions. Thus, the objective of this work was to evaluate the biological potential of eight 4-(4-chlorophenyl)thiazole compounds. Tests were carried out in silico to evaluate the pharmacokinetic properties, the antioxidant, cytotoxic activities in animal cells and antiparasitic activities were evaluated against the different forms of Leishmania amazonensis and Trypanosoma cruzi in vitro. The in silico study showed that the evaluated compounds showed good oral availability. In a preliminary in vitro study, the compounds showed moderate to low antioxidant activity. Cytotoxicity assays show that the compounds showed moderate to low toxicity. In relation to leishmanicidal activity, the compounds presented IC50 values that ranged from 19.86 to 200 µM for the promastigote form, while for the amastigote forms, IC50 ranged from 101 to more than 200 µM. The compounds showed better results against the forms of T. cruzi with IC50 ranging from 1.67 to 100 µM for the trypomastigote form and 1.96 to values greater than 200 µM for the amastigote form. This study showed that thiazole compounds can be used as future antiparasitic agents.

Synthesis, characterization, antioxidant and antiparasitic activities new naphthyl-thiazole derivatives.

In this work, 13 thiosemicarbazones (1a - m) and 16 thiazoles (2a - p) were obtained, which were properly characterized by spectroscopic and spectrometric techniques. The pharmacokinetic properties obtained in silico revealed that the derivatives are in accordance with the parameters established by lipinski and veber, showing that such compounds have good bioavailability or permeability when administered orally. In assays of antioxidant activity, thiosemicarbazones showed moderate to high antioxidant potential when compared to thiazoles. In addition, they were able to interact with albumin and DNA. Screening assays to assess the toxicity of compounds to mammalian cells revealed that thiosemicarbazones were less toxic when compared to thiazoles. In relation to in vitro antiparasitic activity, thiosemicarbazones and thiazoles showed cytotoxic potential against the parasites Leishmania amazonensis and Trypanosoma cruzi. Among the compounds, 1b, 1j and 2l stood out, showing inhibition potential for the amastigote forms of the two parasites. As for the in vitro antimalarial activity, thiosemicarbazones did not inhibit Plasmodium falciparum growth. In contrast, thiazoles promoted growth inhibition. This study shows in a preliminary way that the synthesized compounds have antiparasitic potential in vitro.

Development of solid dispersions based on 3- (2,6-difluorobenzyl) -5- (5-bromo-1H-indol-3-ylmethylene) thiazolidine-2,4-dione for schistosomicidal treatment.

Schistosomiasis is an endemic disease in Brazil. It is important to broaden the treatment options to control and containment of the disease. Thiazolidine derivatives appear as important alternatives to treatment. In vitro studies have demonstrated excellent schistosomiasis activity for LPSF/GQ-238. The molecule, however, has poorly water-soluble. This study focused on increasing the aqueous solubility of LPSF/GQ-238 by obtaining solid dispersions. Were prepared by the solvent techniques, using Soluplus®, Polyethylene glycol (PEG), and Polyvinylpyrrolidone (PVP-K30) as carriers. Solubility tests, Scanning Electron Microscopy (SEM), X-ray Diffraction (XRD), Exploratory Differential Calorimetry (DSC), and Raman Spectroscopy characterized these new intermediate products. The solubility tests showed that the higher the proportion of polymer used in the preparation of the dispersion, the greater the solubility presented. The observation of the morphology by SEM analysis, elucidated, that the new chemical entity (NCE) has a characteristic crystalline structure. The folding of this structure by the polymer was observed in all analyzed dispersions, thus demonstrating the amorphous state of the product. The scales observed in the structures of the dispersions demonstrate the successive wrinkles that occurred. The greater the proportion of the polymer, the greater the number of folds that occurred, which may explain the greater solubility observed in these preparations. The X-ray diffraction profile of the NCE reveals the presence of intense peaks, presenting a crystalline pattern. The polymer, on the other hand, shows amorphous nature, evidenced by the absence of peaks. All the analyzed dispersions did not present the characteristic peaks of the NCE, evidencing the amorphous behavior of the products. The thermal degradation profile of the NCE presents a characteristic crystalline structure endothermic peak. This peak was not observed in any of the obtained dispersions, evidencing the obtaining of a new solid state. Raman spectroscopy showed that peaks in the range 200-400 (cm-1) by NCE were lost when compared to all analyzed dispersions, showing a slight change in the structure of the molecule when dispersed, probably due to the formation of hydrogen bonds with the polymer. The in vitro study showed a significant improvement in the activity of the NCE against the adult worm and to the schistosomulae. It was possible to observe that the obtained solid dispersions were physicochemically and biologically viable for schistosomicidal treatment due to the increase of solubility of the molecule.

Interaction study with DNA/HSA, anti-topoisomerase IIα, cytotoxicity and in vitro antiproliferative evaluations and molecular docking of indole-thiosemicarbazone compounds.

In this work we will discuss the antiproliferative evaluation and the possible mechanisms of action of indole-thiosemicarbazone compounds LTs with anti-inflammatory activity, previously described in the literature. In this perspective, some analyzes were carried out, such as the study of binding to human serum albumin (HSA) and to biological targets: DNA and human topoisomerase IIα (topo). Antiproliferative study was performed with DU-145, Jukart, MCF-7 and T-47D tumor lines and J774A.1, besides HepG2 macrophages and hemolytic activity. In the HSA interaction tests, the highest binding constant was 3.70 × 106 M-1, referring to LT89 and in the fluorescence, most compounds, except for LT76 and LT87, promoted fluorescent suppression with the largest Stern-Volmer constant for the LT88 3.55 × 104. In the antiproliferative assay with DU-145 and Jurkat strains, compounds LT76 (0.98 ± 0.10/1.23 ± 0.32 µM), LT77 (0.94 ± 0.05/1.18 ± 0.08 µM) and LT87 (0.94 ± 0.12/0.84 ± 0.09 µM) stood out, due to their IC50 values mentioned above. With the MCF-7 and T-47D cell lines, the lowest IC50 was presented by LT81 with values of 0.74 ± 0.12 µM and 0.68 ± 0.10 µM, respectively, followed by the compounds LT76 and LT87. As well as the positive control amsacrine, the compounds LT76, LT81 and LT87 were able to inhibit the enzymatic action of human Topoisomerase IIα.

Synthesis, in vitro schistosomicidal activity and ultrastructural alterations caused by thiosemicarbazones and thiazolidinones against juvenile and adult Schistosoma mansoni worms (Sambon, 1907).

Schistosomiasis is a neglected disease that affects about 258 million people worldwide. Caused by Schistosoma mansoni, helminth which, in Brazil, it is present on 19 states and capital. Praziquantel (PZQ) treatment presents low efficacy and adverse effects in parasites juvenile stages. Thiosemicarbazones and thiazolidinones are rising as potent chemical groups that have biological activity wide spectrum, and with radical modifications, they may become more effective and selective. Aiming to evaluate the action of these molecules against S. mansoni, JF series thiosemicarbazones and thiazolidinones (LqIT/UFPE) were synthesized: JF30, JF31, JF33, JF34, JF35, JF36, JF38, JF39, JF42 and JF43. Several parameters were evaluated, such as: their cytotoxicity in VERO cells, in vitro schistosomicidal activity for juvenile and adult worms and their action on worms through ultrastructural changes. Cytotoxicity indices ranged from 272 µM to 725 µM. When evaluating mortality rate, adult and juvenile worms showed 100 % mortality rate within 24 h and 48 h, respectively, when exposed to the compounds JF31 and JF43 at a dose of 200 µM. Also, motility, mortality and oviposition parameters were evaluated: JF31 and JF43 presented a score of 0 in 24 h, meaning total absence of movement, whereas no eggs and soft tissue damage were observed under optical microscopy. Through scanning electron microscopy, integumentary alterations caused by the compounds JF31 and JF43 were observed, such as: exposure of the musculature, formation of integumentary bubbles, integuments with abnormal morphology and destruction of tubercles and spikes. The results shoerd that the compound JF31 was 2.39 times more selective for adult worms and JF43 was 3.74 times more selective for juvenile worms. Thus, the compounds JF43 and JF31 are the most promising for presenting schistosomicidal activity of S. mansoni.

Thiazolidine derivatives: In vitro toxicity assessment against promastigote and amastigote forms of Leishmania infantum and ultrastructural study.

Neglected diseases, such as Leishmaniasis, constitute a group of communicable diseases that occur mainly in tropical countries. Considered a public health problem with limited treatment. Therefore, there is a need for new therapies. In this sense, our proposal was to evaluate in vitro two series of thiazolidine compounds (7a-7e and 8a-8e) against Leishmania infantum. We performed in vitro evaluations through macrophage cytotoxicity assays (J774) and nitric oxide production, activity against promastigotes and amastigotes, as well as ultrastructural analyzes in promastigotes. In the evaluation of cytotoxicity, the thiazolidine compounds presented CC50 values between 8.52 and 126.83 µM. Regarding the evaluation against the promastigote forms, the IC50 values ranged between 0.42 and 142.43 µM. Compound 7a was the most promising, as it had the lowest IC50. The parasites treated with compound 7a showed several changes, such as cell body shrinkage, shortening and loss of the flagellum, intense mitochondrial edema and cytoplasmic vacuolization, leading the parasite to cell inviability. In assays against the amastigote forms, the compound showed a low IC50 (0.65 µM). These results indicate that compound 7a was efficient for both evolutionary forms of the parasite. In silico studies suggest that the compound has good oral bioavailability. These results show that compound 7a is a potential drug candidate for the treatment of Leishmaniasis.

Neurolocomotor Behavior and Oxidative Stress Markers of Thiazole and Thiazolidinedione Derivatives against Nauphoeta cinerea.

Thiazolidine compounds NJ20 {(E)-2-(2-(5-bromo-2-methoxybenzylidene)hydrazinyl)-4-(4-nitrophenyl)thiazole} and NW05 [(2-(benzo (d) (1,3) dioxol-4-ylmethylene)-N-(4-bromophenyl)-thiosemicarbazone] potentiated the effect of norfloxacin in resistant bacteria; however, there are no reports on their effects on Nauphoeta cinerea in the literature. The objective of this work was to evaluate the behavioral effects and oxidative markers of NW05 and NJ20 in lobster cockroach N. cinerea. To evaluate the behavioral study, a video tracking software was used to evaluate the locomotor points and the exploratory profile of cockroaches in the horizontal and vertical regions of a new environment. The total concentration of thiol and reduced glutathione (GSH), substances reactive to thiobarbituric acid (TBARS), free iron (II) content and mitochondrial viability were determined. The antioxidant potential was evaluated by the DPPH method. Both substances induced changes in the behavior of cockroaches, showing a significant reduction in the total distance covered and in the speed. In the cell viability test (MTT), there was a significant reduction for NJ20 (1 mM). NJ20 caused a significant increase in total levels of thiol and non-protein thiol (NPSH), although it also slightly increased the content of malondialdehyde (MDA). Both compounds (NW05 and NJ20) caused a significant reduction in the content of free iron at a concentration of 10 mM. In conclusion, the compound NJ20 caused moderate neurotoxicity (1 mM), but had good antioxidant action, while NW05 did not show toxicity or significant antioxidant activity in the model organism tested. It is desirable to carry out complementary tests related to the antioxidant prospection of these same compounds, evaluating them at different concentrations.

Anti-inflammatory activity of novel thiosemicarbazone compounds indole-based as COX inhibitors.

BACKGROUND: In this article, a series of 20 new thiosemicarbazone derivatives containing indole were synthesized and evaluated for their anti-inflammatory potential. METHODS: The compounds were obtained through a synthetic route of only two steps, with yields that varied between 33.6 and 90.4%, and characterized by spectroscopic and spectrometric techniques. RESULTS: An initial screening through the lymphoproliferation assay revealed that compounds LT76, LT81, and LT87 were able to inhibit lymphocyte proliferation, with CC50 of 0.56 ± 0.036, 0.9 ± 0.01 and 0.5 ± 0.07 µM, respectively, better results than indomethacin (CC50 > 12 µM). In addition, these compounds were able to suppress the in-vitro production of TNF-α and NO, in addition to stimulating the production of IL-4. Reinforcing in-vitro assays, the compounds were able to inhibit COX-2 similar to Celecoxib showing greater selectivity for this isoform (LT81 SI: 23.06 versus Celecoxib SI: 11.88). Animal studies showed that compounds LT76 (64.8% inhibition after 6 h), LT81 (89% inhibition after 6 h) and LT87 (100% inhibition after 4 h) were able to suppress edema in mice after inoculation carrageenan with greater potency than indomethacin, and immunohistochemistry revealed that the groups treated with LT76, LT81 and LT87 reduced the expression of COX-2, similar or better results when compared to indomethacin. Complementarily, in-silico studies have shown that these compounds have a good pharmacokinetic profile, for respecting the parameters of Lipinski and Veber, showing their good bioavailability. CONCLUSIONS: These results demonstrate the potency of thiosemicarbazone derivatives containing indole and confirm their importance as scaffolds of molecules with notorious anti-inflammatory activity.

New Oxazolidines Inhibit the Secretion of IFN-γ and IL-17 by PBMCS from Moderate to Severe Asthmatic Patients.

BACKGROUND: Moderate to severe asthma could be induced by diverse proinflammatory cytokines, as IL-17 and IFN-γ, which are also related to treatment resistance and airway hyperresponsiveness. Oxazolidines emerged as a novel approach for asthma treatment, since some chemical peculiarities were suggested by previous studies. OBJECTIVE: The present study aimed to evaluate the IL-17A and IFN-γ modulatory effect of two new oxazolidine derivatives (LPSF/NB-12 and -13) on mononucleated cells of patients with moderate and severe asthma. METHODS: The study first looked at potential targets for oxazolidine derivatives using SWISS-ADME. After the synthesis of the compounds, cytotoxicity and cytokine levels were analyzed. RESULTS: We demonstrated that LPSF/NB-12 and -13 reduced IFN-γ and IL-17 production in peripheral blood mononucleated cells from asthmatic patients in a concentrated manner. Our in silico analysis showed the neurokinin-1 receptor as a common target for both compounds, which is responsible for diverse proinflammatory effects of moderate and severe asthma. CONCLUSION: The work demonstrated a novel approach against asthma, which deserves further studies of its mechanisms of action.

Novel indole-thiazole and indole-thiazolidinone derivatives as DNA groove binders.

In this study, we report the synthesis of eight novel indole-thiazole and indole-thiazolidinone derivatives, as well as their ability to interact with DNA, analysed through the UV-vis absorption, fluorescence, circular dichroism (CD), viscosity techniques and molecular docking. The ctDNA interaction analysis demonstrated different spectroscopic effects and the affinity constants (Kb) calculated by the UV-vis absorption method were between 2.08 × 105 and 6.99 × 106 M-1, whereas in the fluorescence suppression constants (Ksv) ranged between 0.38 and 0.77 × 104 M-1 and 0.60-7.59 × 104 M-1 using Ethidium Bromide (EB) and 4',6-Diamidino-2-phenylindole (DAPI) as fluorescent probes, respectively. Most derivatives did not alter significantly the secondary structure of the ctDNA according to the CD results. None of the compounds was able to change the relative viscosity of the ctDNA. These results prove that compounds interact with ctDNA via groove binding, which was confirmed by A-T rich oligonucleotide sequence assay with compound JF-252, suggesting the importance of both the phenyl ring coupled to C-4 thiazole ring and the bromo-unsubstituted indole nucleus.

Grafting Diels-Alder moieties on cellulose nanocrystals through carbamation.

The Diels-Alder reaction is a promising click chemistry for the design of advanced materials from cellulose nanocrystals (CNCs). Transferring such chemistry to cellulose nanocrystals requires the precise grafting of reactive Diels-Alder moeities under heterogeneous conditions without compromising the nanocrystals morphology. In this study toluene diisocyanate is used as a spacer to graft Diels-Alder moieties viz the furyl and protected maleimido moieties onto cellulose nanocrystals. A factorial experimental design reveals that reaction time and reactant molar ratio positively affect the grafting efficiency, as evidenced by FTIR and CHNS elemental analysis. The surface degree of substitution was analyzed via CHNS elemental analysis and XPS and found to range between 0.05 to 0.30, with a good agreement between the two techniques. 13C CP/MAS NMR confirmed that the grafted moieties and CNCs are intact after reaction. Side reactions were also observed and their impact on performing controllable click chemistry between cellulose nanocrystals is discussed.

COVID-19 therapy: What weapons do we bring into battle?

Urgent treatments, in any modality, to fight SARS-CoV-2 infections are desired by society in general, by health professionals, by Estate-leaders and, mainly, by the scientific community, because one thing is certain amidst the numerous uncertainties regarding COVID-19: knowledge is the means to discover or to produce an effective treatment against this global disease. Scientists from several areas in the world are still committed to this mission, as shown by the accelerated scientific production in the first half of 2020 with over 25,000 published articles related to the new coronavirus. Three great lines of publications related to COVID-19 were identified for building this article: The first refers to knowledge production concerning the virus and pathophysiology of COVID-19; the second regards efforts to produce vaccines against SARS-CoV-2 at a speed without precedent in the history of science; the third comprehends the attempts to find a marketed drug that can be used to treat COVID-19 by drug repurposing. In this review, the drugs that have been repurposed so far are grouped according to their chemical class. Their structures will be presented to provide better understanding of their structural similarities and possible correlations with mechanisms of actions. This can help identifying anti-SARS-CoV-2 promising therapeutic agents.

Thiophene-thiosemicarbazone derivative (L10) exerts antifungal activity mediated by oxidative stress and apoptosis in C. albicans.

Reactive oxygen species (ROS) cause cell damage and death. To reverse these effects, cells produce substances such as reduced glutathione (GSH) that serve as substrates for antioxidant enzymes. One way to combat microbial resistance includes nullifying the effect of glutathione in microbial cells, causing them to die from oxidative stress. The compound 2-((5-nitrothiophen-2-yl)methylene)-N-(pyridin-3-yl) hydrazine carbothioamide (L10) is a new thiophene-thiosemicarbazone derivative with promising antifungal activity. The aim of this study was to evaluate its mechanism of action against Candida albicans using assays that evaluate its effects on redox balance. Treatment with L10 promoted significant changes in the minimum inhibitory concentration (MIC) values in ascorbic acid and GSH protection tests, the latter increasing up to 64-fold of the MIC. Using nuclear magnetic resonance, we demonstrated interaction of L10 and GSH. At concentrations of 4.0 and 8.0 µg/mL, significant changes were observed in ROS production and mitochondrial membrane potential. The cell death profile showed characteristics of initial apoptosis at inhibitory concentrations (4.0 µg/mL). Transmission electron microscopy data corroborated these results and indicated signs of apoptosis, damage to plasma and nuclear membranes, and to mitochondria. Taken together, these results suggest a possible mechanism of action for L10 antifungal activity, involving changes in cellular redox balance, ROS production, and apoptosis-compatible cellular changes.

Thermodynamic and Kinetic Study of Diels-Alder Reaction between Furfuryl Alcohol and N-Hydroxymaleimides-An Assessment for Materials Application.

The study of Diels-Alder reactions in materials science is of increasing interest. The main reason for that is the potential thermoreversibility of the reaction. Aiming to predict the behavior of a material modified with maleimido and furyl moieties, 1H NMR and UV-Vis solution studies of the Diels-Alder reaction between furfuryl alcohol and two N-hydroxymaleimides are explored in the present study. Rate constants, activation energy, entropy, and enthalpy of formation were determined from each technique for both reacting systems. Endo and exo isomers were distinguished in 1H NMR, and the transition from a kinetic, controlled Diels-Alder reaction to a thermodynamic one could be observed in the temperature range studied. A discussion on the effect of that on the application in a material was performed. The approach selected considers a simplified equilibrium of the Diels-Alder reaction as the kinetic model, allowing materials scientists to evaluate the suitability of using the reacting molecules for the creation of thermoresponsive materials. The proposed approach determines the kinetic constants without the direct influence of the equilibrium constant value, thereby allowing a more objective data analysis. The effects of the selection of kinetic model, analytical method, and data treatment are discussed.

Novel indol-3-yl-thiosemicarbazone derivatives: Obtaining, evaluation of in vitro leishmanicidal activity and ultrastructural studies.

Parasitic diseases still represent serious public health problems, since the high and steady emergence of resistant strains is evident. Because parasitic infections are distributed predominantly in developing countries, less toxic, more efficient, safer and more accessible drugs have become desirable in the treatment of the infected population. This is the case of leishmaniasis, an infectious disease caused by a protozoan of the genus Leishmania sp., responsible for triggering pathological processes from the simplest to the most severe forms leading to high rates of morbidity and mortality throughout the world. In the search for new leishmanicidal drugs, the thiosemicarbazones and the indole fragments have been identified as promising structures for leishmanicidal activity. The present study proposes the synthesis and structural characterization of new indole-thiosemicarbazone derivatives (2a-j), in addition to performing in vitro evaluations through cytotoxicity assays using macrophages (J774) activity against forms of Leishmania infantum and Leishmania amazonensis promastigote as well as ultrastructural analyzes in promastigotes of L. infantum. Results show that the indole-thiosemicarbazone derivatives were obtained with yield values varying from 32.09 to 94.64%. In the evaluation of cytotoxicity, the indole-thiosemicarbazone compounds presented CC50 values between 53.23 and 357.97 µM. Concerning the evaluation against L. amazonensis promastigote forms, IC50 values ranged between 12.31 and  > 481.52 µM, while the activity against L. infantum promastigotes obtained IC50 values between 4.36 and 23.35 µM. The compounds 2d and 2i tested against L. infantum were the most promising in the series, as they showed the lowest IC50 values: 5.60 and 4.36 respectively. The parasites treated with the compounds 2d and 2i showed several structural alterations, such as shrinkage of the cell body, shortening and loss of the flagellum, intense mitochondrial swelling and vacuolization of the cytoplasm leading the parasite to cellular unviability. Therefore, the indole-thiosemicarbazone compounds are promising because they yield considerable synthesis, have low cytotoxicity to mammalian cells and act as leishmanicidal agents.

In vitro activity of aryl-thiazole derivatives against Schistosoma mansoni schistosomula and adult worms.

Schistosomiasis is caused by a trematode of the genus Schistosoma and affects over 200 million people worldwide. The only drug recommended by the World Health Organization for treatment and control of schistosomiasis is praziquantel. Development of new drugs is therefore of great importance. Thiazoles are regarded as privileged structures with a broad spectrum of activities and are potential sources of new drug prototypes, since they can act through interactions with DNA and inhibition of DNA synthesis. In this context, we report the synthesis of a series of thiazole derivatives and their in vitro schistosomicidal activity by testing eight molecules (NJ03-08; NJ11-12) containing thiazole structures. Parameters such as motility and mortality, egg laying, pairing and parasite viability by ATP quantification, which were influenced by these compounds, were evaluated during the assays. Scanning electron microscopy (SEM) was utilized for evaluation of morphological changes in the tegument. Schistosomula and adult worms were treated in vitro with different concentrations (6.25 to 50 µM) of the thiazoles for up to 5 and 3 days, respectively. After in vitro treatment for five days with 6.25 µM NJ05 or NJ07 separately, we observed a decrease of 30% in schistosomula viability, whilst treatment with NJ05+NJ07 lead to a reduction of 75% in viability measured by ATP quantitation and propidium iodide labeling. Adult worms' treatment with 50 µM NJ05, NJ07 or NJ05 + NJ07 showed decreased motility to 30-50% compared with controls. Compound NJ05 was more effective than NJ07, and adult worm viability after three days was reduced to 25% in parasites treated with 50 µM NJ05, compared with a viability reduction to 40% with 50 µM NJ07. SEM analysis showed severe alterations in adult worms with formation of bulges and blisters throughout the dorsal region of parasites treated with NJ05 or NJ07. Oviposition was extremely affected by treatment with the NJ series compounds; at concentrations of 25 µM and 50 µM, oviposition reached almost zero with NJ05, NJ07 or NJ05 + NJ07 already at day one. Tested genes involved in egg biosynthesis were all confirmed by qPCR as downregulated in females treated with 25 µM NJ05 for 2 days, with a significant reduction in expression of p14, Tyrosinase 2, p48 and fs800. NJ05, NJ07 or NJ05+NJ07 treatment of HEK293 (human embryonic cell line) and HES (human epithelial cell line) showed EC50 in the range of 18.42 to 145.20 µM. Overall, our results demonstrate that those molecules are suitable targets for further development into new drugs for schistosomiasis treatment, although progress is needed to lessen the cytotoxic effects on human cells. According to the present study, thiazole derivatives have schistosomicidal activities and may be part of a possible new arsenal of compounds against schistosomiasis.

Novel 4-quinoline-thiosemicarbazone derivatives: Synthesis, antiproliferative activity, in vitro and in silico biomacromolecule interaction studies and topoisomerase inhibition.

Twelve 2-(quinolin-4-ylmethylene) hydrazinecarbothioamide derivatives were synthetized and their biological properties were investigated, among which, the ability to interact with DNA and BSA through UV-Vis absorption, fluorescence, Circular Dichroism, molecular docking and relative viscosity, antiproliferative activity against MCF-7 and T-47D mammary tumor cells and RAW-264.7 macrophages and inhibitory capacity of the enzyme topoisomerase IIα. In the binding study with DNA and BSA, all the compounds displayed affinity for interaction with both biomolecules, especially JF-92 (p-ethyl-substituted), with binding constant of 1.62 × 106 and 1.43 × 105, respectively, and DNA binding mode by intercalation. The IC50 values were obtained between 0.81 and 1.48 µM and topoisomerase inhibition results in 10 µM. Thus, we conclude that the reduction of the acridine to quinoline ring did not disrupt the antitumor action and that substitution patterns are important for biomolecule interaction affinity as they demonstrate the potential of these compounds for anticancer therapy.