Synthesis of New Thiosemicarbazones and Semicarbazones Containing the 1,2,3-1H-triazole-isatin Scaffold: Trypanocidal, Cytotoxicity, Electrochemical Assays, and Molecular Docking

Background: Chagas disease, also known as American trypanosomiasis, is classified as one of the 17 most important neglected diseases by the World Health Organization. The only drugs with proven efficacy against Chagas disease are benznidazole and nifurtimox, however both show adverse effects, poor clinical efficacy, and development of resistance. For these reasons, the search for new effective chemical entities is a challenge to research groups and the pharmaceutical industry. Objective: Synthesis and evaluation of antitrypanosomal activities of a series of thiosemicarbazones and semicarbazones containing 1,2,3-1H triazole isatin scaffold. Method: 5&'-(4-alkyl/aryl)-1H-1,2,3-triazole-isatins were prepared by Huisgen 1,3-dipolar cycloaddition and the thiosemicarbazones and semicarbazones were obtained by the 1:1 reactions of the carbonylated derivatives with thiosemicarbazide and semicarbazide hydrochloride, respectively, in methanol, using conventional reflux or microwave heating. The compounds were assayed for in vitro trypanocidal activity against Trypanosoma cruzi, the aetiological agent of Chagas disease. Beyond the thio/semicarbazone derivatives, isatin and triazole synthetic intermediates were also evaluated for comparison. Results: A series of compounds were prepared in good yields. Among the 37 compounds evaluated, 18 were found to be active, in particular thiosemicarbazones containing a non-polar saturated alkyl chain (IC50 = 24.1, 38.6, and 83.2 &µM; SI = 11.6, 11.8, and 14.0, respectively). To further elucidate the mechanism of action of these new compounds, the redox behaviour of some active and inactive derivatives was studied by cyclic voltammetry. Molecular docking studies were also performed in two validated protein targets of Trypanosoma cruzi, i.e., cruzipain (CRZ) and phosphodiesterase C (TcrPDEC). Conclusion: A class of thio/semicarbazones structurally simple and easily accessible was synthesized. Compounds containing thiosemicarbazone moieties showed the best results in the series, being more active than the corresponding semicarbazones. Our results indicated that the activity of these compounds does not originate from an oxidation-reduction pathway but probably from the interactions with trypanosomal enzymes.

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Zinc 1,2,4-triazolo[1,5-a]pyrimidine complexes: synthesis, structural characterization and their effect against Chagas disease

Medicinal Chemistry ◽

10.2174/1573406417666210812162500 ◽

2021 ◽

Vol 17 ◽

Author(s):

José M. Méndez-Arriaga ◽

Erika Rubio-Mirallas ◽

Miguel Quirós ◽

Manuel Sánchez-Moreno

Keyword(s):

Trypanosoma Cruzi ◽

Chagas Disease ◽

New Drugs ◽

World Health ◽

Neglected Diseases ◽

X Ray Diffraction ◽

X Ray ◽

Health Organization ◽

The Third World

Background: The World Health Organization catalogues illnesses such as Chagas disease as neglected diseases, due the low investment in new drugs to fight them. The search for novel and non-side effects anti-parasitic compounds is one of the urgent needs of the Third World. The use of triazolopyrimidines and their metal complexes have demonstrated hopeful results in this field. Objective: This work studies the antiparasitic efficacy against Trypanosoma cruzi strains of a series of zinc triazolopyrimidine complexes. Method: A series of Zn complexes has been synthesized by the reaction between the triazolopyrimidine derivatives 7-amino-1,2,4-triazolo[1,5-a]pyrimidine (7atp) and 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp) with Zn(SO4) • 7H2O, ZnCl2, and Zn(NO3)2 • 6H2O salts. The complexes have been analyzed by spectroscopic and thermal assays and X-ray diffraction methods have been used to dilucidate the crystalline structure of one of them. The antiparasitic efficacy was tested in vitro against Trypanosoma cruzi to compare the trypanocidal effect of different ligands and counteranions to fight Chagas disease. Results: The efficacy of these compounds against Trypanosoma cruzi has also been tested to compare the influence of different ligands and counteranions on the trypanocidal effect against Chagas disease. Conclusion: Antiproliferative tests corroborate the synergistic trypanocidal effect of the triazolopyrimidine coordination complexes.

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Capsaicin inhibits arginine kinase and exerts anti-Trypanosoma cruzi activity

10.1101/2020.06.23.167346 ◽

2020 ◽

Author(s):

Edward A. Valera-Vera ◽

Chantal Reigada ◽

Melisa Sayé ◽

Fabio A. Digirolamo ◽

Mariana R. Miranda ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Chagas Disease ◽

Stress Responses ◽

Mammalian Cells ◽

Arginine Kinase ◽

Chronic Phase ◽

New Drugs ◽

World Health ◽

Neglected Diseases ◽

Health Organization

ABSTRACTTrypanosoma cruzi is the causative agent of Chagas disease, considered within the list of twenty neglected diseases according to the World Health Organization. There are only two therapeutic drugs for Chagas disease, both of them unsuitable for the chronic phase, therefore the development of new drugs is a priority.T. cruzi arginine kinase (TcAK) is a promising drug target since it is absent in humans and it is involved in cellular stress responses. In a previous study from our laboratory, possible TcAK inhibitors were identified through computer simulations, resulting in the best-scoring compounds cyanidin derivatives and capsaicin. Considering these results, in this work we evaluate the effect of capsaicin on TcAK activity and its trypanocidal effect. Although capsaicin produced a weak inhibition on the recombinant TcAK activity (IC50 ≈ 800 µM), it had a strong trypanocidal effect on epimastigotes and trypomastigotes (IC50 = 6.26 µM and 0.26 µM, respectively) being 20-fold more active on trypomastigotes than mammalian cells. Epimastigotes that overexpress TcAK were 37% more resistant to capsaicin than wild type parasites, suggesting that trypanocidal activity could be due, in part, to the enzyme inhibition. However, the difference between the concentrations at which the enzyme is inhibited and the parasite death is caused implies the presence of other targets. In this sense, the prohibitin-2 and calmodulin were identified as other possible capsaicin targets. Capsaicin is a strong and selective trypanocidal agent active in nanomolar concentrations, with an IC50 57-fold lower than benznidazole, the drug currently used for treating Chagas disease.

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Indeterminate Chagas’ disease: Trypanosoma cruzi strain and re-infection are factors involved in the progression of cardiopathy

Clinical Science ◽

10.1042/cs1040415 ◽

2003 ◽

Vol 104 (4) ◽

pp. 415-420 ◽

Cited By ~ 23

Author(s):

Juan M. BUSTAMANTE ◽

Héctor W. RIVAROLA ◽

Alicia R. FERNÁNDEZ ◽

Julio E. ENDERS ◽

Ricardo FRETES ◽

...

Keyword(s):

Survival Rate ◽

Trypanosoma Cruzi ◽

Chagas Disease ◽

Infected Group ◽

World Health ◽

Cardiac Lesions ◽

Health Organization ◽

Host Parasite ◽

Β Adrenergic Receptors ◽

First Time

Chagas' disease is caused by Trypanosoma cruzi, which is transmitted by reduviid bugs. The World Health Organization has estimated that about 16–18 million people in the Americas are infected, and that more than 100 million are at risk. In the present study we have used a murine model to analyse if particular T. cruzi strains (Tulahuen strain and SGO-Z12 isolate from a chronic patient) and/or re-infection may determine, during the indeterminate phase of experimental Chagas' disease, changes that could explain the different evolution of cardiac lesions. Re-infected mice reached higher parasitaemias than those infected for the first time. The survival in the indeterminate phase of mice infected with Tulahuen strain was 50.0%, while the SGO-Z12-infected group presented a significantly higher survival rate (77.1%; P<0.01). The SGO-Z12-re-infected group showed a survival rate (70.9%) significantly higher than that of the Tulahuen-re-infected group (37.0%; P<0.01). Electrocardiographic abnormalities were found in 66% of Tulahuen-infected mice, while in SGO-Z12-infected group such abnormalities were found in only 36% of animals (P<0.01). The two groups exhibited similar percentages of electrocardiographic dysfunction on re-infection, although intraventricular blocks were more frequent in Tulahuen-re-infected mice (P<0.01). Hearts from infected or re-infected mice with either parasite showed mononuclear infiltrates. The SGO-Z12-re-infected and Tulahuen-re-infected groups exhibited a significantly diminished affinity (P<0.05) and a significantly increased density (P<0.05) of cardiac β-adrenergic receptors compared with the infected and non-infected groups. The indeterminate phase of Chagas' disease is defined as a prolonged period that is clinically silent, but the present findings show that different T. cruzi strains and re-infection are able to alter the host–parasite equilibrium, and these factors may be responsible for inducing progressive cardiopathy.

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Molecular Docking Studies on the Anti-viral Effects of Compounds From Kabasura Kudineer on SARS-CoV-2 3CLpro

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.613401 ◽

2020 ◽

Vol 7 ◽

Author(s):

Savariar Vincent ◽

Selvaraj Arokiyaraj ◽

Muthupandian Saravanan ◽

Manoj Dhanraj

Keyword(s):

Molecular Docking ◽

Critical Role ◽

Drug Repurposing ◽

Docking Studies ◽

World Health ◽

Synthetic Drugs ◽

Energy Score ◽

Main Protease ◽

Novel Coronavirus ◽

Health Organization

The COVID-19 has now been declared a global pandemic by the World Health Organization. No approved drug is currently available; therefore, an urgent need has been developed for any antiviral therapy for COVID-19. Main protease 3CLpro of this novel Coronavirus (SARS-CoV-2) play a critical role in the disease propagation, and hence represent a crucial target for the drug discovery. Herein, we have applied a bioinformatics approach for drug repurposing to identify the possible potent inhibitors of SARS-CoV-2 main proteases 3CLpro (6LU7). In search of the anti-COVID-19 compound, we selected 145 phyto-compounds from Kabasura kudineer (KK), a poly-herbal formulation recommended by AYUSH for COVID-19 which are effective against fever, cough, sore throat, shortness of breath (similar to SARS-CoV2-like symptoms). The present study aims to identify molecules from natural products which may inhibit COVID-19 by acting on the main protease (3CLpro). Obtained results by molecular docking showed that Acetoside (−153.06), Luteolin 7 -rutinoside (−134.6) rutin (−133.06), Chebulagic acid (−124.3), Syrigaresinol (−120.03), Acanthoside (−122.21), Violanthin (−114.9), Andrographidine C (−101.8), myricetin (−99.96), Gingerenone -A (−93.9), Tinosporinone (−83.42), Geraniol (−62.87), Nootkatone (−62.4), Asarianin (−79.94), and Gamma sitosterol (−81.94) are main compounds from KK plants which may inhibit COVID-19 giving the better energy score compared to synthetic drugs. Based on the binding energy score, we suggest that these compounds can be tested against Coronavirus and used to develop effective antiviral drugs.

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First Example of Antiparasitic Activity Influenced by Thermochromism: Leishmanicidal Evaluation of 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine Metal Complexes

Medicinal Chemistry ◽

10.2174/1573406415666190401120607 ◽

2020 ◽

Vol 16 (3) ◽

pp. 422-430 ◽

Cited By ~ 1

Author(s):

José M. Méndez-Arriaga ◽

Itziar Oyarzabal ◽

Álvaro Martín-Montes ◽

Judith García-Rodríguez ◽

Miguel Quirós ◽

...

Keyword(s):

Physical Properties ◽

Metal Complexes ◽

New Drugs ◽

Host Cells ◽

World Health ◽

Neglected Diseases ◽

Leishmania Spp ◽

Different Strains ◽

Health Organization

Background: The World Health Organization catalogues illnesses such as Leishmaniasis as neglected diseases, due to low investment in new drugs to fight them. The search of novel and non-side effects anti-parasitic compounds is one of the urgent needs for the Third World. The use of triazolopyrimidines and their metallic complexes has demonstrated hopeful results in this field. Objective: This work studies the antiparasitic efficacy of a series of 5,7-dimethyl-1,2,4- triazolo[1,5-a]pyrimidine first row transition metal complexes against three leishmania spp. strains. Methods: The in vitro antiproliferation of promastigote forms of different strains of leishmania spp. (L. infantum, L. braziliensis and L donovani) and the cytotoxicity in macrophage host cells are reported here. The antiparasitic assays have been complemented with enzymatic tests to elucidate the mechanisms of action. New crystal structure description, thermal analysis, magnetic susceptibility and magnetization experiments have also been carried out in order to present a whole characterization of the studied compounds and interesting physical properties besides the biological tests. Results: The results of antiproliferation screening and cytotoxicity show great antiparasitic efficacy in the studied complexes. The superoxide dismutase enzymatic assays exhibit a different behaviour according to the thermochromic triazolopyrimidine form tested. Conclusion: Antiproliferative assays and enzymatic tests corroborate the synergetic leishmanicidal effect present in coordination triazolopyrimidine complexes. The changes in coordination sphere derived from thermochromism affect the physical properties as well as the biological efficacy.

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In Silico Identification of New Targets for Diagnosis, Vaccine, and Drug Candidates against Trypanosoma cruzi

Disease Markers ◽

10.1155/2020/9130719 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15

Author(s):

Rafael Obata Trevisan ◽

Malú Mateus Santos ◽

Chamberttan Souza Desidério ◽

Leandro Gomes Alves ◽

Thiago de Jesus Sousa ◽

...

Keyword(s):

Molecular Docking ◽

Trypanosoma Cruzi ◽

Chagas Disease ◽

Drug Targets ◽

Hot Spot ◽

Mhc I ◽

Drug Candidates ◽

Subtractive Genomics

Chagas disease is a neglected tropical disease caused by the parasite Trypanosoma cruzi. Despite the efforts and distinct methodologies, the search of antigens for diagnosis, vaccine, and drug targets for the disease is still needed. The present study is aimed at identifying possible antigens that could be used for diagnosis, vaccine, and drugs targets against T. cruzi using reverse vaccinology and molecular docking. The genomes of 28 T. cruzi strains available in GenBank (NCBI) were used to obtain the genomic core. Then, subtractive genomics was carried out to identify nonhomologous genes to the host in the core. A total of 2630 conserved proteins in 28 strains of T. cruzi were predicted using OrthoFinder and Diamond software, in which 515 showed no homology to the human host. These proteins were evaluated for their subcellular localization, from which 214 are cytoplasmic and 117 are secreted or present in the plasma membrane. To identify the antigens for diagnosis and vaccine targets, we used the VaxiJen software, and 14 nonhomologous proteins were selected showing high binding efficiency with MHC I and MHC II with potential for in vitro and in vivo tests. When these 14 nonhomologous molecules were compared against other trypanosomatids, it was found that the retrotransposon hot spot (RHS) protein is specific only for T. cruzi parasite suggesting that it could be used for Chagas diagnosis. Such 14 proteins were analyzed using the IEDB software to predict their epitopes in both B and T lymphocytes. Furthermore, molecular docking analysis was performed using the software MHOLline. As a result, we identified 6 possible T. cruzi drug targets that could interact with 4 compounds already known as antiparasitic activities. These 14 protein targets, along with 6 potential drug candidates, can be further validated in future studies, in vivo, regarding Chagas disease.

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Synthesis of New Selenides-1,2,3-Triazoles with Potential Activity against Trypanossoma cruzi

Chemistry Proceedings ◽

10.3390/eccs2020-07757 ◽

2020 ◽

Vol 2 (1) ◽

pp. 22

Author(s):

Beatrice Brasil ◽

Ingrid Chipoline ◽

Vanessa Nascimento

Keyword(s):

Chagas Disease ◽

Treatment Time ◽

World Health ◽

Neglected Diseases ◽

Hybridization Technique ◽

Target Molecules ◽

Potential Activity ◽

Health Organization ◽

The Individual

Chagas disease, considered by the World Health Organization as a neglected tropical disease, is responsible for the deaths of more than 10,000 people annually. The main drugs used to overcome the disease, Benzonidazole and Nifurtimox, besides being old, have limitations regarding the adverse effects related to the treatment time and, consequently, their toxicity. Therefore, the need for a new drug to be used against this disease becomes evident. The classes of organoselenium and aromatic heterocycles 1,2,3-triazoles are promising for the issue of the profile of both classes for further evaluation against Trypanossoma cruzi, since the known chemistry and antiparasitic activity of both have already been described. In this work, the molecular hybridization technique was used in order to combine the individual bioactive protozoan that causes Chagas disease. The methodology used was based on works described in the literature. Initially, benzene azides were synthesized from commercial anilines, while ethynyl(phenyl)selane came from different aromatic diselenides. With these intermediates, a 1,3-dipolar cycle-addition was performed to obtain the new target molecules 1-phenyl-4-(phenylselanyl)-1H-1,2,3-triazoles, with moderate to good yields ranging from 52 to 75%. The characterization of the final molecules is in process and, when finished, they will be sent for evaluation of biological activity. It is possible to conclude that the method used is simple and easy to access, an important factor for potential drugs against neglected diseases. After the assessment of bioactivity, it will be possible to identify the efficiency of these substances, as well as, if necessary, the optimization of their structure.

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Naturally Occurring Anthraquinones as Potential Inhibitors of SARS-CoV-2 Main Protease: A Molecular Docking Study

10.26434/chemrxiv.12245270.v1 ◽

2020 ◽

Author(s):

Sourav Das ◽

Atanu Singha Roy

Keyword(s):

Molecular Docking ◽

Drug Targets ◽

Docking Study ◽

Docking Studies ◽

World Health ◽

Molecular Docking Study ◽

Inhibitory Potential ◽

Novel Coronavirus ◽

Health Organization ◽

Potential Inhibitors

Background: The novel coronavirus (COVID-19) has quickly spread throughout the globe, affecting millions of people. The World Health Organization (WHO) has recently declared this infectious disease as a pandemic. At present, several clinical trials are going on to identify possible drugs for treating this infection. SARS-CoV-2 Mpro is one of the most critical drug targets for the blockage of viral replication. Method: The blind molecular docking analyses of natural anthraquinones with SARS-CoV-2 Mpro were carried out in an online server, SWISSDOCK, which is based on EADock DSS docking software. Results: Blind molecular docking studies indicated that several natural antiviral anthraquinones could prove to be effective inhibitors for SARS-CoV-2 Mpro of COVID-19 as they bind near the active site having the catalytic dyad, HIS41 and CYS145 through non-covalent forces. The anthraquinones showed less inhibitory potential as compared to the FDA approved drug, remdesivir. Conclusion: Among the natural anthraquinones, alterporriol Q could be the most potential inhibitor of SARS-CoV-2 Mpro among the natural anthraquinones studied here, as its ∆G value differed from that of remdesivir only by 0.51 kcal/ mol. The uses of these alternate compounds might be favorable for the treatment of the COVID-19.

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Synthesis, biological evaluation and molecular docking studies of new 2-ethoxy-4-{[3-alkyl(aryl)-4,5-dihydro-1H-1,2,4-triazol-5-on-4-yl]-azomethine}-phenyl benzenesulfonate derivatives on human aldose reductase enzyme

10.3762/bxiv.2021.31.v1 ◽

2021 ◽

Author(s):

Gül Özdemir ◽

Namık Kılınç ◽

Sevda Manap ◽

Murat Beytur ◽

Muzaffer Alkan ◽

...

Keyword(s):

Molecular Docking ◽

Antibacterial Activities ◽

Docking Studies ◽

Biological Evaluation ◽

Binding Energies ◽

Diffusion Method ◽

Alkyl Aryl ◽

Molecular Docking Studies ◽

New Compounds

A series of 2-ethoxy-4-{[3-alkyl(aryl)-4,5-dihydro-1H-1,2,4-triazol-5-on-4-yl]-azomethine}-phenyl benzenesulfonates (3) were synthesized from the reactions of 3-alkyl(aryl)-4-amino-4,5-dihydro-1H-1,2,4-triazol-5-ones (1) with 2-ethoxy-4-formyl-phenyl benzenesulfonate (2). N-acetyl derivatives (4) of compounds 3 were also obtained. Then, the compounds 3 have been treated with morpholine and 2,6-dimethylmorpholine in the presence of formaldehyde to synthesize 2-ethoxy-4-{[1-(morpholine-4-yl-methyl)-3-alkyl(aryl)-4,5-dihydro-1H-1,2,4-triazol-5-on-4-yl]-azomethine}-phenyl benzenesulfonates (5) and 2-ethoxy-4-{[1-(2,6-dimethylmorpholine-4-yl-methyl)-3-alkyl(aryl)-4,5-dihydro-1H-1,2,4-triazol-5-on-4-yl]-azomethine}-phenyl benzenesulfonates (6), respectively. The structures of twenty-six new compounds were identified by using elemental analysis, IR, 1H NMR, 13C NMR, and MS spectral data. In addition, in vitro antibacterial activities of the new compounds were evaluated against six bacteria such as Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis, Bacillus cereus and Klepsiella pneumonia according to agar well diffusion method. Furthermore, in order to determine the possible antidiabetic properties of the synthesized 1,2,4-triazole derivatives, inhibition effects on the AR enzyme were investigated and molecular docking studies were carried out to determine the receptor-ligand interactions of these compounds. IC50 values of triazole-derived compounds (6a, 6b, 6d-g) against AR enzyme were determined as 0.95 µM, 0.75 µM, 1.83 µM, 0.62 µM, 1.05 µM, 1.06 µM, respectively. Considering the docking scores and binding energies obtained docking studies, it has been shown that molecules fit very well to the active site of the AR enzyme.

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Repurposing strategies for Chagas disease therapy: the effect of imatinib and derivatives against Trypanosoma cruzi

Parasitology ◽

10.1017/s0031182019000234 ◽

2019 ◽

Vol 146 (8) ◽

pp. 1006-1012 ◽

Cited By ~ 7

Author(s):

M. R. Simões-Silva ◽

J. S. De Araújo ◽

R. B. Peres ◽

P. B. Da Silva ◽

M. M. Batista ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Chagas Disease ◽

Kinase Inhibitor ◽

Fixed Ratio ◽

Chronic Phase ◽

Host Cells ◽

Public Health Issue ◽

Mammalian Host ◽

Neglected Diseases

AbstractChagas disease (CD) is a neglected parasitic condition endemic in the Americas caused by Trypanosoma cruzi. Patients present an acute phase that may or not be symptomatic, followed by lifelong chronic stage, mostly indeterminate, or with cardiac and/or digestive progressive lesions. Benznidazole (BZ) and nifurtimox are the only drugs approved for treatment but not effective in the late chronic phase and many strains of the parasite are naturally resistant. New alternative therapy is required to address this serious public health issue. Repositioning and combination represent faster, and cheaper trial strategies encouraged for neglected diseases. The effect of imatinib (IMB), a tyrosine kinase inhibitor designed for use in neoplasias, was assessed in vitro on T. cruzi and mammalian host cells. In comparison with BZ, IMB was moderately active against different strains and forms of the parasite. The combination IMB + BZ in fixed-ratio proportions was additive. Novel 14 derivatives of IMB were screened and a 3,2-difluoro-2-phenylacetamide (3e) was as potent as BZ on T. cruzi but had low selectivity index. The results demonstrate the importance of phenotypic assays, encourage the improvement of IMB derivatives to reach selectivity and testify to the use of repurposing and combination in drug screening for CD.

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