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.

In Vitro Effects of 2-{4-[Methylthio(methylsulfonyl)]phenyl}-3-substitutedthiazolidin-4-ones on the Acetylcholinesterase Activity in Rat Brain and Lymphocytes: Isoform Selectivity, Kinetic Analysis, and Molecular Docking.

This work evaluated the in vitro effect of thiazolidin-4-ones on the activity of AChE (total and isoforms) isolated from the cerebral cortex, hippocampus, and lymphocytes. Kinetic parameters were evaluated and molecular docking was performed. Our results showed that thiazolidinones derived from 4-(methylthio)benzaldehyde (1) and from 4-(methylsulfonyl)benzaldehyde (2) were capable of inhibiting the AChE activity in vitro. Three compounds, two with a propylpiperidine (1b and 2b) moiety and one with a 3-(diethylamino)propyl (1c) moiety showed IC50 values of 13.81 µM, and 3.13 µM (1b), 55.36 µM and 44.33 µM (1c) for cerebral cortex and hippocampus, respectively, and 3.11 µM for both (2b). Enzyme kinetics revealed that the type of AChE inhibition was mixed. Compound 1b inhibited the G1 and G4 AChE isoforms, while compounds 1c and 2b selectively inhibited the G4 isoform. Molecular docking showed a possible three-dimensional fit into the enzyme. Our findings showed that these thiazolidin-4-ones, especially those containing the propylpiperidine core, have a potential cholinesterase inhibitory activity and can be considered good candidates for future Alzheimer's therapy.

Synthesis of thiazolidin-4-ones and thiazinan-4-ones from 1-(2-aminoethyl)pyrrolidine as acetylcholinesterase inhibitors.

The present study describes the synthesis of a novel series of thiazolidin-4-one and thiazinan-4-one using 1-(2-aminoethyl)pyrrolidine as amine precursor. All compounds were synthesised by one-pot three component cyclocondensation reaction from the amine, a substituted benzaldehyde and a mercaptocarboxylic acid. The compounds were obtained in moderate to good yields and were identified and characterised by 1H, 13 C, 2 D NMR and GC/MS techniques. The compounds also were screened for their in vitro acetylcholinesterase (AChE) activity in hippocampus and cerebral cortex on Wistar rats. The six most potent compounds have been investigated for their cytotoxicity by cell viability assay of astrocyte primary culture, an important cell of central nervous system. We highlighted two compounds (6a and 6k) that had the lowest IC50 in hippocampus (5.20 and 4.46 µM) and cerebral cortex (7.40 and 6.83 µM). These preliminary and important results could be considered a starting point for the development of new AChE inhibitory agents.

2-(2-Methoxyphenyl)-3-((Piperidin-1-yl)ethyl)thiazolidin-4-One-Loaded Polymeric Nanocapsules: In Vitro Antiglioma Activity and In Vivo Toxicity Evaluation.

Among gliomas types, glioblastoma is considered the most malignant and the worst form of primary brain tumor. It is characterized by high infiltration rate and great angiogenic capacity. The presence of an inflammatory microenvironment contributes to chemo/radioresistance, resulting in poor prognosis for patients. Recent data show that thiazolidinones have a wide range of pharmacological properties, including anti-inflammatory and antiglioma activities. Nanocapsules of biodegradable polymers become an alternative to cancer treatment since they provide targeted drug delivery and could overcome blood-brain barrier. Therefore, here we investigated the in vitro antiglioma activity and the potential in vivo toxicity of 2- (2-methoxyphenyl) -3- ((piperidin-1-yl) ethyl) thiazolidin-4-one-loaded polymeric nanocapsules (4L-N). Nanocapsules were prepared and characterized in terms of particle size, polydispersity index, zeta potential, pH, molecule content and encapsulation efficiency. Treatment with 4L-N selectively decreased human U138MG and rat C6 cell lines viability and proliferation, being even more efficient than the free-form molecule (4L). In addition, 4L-N did not promote toxicity to primary astrocytes. We further demonstrated that the treatment with sub-therapeutic dose of 4L-N did not alter weight, neither resulted in mortality, toxicity or peripheral damage to Wistar rats. Finally, 4L as well as 4L-N did not alter makers of oxidative damage, such as TBARS levels and total sulfhydryl content, and did not change antioxidant enzymes SOD and CAT activity in liver and brain of treated rats. Taken together, these data indicate that the nanoencapsulation of 4L has potentiated its antiglioma effect and does not cause in vivo toxicity.

Thiosemicarbazones and 4-thiazolidinones indole-based derivatives: Synthesis, evaluation of antiproliferative activity, cell death mechanisms and topoisomerase inhibition assay.

In this study, we report the synthesis and structural characterization of a series of thiosemicarbazone and 4-thiazolidinones derivatives, as well as their in vitro antiproliferative activity against eight human tumor cell lines. For the most potent compound further studies were performed evaluating cell death induction, cell cycle profile, ctDNA interaction and topoisomerase IIα inhibition. A synthetic three-step route was established for compounds (2a-e and 3a-d) with yields ranging from 32 to 95%. Regarding antiproliferative activity, compounds 2a-e and 3a-d showed mean GI50 values ranging between 1.1 µM (2b) - 84.65 µM (3d). Compound 2b was the most promising especially against colorectal adenocarcinoma (HT-29) and leukemia (K562) cells (GI50 = 0.01 µM for both cell lines). Mechanism studies demonstrated that 24 h-treatment with compound 2b (5 µM) induced phosphatidylserine residues exposition and G2/M arrest on HT-29 cells. Moreover, 2b (50 µM) was able to interact with ctDNA and inhibited topoisomerase IIα activity. These results demonstrate the importance of thiosemicarbazone, especially the derivative 2b, as a promising candidate for anticancer therapy.

Thiazolidin-4-ones from 4-(methylthio)benzaldehyde and 4-(methylsulfonyl)benzaldehyde: Synthesis, antiglioma activity and cytotoxicity.

The present study assessed the biological potential of fourteen 1,3-thiazolidin-4-ones evaluating the antiglioma effect through decreasing of cell viability of glioblastoma multiform cells. The new compounds were efficient synthesized through multicomponent or multicomponent one-pot procedures in moderate to good yields (22-86%) from two arenealdehydes (4-(methylthio)benzaldehyde and 4-(methylsulfonyl)benzaldehyde), seven amines (aromatic and aliphatic) and mercaptoacetic acid. The compounds were identified and characterized by GC/MS and NMR, five of them by HRMS. Six thiazolidinones showed significant effect of decreasing cell viability compared to standard drug TMZ at 100 µM in 72 h in C6 cell line by MTT assay. The compounds 5b, 5e, 5g and 6e showed the best results in the screening at 100 µM and were analyzed at different concentrations (5, 25, 50, 100 and 250 µM). Compounds 5b and 5e showed statistical difference at 5 µM, 6e at 25 µM and 5g at 50 µM in 72 h of treatment. The cytotoxicity study in primary astrocytes cells was evaluated and none of fourteen compounds showed toxicity at 100 µM, eight of them were not cytotoxic at 250 µM, both in 72 h. In addition, the propidium iodide assay demonstrated that the compounds might induce cell death by necrosis. In conclusion, this work reports at least four compounds (5b, 5e, 5g and 6e) with potential anti-tumor effect against glioblastoma multiform cell presenting activity at low concentrations and safe profile of cytotoxicity.

Design, synthesis, molecular docking and biological evaluation of thiophen-2-iminothiazolidine derivatives for use against Trypanosoma cruzi.

In this study, we designed and synthesized a series of thiophen-2-iminothiazolidine derivatives from thiophen-2-thioureic with good anti-Trypanosoma cruzi activity. Several of the final compounds displayed remarkable trypanocidal activity. The ability of the new compounds to inhibit the activity of the enzyme cruzain, the major cysteine protease of T. cruzi, was also explored. The compounds 3b, 4b, 8b and 8c were the most active derivatives against amastigote form, with significant IC50 values between 9.7 and 6.03µM. The 8c derivative showed the highest potency against cruzain (IC50=2.4µM). Molecular docking study showed that this compound can interact with subsites S1 and S2 simultaneously, and the negative values for the theoretical energy binding (Eb=-7.39kcal·mol(-1)) indicates interaction (via dipole-dipole) between the hybridized sulfur sp(3) atom at the thiazolidine ring and Gly66. Finally, the results suggest that the thiophen-2-iminothiazolidines synthesized are important lead compounds for the continuing battle against Chagas disease.

2-Aryl-3-(2-morpholinoethyl)thiazolidin-4-ones: Synthesis, anti-inflammatory in vivo, cytotoxicity in vitro and molecular docking studies.

Seven new 4-thiazolidinones bearing the morpholino moiety were easily synthesized by one-pot reactions of 4-(2-aminoethyl)morpholine (2-morpholinoethylamine), arenealdehydes and mercaptoacetic acid refluxing toluene for 19 h with moderate to good yields (45-97%). These novel compounds were fully identified and characterized by NMR spectroscopy and mass spectrometry. Thiazolidin-4-ones in vivo anti-inflammatory activities were determined using a croton oil-induced ear edema model of inflammation in BALB C mice. The best results were found for compounds 4c (49.20 mmol/kg), 4d (49.20 mmol/kg) and 4f (52.48 mmol/kg), which showed the ability to decrease the ear edema in mice by 50%, 48% and 54%, respectively, when compared to the standard drug indomethacin. In addition, the in vitro cytotoxicity activity of thiazolidin-4-ones against Vero cells was also performed and four compounds (4a, 4c, 4d and 4f) showed no toxic effect at 500 µg/mL. A docking simulation of compounds into the 1Q4G (COX-1) and 4PH9 (COX-2) enzymes binding site was conducted. This preliminary result will guide us in for further studies to improve the anti-inflammatory activity.

Synthesis and antimicrobial activities of 5-Arylidene-thiazolidine-2,4-dione derivatives.

Antibiotic resistance is considered one of the world's major public health concerns. The main cause of bacterial resistance is the improper and repeated use of antibiotics. To alleviate this problem, new chemical substances against microorganisms are being synthesized and tested. Thiazolidines are compounds having many pharmacological activities including antimicrobial activities. For this purpose some thiazolidine derivatives substituted at position 5 in the thiazolidine nucleus were synthesized and tested against several microorganisms. Using a disc diffusion method, antimicrobial activity was verified against Gram-positive, Gram-negative, and alcohol acid resistant bacteria and yeast. The minimum inhibition concentrations (MIC) and minimum bactericidal concentrations (MBC) were determined. All derivatives showed antimicrobial activity mainly against Gram-positive bacteria, with MIC values ranging from 2 to 16 µg/mL.

Discovering Echinococcus granulosus thioredoxin glutathione reductase inhibitors through site-specific dynamic combinatorial chemistry.

In this study, we report a strategy using dynamic combinatorial chemistry for targeting the thioredoxin (Trx)-reductase catalytic site on Trx glutathione reductase (TGR), a pyridine nucleotide thiol-disulfide oxido-reductase. We chose Echinococcus granulosus TGR since it is a bottleneck enzyme of platyhelminth parasites and a validated pharmacological target. A dynamic combinatorial library (DCL) was constructed based on thiol-disulfide reversible exchange. We demonstrate the use of 5-thio-2-nitrobenzoic acid (TNB) as a non-covalent anchor fragment in a DCL templated by E. granulosus TGR. The heterodimer of TNB and bisthiazolidine (2af) was identified, upon library analysis by HPLC (IC50 = 24 µM). Furthermore, 14 analogs were synthetically prepared and evaluated against TGR. This allowed the study of a structure-activity relationship and the identification of a disulfide TNB-tricyclic bisthiazolidine (2aj) as the best enzyme inhibitor in these series, with an IC50 = 24 µM. Thus, our results validate the use of DCL for targeting thiol-disulfide oxido-reductases.

Efficient synthesis and antioxidant evaluation of 2-aryl-3-(pyrimidin-2-yl)-thiazolidinones.

In the present study, we reported the efficient synthesis of 11 3-(pyrimidin-2-yl)-thiazolidinones in good yields using molecular sieve as the desiccant agent. In addition, we have evaluated the antioxidant capacity of the synthesized compounds by the 2,2-diphenyl-2-picrylhydrazyl hydrate (DPPH•) and the 2,2-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS(+•) ) radicals scavenging assay. Six compounds showed antioxidant activity towards DPPH• (EC50 between 16.13 and 49.94 µg/mL) and also demonstrated excellent activity regarding ABTS(+•) (TEAC: 10.32-53.52). These results showed that compounds 3-(pyrimidin-2-yl)-thiazolidinones may be easily synthesized by a less expensive procedure and could be a good starting point to the development of new antioxidant compounds.

Synthesis, antifungal and cytotoxic activities of 2-aryl-3-((piperidin-1-yl)ethyl)thiazolidinones.

A series of sixteen novel thiazolidinone derivatives were synthesized from the efficient one-pot reaction of 2-(piperidin-1-yl)ethylamine, arenealdehydes and mercaptoacetic acid in good yields. Identification and characterization of products were achieved by NMR and GC-MS techniques. The in vitro antifungal activities of all synthesized compounds were evaluated against seven fungi: Candida albicans, Candida parapsilosis, Candida guilliermondii, Cryptococcus laurentii, Geotrichum sp, Trichosporon asahii and Rhodotorula sp. The results are expressed as the Minimum Inhibitory Concentration (MIC) and Minimum Fungicidal Concentration (MFC) and the best results were found against the Rhodotorula sp yeast. Two thiazolidinones (4h and 4l), MIC and MFC (16.5 µg/mL) proved to be 1.6 times more active than fluconazole and four of them (4b, 4e, 4g and 4k (MIC and MFC 25 µg/mL)) showed similar activity of standard drug to Rhodotorula sp. In addition, the cytotoxicity of thiazolidinones 4a-p was evaluated on cultured Vero cells and most of them displayed low toxicity (above 98 µg/mL). These preliminary and important results could be considered a starting point for the development of new antifungal agents.

Structural investigation of anti-Trypanosoma cruzi 2-iminothiazolidin-4-ones allows the identification of agents with efficacy in infected mice.

We modified the thiazolidinic ring at positions N3, C4, and C5, yielding compounds 6-24. Compounds with a phenyl at position N3, 15-19, 22-24, exhibited better inhibitory properties for cruzain and against the parasite than 2-iminothiazolidin-4-one 5. We were able to identify one high-efficacy trypanocidal compound, 2-minothiazolidin-4-one 18, which inhibited the activity of cruzain and the proliferation of epimastigotes and was cidal for trypomastigotes but was not toxic for splenocytes. Having located some of the structural determinants of the trypanocidal properties, we subsequently wished to determine if the exchange of the thiazolidine for a thiazole ring leaves the functional properties unaffected. We therefore tested thiazoles 26-45 and observed that they did not inhibit cruzain, but they exhibited trypanocidal effects. Parasite development was severely impaired when treated with 18, thus reinforcing the notion that this class of heterocycles can lead to useful cidal agents for Chagas disease.

Synthesis and cytotoxic activity of new acridine-thiazolidine derivatives.

Although their exact role in controlling tumour growth and apoptosis in humans remains undefined, acridine and thiazolidine compounds have been shown to act as tumour suppressors in most cancers. Based on this finding, a series of novel hybrid 5-acridin-9-ylmethylene-3-benzyl-thiazolidine-2,4-diones were synthesised via N-alkylation and Michael reaction. The cell viability was analysed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and DNA interaction assays were performed using electrochemical techniques.

Ultrasonics promoted synthesis of thiazolidinones from 2-aminopyridine and 2-picolilamine.

The efficient multicomponent synthesis of thiazolidinones from the reaction of arenealdehydes, mercaptoacetic acid and 2-picolilamine or 2-aminopyridine under ultrasound irradiation are reported. The reaction with 2-aminopyridine needs a Lewis acid catalysis to afford the corresponding 2-aryl-3-(pyridin-2-yl)-1,3-thiazolidin-4-ones. All novel compounds were identified and characterized by (1)H and (13)C NMR spectra. Applying the sonochemical methodology, two series of heterocyclic thiazolidinones were synthesized in good yields after short reaction times.

Synthesis and antimalarial activity of new heterocyclic hybrids based on chloroquine and thiazolidinone scaffolds.

A series of new 21 chloroquine heterocyclic hybrids containing either benzylamino fragment or N-(aminoalkyl)thiazolidin-4-one moiety were synthesized and screened for their antimalarial activity against chloroquine (CQ)-sensitive 3D7 and multidrug-resistance Dd2 strains of Plasmodium falciparum. Although no compounds more active than CQ against 3D7 was found; against Dd2 strain, six compounds, four of them with benzylamino fragment, showed an excellent activity, up to 3-fold more active than CQ. Non specific cytotoxicity on J774 macrophages was observed in some compounds whereas only two of them showed liver toxicity on HepG2 cells. In addition, all active compounds inhibited the ferriprotoporphyrin IX biocrystalization process in concentrations around to CQ. In vivo preliminary results have shown that at least two compounds are as active as CQ against Plasmodium berghei ANKA.

Efficient sonochemical synthesis of thiazolidinones from piperonilamine.

An efficient multicomponent reaction of arenealdehydes, mercaptoacetic acid and piperonilamine under ultrasound irradiation to afford 2-aryl-3-(piperonylmethyl)-1,3-thiazolidin-4-ones is reported. Applying this methodology, eleven heterocycles were synthesized and isolated in good yields after short reaction times.

Synthesis and evaluation of anti-Toxoplasma gondii and antimicrobial activities of thiosemicarbazides, 4-thiazolidinones and 1,3,4-thiadiazoles.

In this work we reported the synthesis and evaluation of anti-Toxoplasma gondii and antimicrobial activities in vitro of three new compound series obtained from ethyl(5-methyl-1-H-imidazole-4-carboxylate): acylthiosemicarbazide analogues 3a-d, 4-thiazolidinone analogues 4a-d and 1,3,4-thiadiazole analogues 5a-d. All synthesized compounds were characterized by IR, (1)H, (13)C NMR and HRMS. The majority of the tested compounds show excellent anti-T. gondii activity when compared to hydroxyurea and sulfadiazine. In addition it was also shown that most of the compounds in this study have a better performance against intracellular tachyzoites. The results for antimicrobial activity evaluation showed weak antibacterial and antifungal activities for all the tested molecules, when compared with the standard drugs (chloramphenicol and rifampicin for antibacterial activity; nistatin and ketoconazole for antifungal activity).

Synthesis, antimicrobial and cytotoxic activities of some 5-arylidene-4-thioxo-thiazolidine-2-ones.

Several 5-arylidene-4-thioxo-thiazolidine-2-ones (3a-n) were synthesized and evaluated as antimicrobial agents against representative strains, including multidrug-resistant strains of clinical isolates. Also, the antiproliferative activity was evaluated against two human carcinoma cell lines (NCI-H292 and HEp-2). The compounds containing the 5-arylidene subunit presented greater antimicrobial activities against Gram positive bacteria, including the multidrug-resistant clinical isolates, than the 4-thioxo-thiazolidine-2-one. Important SAR information was also gathered, such as the contribution of thiocarbonyl attached at 4-position on the thiazolidine heterocyclic for antimicrobial properties. None of the derivatives exhibited significant antiproliferative activity against the human carcinoma cell lines.

Lithium thiazolidine-4-carboxylate: synthesis, spectroscopic characterization and preliminary in vitro cytotoxic studies in human HeLa cells.

A new water-soluble lithium salt of thiazolidine-4-carboxylic acid was synthesized and characterized by chemical and spectroscopic techniques. Elemental and mass spectrometric (ESI-MS) analyses of the solid compound fit to the composition LiC(4)H(6)NSO(2). (1)H, (13)C nuclear magnetic resonance (NMR), [(1)H-(15)N] NMR and infrared (IR) analyses permitted to elucidate the structure of the compound. Biological activity was evaluated by cytotoxic analysis using HeLa cells. Determination of cell death was assessed using a tetrazolium salt colorimetric assay, which reflects the cells viability.