Triazole-Based Compound as a Candidate To Develop Novel Medicines To Treat Toxoplasmosis

This article reports anti-Toxoplasma gondii activity of 3-(thiophen-2-yl)-1,2,4-triazole-5-thione. The compound displayed significant and reproducible antiparasitic effects at nontoxic concentrations for the host cells, with an experimentally determined 50% inhibitory concentration (IC50) at least 30 times better than that of the known chemotherapeutic agent sulfadiazine. Purine nucleoside phosphorylase was defined as the probable target for anti-Toxoplasma activity of the tested compound. These results provide the foundation for future work to develop a new class of medicines to better treat toxoplasmosis

1,4-disubstituted thiosemicarbazide derivatives are potent inhibitors of toxoplasma gondii proliferation.

A series of 4-arylthiosemicarbazides substituted at the N1 position with a 5-membered heteroaryl ring was synthesized and evaluated in vitro for T. gondii inhibition proliferation and host cell cytotoxicity. At non-toxic concentrations for the host cells all studied compounds displayed excellent anti-parasitic effects when compared to sulfadiazine, indicating a high selectivity of their anti-T. gondii activity. The differences in bioactivity investigated by DFT calculations suggest that the inhibitory activity of 4-arylthiosemicarbazides towards T. gondii proliferation is connected with the electronic structure of the molecule. Further, these compounds were tested as potential antibacterial agents. No growth-inhibiting effect on any of the test microorganisms was observed for all the compounds, even at high concentrations

Determination of the Primary Molecular Target of 1,2,4-Triazole-Ciprofloxacin Hybrids

We have synthesized and examined the antibacterial activity, toxicity and affinity towards bacterial type II topoisomerases of a series of 1,2,4-triazole-ciprofloxacin hybrids. A number of these compounds displayed enhanced activity against Gram-positive and Gram-negative bacteria when compared to ciprofloxacin. The toxic concentrations of the obtained derivatives, evaluated on HEK-293 cells using MTT assay, were much higher than concentrations required to produce antibacterial effect. Finally, the results of enzymatic studies showed that the analyzed compounds demonstrated other preferences as regards primary and secondary molecular targets than ciprofloxacin.This research was supported by the Ministry of Science and Higher Education under Iuventus Plus grant No. IP2014 037473. Tomasz Plech is a recipient of the Fellowship for Young Researchers with Outstanding Scientific Achievements from the Medical University of Lublin (Lublin, Poland)

Pharmacological and Structure-Activity Relationship Evaluation of 4-aryl-1-Diphenylacetyl(thio)semicarbazides

This article describes the synthesis of six 4-aryl-(thio)semicarbazides (series a and b) linked with diphenylacetyl moiety along with their pharmacological evaluation on the central nervous system in mice and computational studies, including conformational analysis and electrostatic properties. All thiosemicarbazides (series b) were found to exhibit strong antinociceptive activity in the behavioural model. Among them, compound 1-diphenylacetyl-4-(4-methylphenyl)thiosemicarbazide 1b was found to be the most potentan algesic agent, whose activity is connected with the opioid system. For compounds from series a significant anti-serotonergic effect, especially for compound 1-diphenylacetyl-4- (4-methoxyphenyl)semicarbazide 2b was observed. The computational studies strongly support the obtained results

Preclinical evaluation of 1,2,4-triazole-based compounds targeting voltage-gated sodium channels (VGSCs) as promising anticonvulsant drug candidates

Epilepsy is a chronic neurological disorder affecting nearly 65–70 million people worldwide. Despite the observed advances in the development of new antiepileptic drugs (AEDs), still about 30-40% of patients cannot achieve a satisfactory seizure control. In our current research, we aimed at using the combined results of radioligand binding experiments, PAMPA-BBB assay and animal experimentations in order to design a group of compounds that exhibit broad spectrum of anticonvulsant activity. The synthesized 4-alkyl-5-substituted-1,2,4-triazole-3-thione derivatives were primarily screened in the maximal electroshock-induced seizure (MES) test in mice. Next, the most promising compounds (17, 22) were investigated in 6 Hz (32 mA) psychomotor seizure model. Protective effect of compound 22 was almost similar to that of levetiracetam. Moreover, these compounds did not induce genotoxic and hemolytic changes in human cells as well as they were characterized by low cellular toxicity. Taking into account the structural requirements for good anticonvulsant activity of 4-alkyl-5-aryl-1,2,4-triazole-3-thiones, it is visible that small electron-withdrawing substituents attached to phenyl ring have beneficial effects both on affinity towards VGSCs and protective activity in the animal models of epilepsy

Studies on the Anticonvulsant Activity and Influence on GABA-ergic Neurotransmission of 1,2,4-Triazole-3-thione- Based Compounds

The anticonvulsant activity of several 1,2,4-triazole-3-thione derivatives on mouse maximal electroshock-induced seizures was tested in this study. Characteristic features of all active compounds were rapid onset of action and long lasting effect. Structure-activity observations showed that the probability of obtaining compounds exerting anticonvulsant activity was much higher when at least one of the phenyl rings attached to 1,2,4-triazole nucleus had a substituent at the para position. The obtained results, moreover, permit us to conclude that despite the structural similarity of loreclezole (second-generation anticonvulsant drug) and the titled compounds, their anticonvulsant activity is achieved via completely different molecular mechanisms

Determination of the Primary Molecular Target of 1,2,4-Triazole-Ciprofloxacin Hybrids

We have synthesized and examined the antibacterial activity, toxicity and affinity towards bacterial type II topoisomerases of a series of 1,2,4-triazole-ciprofloxacin hybrids. A number of these compounds displayed enhanced activity against Gram-positive and Gram-negative bacteria when compared to ciprofloxacin. The toxic concentrations of the obtained derivatives, evaluated on HEK-293 cells using MTT assay, were much higher than concentrations required to produce antibacterial effect. Finally, the results of enzymatic studies showed that the analyzed compounds demonstrated other preferences as regards primary and secondary molecular targets than ciprofloxacin

UVB Radiation and Selected Tryptophan-Derived AhR Ligands—Potential Biological Interactions in Melanoma Cells

Excessive UV exposure is considered the major environmental factor in melanoma progression. Human skin is constantly exposed to selected tryptophan-derived aryl hydrocarbon receptor (AhR) ligands, including kynurenine (KYN) and kynurenic acid (KYNA), as they are endogenously produced and present in various tissues and body fluids. Importantly, recent studies confirmed the biological activity of KYN and KYNA toward melanoma cells in vitro. Thus, in this study, the potential biological interactions between UVB and tryptophan metabolites KYN and KYNA were studied in melanoma A375, SK-MEL-3, and RPMI-7951 cells. It was shown that UVB enhanced the antiproliferative activity of KYN and KYNA in melanoma cells. Importantly, selected tryptophan-derived AhR ligands did not affect the invasiveness of A375 and RPMI-7951 cells; however, the stimulatory effect was observed in SK-MEL-3 cells exposed to UVB. Thus, the effect of tryptophan metabolites on metabolic activity, cell cycle regulation, and cell death in SK-MEL-3 cells exposed to UVB was assessed. In conclusion, taking into account that both UVB radiation and tryptophan-derived AhR ligands may have a crucial effect on skin cancer formation and progression, these results may have a significant impact, revealing the potential biological interactions in melanoma cells in vitro