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Synthesis and In Vitro Anti-Toxoplasma gondii Activity of Novel Thiazolidin-4-one Derivatives.

ABSTRACT: Recent findings on the biological activity of thiazolidin-4-ones and taking into account the lack of effective drugs used in the treatment of toxoplasmosis, their numerous side effects, as well as the problem of drug resistance of parasites prompted us to look for new agents. We designed and synthesized a series of new thiazolidin-4-one derivatives through a two-step reaction between 4-substituted thiosemicarbazides with hydroxybenzaldehydes followed by the treatment with ethyl bromoacetate; maleic anhydride and dimethyl acetylenedicarboxylate afforded target compounds. The thiazolidin-4-one derivatives were used to assess the inhibition of Toxoplasma gondii growth in vitro. All active thiazolidine-4-one derivatives (12 compounds) inhibited T. gondii proliferation in vitro much better than used references drugs both sulfadiazine as well as the synergistic effect of sulfadiazine + trimethoprim (weight ratio 5:1). Most active among them derivatives 94 and 95 showed inhibition of proliferation at about 392-fold better than sulfadiazine and 18-fold better than sulfadiazine with trimethoprim. All active compounds (82-88 and 91-95) against T. gondii represent values from 1.75 to 15.86 (CC₃₀/IC₅₀) lower than no cytotoxic value (CC₃₀).

SUBMITTER: Trotsko N

PROVIDER: S-EPMC6749389 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Synthesis and In Vitro Anti-<i>Toxoplasma gondii</i> Activity of Novel Thiazolidin-4-one Derivatives.

Trotsko Nazar N Bekier Adrian A Paneth Agata A Wujec Monika M Dzitko Katarzyna K

Molecules (Basel, Switzerland) 20190821 17

Recent findings on the biological activity of thiazolidin-4-ones and taking into account the lack of effective drugs used in the treatment of toxoplasmosis, their numerous side effects, as well as the problem of drug resistance of parasites prompted us to look for new agents. We designed and synthesized a series of new thiazolidin-4-one derivatives through a two-step reaction between 4-substituted thiosemicarbazides with hydroxybenzaldehydes followed by the treatment with ethyl bromoacetate; mal ...[more]

PMID: 31438527

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Project description:Background and purposeThe aim of this study was to evaluate the in vitro and in vivo anti-Toxoplasma gondii (T. gondii) effect of 5-oxo-hexahydroquinoline compounds. Moreover, molecular docking study of the compounds into the active site of enoyl-acyl carrier protein reductase (ENR) as a necessary enzyme for the vitality of apicoplast was carried out.Experimental approachA number of 5-oxo-hexahydoquinoline derivatives (Z1-Z4) were synthesized. The T. gondii tachyzoites of RH strain were treated by different concentrations (1-64 μg/mL) of the compounds. The viability of the encountered parasites with compounds was assessed using flow cytometry and propidium iodide (PI) staining. Due to the high mortality effect of Z3 and Z4 in vitro, their chemotherapy effect was assessed by inoculation of tachyzoites to four BALB/c mice groups (n = 5), followed by the gavage of various concentrations of the compounds to the mice. Molecular docking was done to study the binding affinity of the synthesized 5-oxo-hexahydroquinolines into ENR enzyme active site byusing AutoDock Vina® software. Docking was performed by a Lamarckian Genetic Algorithm with 100 runs.Findings / resultsFlow cytometry assay results indicated compounds Z3 and Z4 had relevant mortality effect on parasite tachyzoites. Besides, in vivo experiments were also performed and a partial increase of mice longevity between control and experiment groups was recorded. Molecular docking of Z3 and Z4 in the binding site of ENR enzyme indicated that the compounds were well accommodated within the binding site. Therefore, it could be suggested that these compounds may exert their anti-T. gondii activity through the inhibition of the ENR enzyme.Conclusion and implicationsCompounds Z3 and Z4 are good leads in order to develop better anti-T. gondii agents as they demonstrated both in vitro and in vivo inhibitory effects on tachyzoites viability and infection. Further studies on altering the route of administration along with additional pharmacokinetics evaluations are needed to improve the anti-T. gondii impacts of 5-oxo-hexahydroquinoline compounds.

Dataset Information

Synthesis and In Vitro Anti-Toxoplasma gondii Activity of Novel Thiazolidin-4-one Derivatives.

Publications

Synthesis and In Vitro Anti-<i>Toxoplasma gondii</i> Activity of Novel Thiazolidin-4-one Derivatives.

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