Discovery of Potent and Selective Halogen-Substituted Imidazole-Thiosemicarbazides for Inhibition of Toxoplasma gondii Growth In Vitro via Structure-Based Design

Paneth, Agata; Węglińska, Lidia; Bekier, Adrian; Stefaniszyn, Edyta; Wujec, Monika; Trotsko, Nazar; Hawrył, Anna; Hawrył, Mirosław; Dzitko, Katarzyna

doi:10.3390/molecules24081618

Cited by 17 publications

(31 citation statements)

References 31 publications

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“…Recently [ 25 ], we published a new series of halophenyl-substituted imidazole thiosemicarbazides with much better and selective anti- Toxoplasma effects than sulfadiazine (IC 50s 10.30–113.45, selectivity index SI 3.15–19.16, vs. 2721.45 μg/mL, SI < 0.92). Moreover, the most potent of them inhibited tachyzoites proliferation more potently and more selectively than trimethoprim (IC 50 12.13 μg/mL, SI > 2.64) and more potently than sulfadiazine in combination with trimethoprim (IC 50 37.15 μg/mL).…”

Section: Introductionmentioning

confidence: 99%

1,3,4-Thiadiazoles Effectively Inhibit Proliferation of Toxoplasma gondii

Węglińska

Bekier

Dzitko

et al. 2021

Cells

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Congenital and acquired toxoplasmosis caused by the food- and water-born parasite Toxoplasma gondii (T. gondii) is one of the most prevalent zoonotic infection of global importance. T. gondii is an obligate intracellular parasite with limited capacity for extracellular survival, thus a successful, efficient and robust host cell invasion process is crucial for its survival, proliferation and transmission. In this study, we screened a series of novel 1,3,4-thiadiazole-2-halophenylamines functionalized at the C5 position with the imidazole ring (1b–12b) for their effects on T. gondii host cell invasion and proliferation. To achieve this goal, these compounds were initially subjected to in vitro assays to assess their cytotoxicity on human fibroblasts and then antiparasitic efficacy. Results showed that all of them compare favorably to control drugs sulfadiazine and trimethoprim in terms of T. gondii growth inhibition (IC50) and selectivity toward the parasite, expressed as selectivity index (SI). Subsequently, the most potent of them with meta-fluoro 2b, meta-chloro 5b, meta-bromo 8b, meta-iodo 11b and para-iodo 12b substitution were tested for their efficacy in inhibition of tachyzoites invasion and subsequent proliferation by direct action on established intracellular infection. All the compounds significantly inhibited the parasite invasion and intracellular proliferation via direct action on both tachyzoites and parasitophorous vacuoles formation. The most effective was para-iodo derivative 12b that caused reduction in the percentage of infected host cells by 44% and number of tachyzoites per vacuole by 93% compared to non-treated host cells. Collectively, these studies indicate that 1,3,4-thiadiazoles 1b–12b, especially 12b with IC50 of 4.70 µg/mL and SI of 20.89, could be considered as early hit compounds for future design and synthesis of anti-Toxoplasma agents that effectively and selectively block the invasion and subsequent proliferation of T. gondii into host cells.

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Section: Introductionmentioning

confidence: 99%

1,3,4-Thiadiazoles Effectively Inhibit Proliferation of Toxoplasma gondii

Węglińska

Bekier

Dzitko

et al. 2021

Cells

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“…Hitherto, our research group identified thiazolidine-chlorophenylhydrazone hybrids with antiproliferative activity comparable to that of irinotecan [17] and thiazolidine-thiohydantoin and thiazolidine-chlorophenylthiosemicarbazone hybrids with antibacterial activity comparable to that of cefuroxime [18,19]. The results of the latest research work [20,21,22] in the field of inhibitory activity of thiosemicarbazide derivatives against protozoan T. gondii , identified that in particular those compounds which in position 4 contain halogen(alkyl)phenyl group are characterized by antiparasitic activity much more advantageous than the commonly used drug sulfadiazine (IC 50 25.67–68.18 μM vs. 10,873.71 μM). These results prompted us to start a pilot synthesis of a series of thiazolidin-4-one derivatives containing in their structure the above-mentioned a thiosemicarbazide moiety (shown in red in Figure 1) to confirm (or exclude) their inhibitory potential against T. gondii tachyzoites; from our research to date, it appears that, although there are objective indications of anti-toxoplasmic activity for the proposed group of compounds, strengthened by reports by Góes and colleagues [14,15,16], in practice these compounds may be quite significantly different in bioactivity or even inactive.…”

Section: Resultsmentioning

confidence: 99%

“…The influence of compounds and drugs on T. gondii proliferation was described in our previous work [20,21,22]. Due to the fact that T. gondii is an intracellular parasite and host cells should not be destroyed by the cytotoxic concentration of compounds, to determine the initial dose of each compound to antiparasitic study CC 30 value was calculated (data not shown).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2019

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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).

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“…In our laboratory, we obtained earlier and evaluated some thiosemicarbazides with good activity towards T. gondii [ 21 , 22 ]. Continuing in this direction, we designed and obtained thiosemicarbazide derivatives having a nitroimidazole substituent found in Metronidazole—the popular available antiparasitic drug.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Anthelmintic Activity of New Thiosemicarbazide Derivatives—A Preliminary Study

et al. 2020

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Parasitic infections caused by different species of intestinal helminths still poses a threat to public health. There is a need to search for new, effective anthelmintic drugs. A series of novel thiosemicarbazides were synthesized and evaluated for their in vitro anthelmintic activity. The preliminary results showed that the most of synthesized compounds were very active. 4-Phenyl-1-[(1-methyl-4-nitroimidazol-2-yl)carbonyl]thiosemicarbazide and 4-(3-chlorophenyl)-1-[(1-methyl-4-nitroimidazol-2-yl)carbonyl]thiosemicarbazide showed a 100% mortality of nematodes and a high anthelmintic activity in both tested concentrations.

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Discovery of Potent and Selective Halogen-Substituted Imidazole-Thiosemicarbazides for Inhibition of Toxoplasma gondii Growth In Vitro via Structure-Based Design

Cited by 17 publications

References 31 publications

1,3,4-Thiadiazoles Effectively Inhibit Proliferation of Toxoplasma gondii

1,3,4-Thiadiazoles Effectively Inhibit Proliferation of Toxoplasma gondii

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

Synthesis and Anthelmintic Activity of New Thiosemicarbazide Derivatives—A Preliminary Study

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