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).

The Current Directions of Searching for Antiparasitic Drugs

“…In the first stage, thiosemicarbazones were obtained by condensing thiosemicarbazide derivatives with hydroxybenzaldehydes. In the next stage in the first series of compounds thiazolidin-4-one derivatives were obtained, the second series (74-88) consisted of (4-oxothiazolidin-5-yl)acetic acid derivatives, and the third series of (4-oxothiazolidine)acid derivatives -5-ylidene)acetic acid (89-104) (Figure 11) [71]. Among the last series, derivatives 94 and 95 turned out to be the most active compounds.…”

“…However, the lack of a substituent in this fragment, as in the case of compound 91 , increases the activity of the substance, IC 50 = 92.88 ± 21.91 μM. The introduction of a chlorine or bromine atom, as in the case of compounds 94 and 95 , increases their activity IC 50 ~27–28 ± 5.05 μM [ 71 ].…”

Conformational Properties and Putative Bioactive Targets for Novel Thiosemicarbazone Derivatives

“…The main synthetic route to thiazolidine-4-ones is the reaction between thiosemicarbazones and α-halo carboxylic esters, with several interesting structures obtained recently with this method [ 10 , 11 , 12 , 13 ].…”

Anticancer, Antioxidant Activities and Molecular Docking Study of Thiazolidine -4-one and Thiadiazol Derivatives

“…And have a strong biological activity, therefore widely used in the pharmaceutical, medicinally, and as pesticides [22][23][24]. Therefore, for the synthesis of new 1,3,4-thiadiazolines and thaiazolidinone derivatives, there are several methods to obtain 1,3,4-thiadiazoles, mostly achieved by condensation substituted thiohydrazide with thiocyanate, also by the reaction between thiosemicarbazone with acetic anhydride [25][26][27][28][29]. The heterocyclic thaiazolidinone is mostly achieved by the reaction from the reaction isomethan group with thioglycolic acid [30], also a reaction chloroacetic acid with thiosemicarbazones [31][32][33].…”