Here, we describe the synthesis and anticonvulsant activity of thiazole-bearing hybrids based on 2-imino-4-thiazolidinone and 2,4-dioxothiazolidine-5-carboxylic acid cores. The structure of target compounds was based on the following: (i) A combination of two thiazole cores; (ii) similarity to ralitolin’s structure; (iii) the compliance with structural requirements for the new anticonvulsants. Target compounds were synthesized via known approaches based on Knoenavegel reaction, alkylation reaction, and one-pot three-component reaction. Anticonvulsant properties of compounds were evaluated in two different models—pentylenetetrazole-induced seizures and maximal electroshock seizure tests. Among the tested compounds 5Z-(3-nitrobenzylidene)-2-(thiazol-2-ylimino)-thiazolidin-4-one Ib, 2-[2,4-dioxo-5-(thiazol-2- ylcarbamoylmethyl)-thiazolidin-3-yl]-N-(2-trifluoromethylphenyl)acetamide IId and (2,4-dioxo-5- (thiazol-2-ylcarbamoylmethylene)-thiazolidin-3-yl)acetic acid ethyl ester IIj showed excellent anticonvulsant activity in both models. The directions of compounds modification based on SAR aspects were discussed. The results of the study provide a basis for further study of the anticonvulsant properties of selected thiazole-thiazolidinones.

Neuroinflammation is an integral part of epilepsy pathogenesis and other convulsive conditions, and non-steroidal anti-inflammatory drugs (NSAIDs) present a potent tool for the contemporary search and design of novel anticonvulsants. In the present paper, evaluation of the anticonvulsant activity of the potential NSAID dual COX-2/5-LOX inhibitor darbufelone methanesulfonate using an scPTZ model in mice in dose 100 mg/kg is reported. Darbufelone possesses anticonvulsant properties in the scPTZ model and presents interest for in-depth studies as a possible anticonvulsant multi-target agent with anti-inflammatory activity. The series of 4-thiazolidinone derivatives have been synthesized following the analogue-based drug design and hybrid-pharmacophore approach using a darbufelone matrix. The synthesized derivatives showed a significant protection level for animals in the scPTZ model and are promising compounds for the design of potential anticonvulsants with satisfactory drug-like parameters.

The aim. The purpose of this review is to summarize data on the synthesis and structural modification of heterocyclic systems with triazole and thiadiazole fragments in molecules as promising objects in bioorganic and medicinal chemistry. Materials and methods. The research based on bibliosemantic and analytical methods using bibliographic and abstract databases, as well as databases of chemical compounds. Results. Modern medicinal chemistry faces many challenges, one of which is the determination of the activity and specificity of therapeutic agents. Recent scientific data showed that triazoles and/or thiadiazoles have broad spectrum of biological activities, in particular antimicrobial, antifungal, antiviral, anticancer and anticonvulsant. Synthetic research allows to propose a whole number of new molecular design directions of biological active triazole and/or thiadiazole derivatives, as well as to obtain directed library that include hundreds of new compounds. This review is an effort to summarize data of its analgesic and anti-inflammatory activity over the last decade. We summarized and analyzed the series of triazole and/or thiadiazole derivatives and provided data of their structure-activity relationship. For optimization and rational design of highly active molecules with optimal «drug-like» characteristics and discovering of possible mechanism of action SAR, QSAR analysis and molecular docking were summarized. Conclusions. It has been shown that heterocyclic systems containing fragments of triazole and / or thiadiazole are a significant source of promising analgesic and/or anti-inflammatory agents. It has been established that the mentioned heterocyclic derivatives have a high selectivity of action, low toxicity and an effect commensurate with standard drugs

Heat trauma (HT) is an urgent medical and social problem. Heat damage is a widespread effect of the environment on humans, driven by global warming, military conflicts, technological disasters, work in hot environments, and engagement in extreme sports and tourism. The aim of the study: to propose a model of acute HT in rats that does not cause the death of animals, to determine the dependence of thermoresistance on gender, and to compare the effectiveness of the thermoprotective effects of a range of non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol, and glucosamine hydrochloride in this model. Materials and Methods: The experiment was conducted on adult white rats of both genders. Acute HT was modelled by using a specially developed method involving heat exposure to animals at +55 °C for 30 minutes, followed by a recovery period of 60 minutes. Rectal temperature was measured every 15 minutes. The degree of hyperthermia in males and females was determined. The presence and intensity of the thermoprotective effect of glucosamine hydrochloride (G h/ch), diclofenac sodium, acetylsalicylic acid (ASA), nimesulide, etoricoxib, celecoxib, and paracetamol were evaluated through intragastric administration 60 minutes before heat exposure. The results were analyzed using the STATISTICA 12.0 program. Results: It was established that heat exposure at +55 °C for 30 minutes effectively replicates acute HT in rats without causing animal fatalities, adhering to bioethical requirements. Body temperature increases by 10-13 %, characterized as a heat stroke. Occasionally, thermoresistant animals are encountered, where the temperature increase during the first 15 minutes of exposure is less than 1 °C. These animals should not be used for further modelling of heat trauma. Male rats are more sensitive to the effect of high environmental temperatures than females, exhibiting greater hyperthermia (temperature increase of 5.03±0.39°C compared to 3.72±0.22 °C in females, p<0.01). The thermoprotective effect of glucosamine hydrochloride depends on gender, being more pronounced in males. Among the 6 tested COX inhibitors, the most significant thermoprotective effect was observed in the highly selective COX-2 inhibitor celecoxib and the weakly selective central inhibitor paracetamol, warranting in-depth research into their impact on organ and system states following heat trauma, as well as the mechanisms of their thermoprotective action. The thermoprotective effect is not associated with selectivity towards COX (cyclooxygenase): it is not observed in the highly selective COX-2 inhibitor etoricoxib and moderately selective COX-2 inhibitor nimesulide, as well as in non-selective COX inhibitors such as diclofenac sodium and aspirin, which also slows down the recovery of body temperature after heat exposure. Conclusions: A convenient and simple model of acute HT in rats is proposed, demonstrating higher thermosensitivity and a more pronounced thermoprotective effect of glucosamine hydrochloride in males. A significant thermoprotective effect was identified in celecoxib and paracetamol, surpassing other investigated NSAIDs. The mechanism and specific features of this effect require further clarification

"Non-antiepileptic" drugs have a strong potential as adjuvants in multidrug-resistant epilepsy treatment. In previous study the influence of low doses of digoxin, which do not affect the myocardium, on the anticonvulsant potential of classical commonly used anti-epileptic drugs under conditions of seizures, induced by pentylenetetrazole and maximal electroshock, has been investigated. The aim of the study was to investigate the influence of digoxin at a sub-cardiotonic dose on the anticonvulsant potential of carbamazepine and lamotrigine in experimental seizures with different neurochemical mechanisms. Material and methods: A total of 192 random-bred male albino mice weighting 22–25 g were used. Carbamazepine and lamotrigine were administered intragastrically in conditionally effective (ED50) and sub-effective (½ ED50) doses: carbamazepine at doses of 100 and 50 mg/kg; lamotrigine at doses of 25 and 12.5 mg/kg. Digoxin was administered subcutaneously at a sub-cardiotonic dose of 0.8 mg/kg as an adjuvant to carbamazepine and lamotrigine in ½ ED50. Picrotoxin (2.5 mg/kg subcutaneously); thiosemicarbazide (25 mg/kg intraperitoneally); strychnine (1.2 mg/kg subcutaneously); camphor (1000 mg/kg intraperitoneally) were used as convulsant agents. Results: It was found that digoxin not only has its own permanent anticonvulsant effect on different models of paroxysms with different neurochemical mechanisms of development, but also significantly enhances the anticonvulsant potential of carbamazepine (to a lesser extent – lamotrigine) regardless of the pathogenesis of experimental paroxysms. Conclusion: Based on the results, it can be concluded that digoxin has a high potential as an adjuvant medicine in complex epilepsy treatment because it enhances the efficiency of low-dose traditional anticonvulsants carbamazepine and lamotrigine