Thiadiazine Derivatives Research Articles

Assessment In vitro and In silico of the Activity of Thiadiazines as NorA Efflux Pump Inhibitors.

Antimicrobials fight microorganisms, preventing and treating infectious diseases. However, antimicrobial resistance (AMR) is a growing concern due to the inappropriate and excessive use of these drugs. Several mechanisms can lead to resistance, including efflux pumps such as the NorA pump in Staphylococcus aureus, which reduces the effectiveness of fluoroquinolones. Thiadiazines are heterocyclic compounds whose chemical structure resembles that of cephalosporins. Therefore, these compounds and their derivatives have been studied for their potential in combating increased bacterial resistance. To analyze this hypothesis, direct activity assays, antibiotic action-modifying activity, fluorescence assays to evaluate the retention of ethidium bromide inside bacteria, and molecular docking were carried out. These experiments involved serial dilutions in microplates against Staphylococcus aureus strain 1199B under the influence of six thiadiazine derivatives (IJ10, IJ11, IJ21, IJ22, IJ23, and IJ25). The tests revealed that, despite not showing effective direct activity, some thiadiazine derivatives (IJ11, IJ21, and IJ22) inhibited the function of the bromide pump both in microdilution tests and in fluorescence and docking assays. Particularly, the IJ11 compound stood out for its activity similar to efflux inhibitors, as well as its inhibition of the norfloxacin pump of this bacterium. Among the results of this study, it deserves to be highlighted for anchoring future experiments, as it represents the first investigation of this group of thiadiazine derivatives against the NorA pump.

Design, Synthesis, In Vitro, and In Silico Studies of Some Newly Fused Thiadiazole and Thiadiazine Derivatives Incorporating 1,2,4-Triazole Derivatives as Aromatase Enzyme Inhibitor

Design, Synthesis, In Vitro, and In Silico Studies of Some Newly Fused Thiadiazole and Thiadiazine Derivatives Incorporating 1,2,4-Triazole Derivatives as Aromatase Enzyme Inhibitor

An efficient one‐pot, three‐component synthesis of novel [1,2,4]triazolo [4′,3′:1,5][1,2,4]triazolo[3,4‐b][1,3,4]thiadiazine derivatives and their molecular docking studies

AbstractA series of novel [1,2,4]triazolo[4′,3′:1,5][1,2,4]triazolo[3,4‐b][1,3,4]thiadiazines (4a‐p) were synthesized from the reaction of 4‐amino‐5‐hydrazinyl‐4H‐1,2,4‐triazole‐3‐thiol (1) with different bromoethanones (2a‐p) and substituted benzoic acids (3) via a one‐pot, three‐component reaction with good to excellent yields. The new fused tri‐cyclic system was achieved without using a catalyst and metal by cyclo‐condensation reaction through a one‐pot approach. The structures of newly synthesized molecules were confirmed by using IR, 1H‐NMR, 13C‐NMR, Mass spectral, and analytical data. Molecular docking studies were carried out for the newly synthesized compounds against human cancer receptors (2TKB) with good results.

The Effect of Two Novel Substituted Thiazole and Thiadiazine Derivatives on Experimental Type-1 Diabetes Mellitus

Thiazole and thiadiazine derivatives are heterocyclic compounds containing nitrogen and sulfur. They have a wide range of medicinal applications. The present study aimed to investigate the anti-hyperglycemic and antioxidant properties of two novel thiazole and thiadiazine derivatives using streptozotocin (STZ)-induced diabetic mice. The two synthesized compounds significantly reduced hyperglycemia and restored pancreatic insulin secretion in the treated diabetic mice. Also, the two compounds lead to a decrease in the serum triglyceride level and an increase in pancreatic SOD activity in the treated diabetic mice. The LD50 value of the two compounds using the IP injection route was greater than 300 mg/kg body weight. Further studies on these two compounds, especially mechanisms of action, are required to develop them into potential anti-diabetic drugs.

Synthetic Methods and Pharmacological Potentials of Triazolothiadiazines: A Review.

This review article examines the synthetic pathways for triazolothiadiazine derivatives, such as triazolo[3,4-b]thiadiazines, triazolo[5,1-b]thiadiazines, and triazolo[4,3-c]thiadiazines, originating from triazole derivatives, thiadiazine derivatives, or thiocarbohydrazide. The triazolothiadiazine derivatives exhibit several biological actions, including antibacterial, anticancer, antiviral, antiproliferative, analgesic, anti-inflammatory, and antioxidant properties. The review article aims to assist researchers in creating new biologically active compounds for designing target-oriented triazolothiadiazine-based medicines to treat multifunctional disorders.

Nickel Pincer Complexes Catalyzed Sustainable Synthesis of 3,4-Dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxides via Acceptorless Dehydrogenative Coupling of Primary Alcohols.

We report the atom-economic and sustainable synthesis of biologically important 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide (DHBD) derivatives from readily available aromatic primary alcohols and 2-aminobenzenesulfonamide catalyzed by nickel(II)-N∧N∧S pincer-type complexes. The synthesized nickel complexes have been well-studied by elemental and spectroscopic (FT-IR, NMR, and HRMS) analyses. The solid-state molecular structure of complex 2 has been authenticated by a single-crystal X-ray diffraction study. Furthermore, a series of 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide derivatives have been synthesized (24 examples) utilizing a 3 mol % Ni(II) catalyst through acceptorless dehydrogenative coupling of benzyl alcohols with benzenesulfonamide. Gratifyingly, the catalytic protocol is highly selective with the yield up to 93% and produces eco-friendly water/hydrogen gas as byproducts. The control experiments and plausible mechanistic investigations indicate that the coupling of the in situ generated aldehyde with benzenesulfonamide leads to the desired product. In addition, a large-scale synthesis of one of the thiadiazine derivatives unveils the synthetic usefulness of the current methodology.

SYNTHESIS AND ANTIOXIDANT ACTIVITY OF THIADIAZINE DERIVATIVES WITH PHENOLIC FRAGMENTS

A series of thiocarbohydrazones based on 3,5-di-tert-butyl-4-hydroxybenzaldehyde, salicylaldehyde, vanillin and 4,6-di-tert-butyl-2,3-dihydroxybenzaldehyde were synthesized. The reaction between thiocarbohydrazones and bromoacetylcoumarin was used to obtain and characterize a number of thiadiazine derivatives containing a phenolic fragment. The yields were 56–90%. The structural properties of the synthesized substances were studied by IR-Fourier, 1H, 13C NMR spectroscopy. In the IR spectra of thiadiazines there are characteristic bands of the stretching vibrations of the OH group (3622 cm-1), N-H bond (3450 cm-1), double bonds C=C and C=N 1608 and 1541 cm-1, respectively. In contrast to the spectrum of the starting compounds, there is a peak corresponding to vibrations of the C=O bond (1722 cm-1), which appeared due to the coumarin fragment. The 1Н NMR spectra of the obtained compounds contain peaks at 3.9 ppm, corresponding to the protons of the thiadiazine fragment. There are no signals at 6.8 ppm, related to the CH proton of the thiazole ring, and there is also a set of peaks in the region of 7.5-8.4 ppm., characteristic of the coumarin ring. Antioxidant activity of all products was determined in vitro: radical cation inhibition activity was determined using 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate) and electron donating activity was determined by ferric reduction ability using the ferricyanide/Prussian blue method. In both cases, agidol was used as a standard. All tested substances showed higher activity in both tests compared to the standard. The best antioxidant properties in both methods were shown by the derivative of 4,6-di-tert-butyl-2,3-dihydroxybenzaldehyde, thiadiazine based on salicylaldehyde also showed high antiradical activity, and thiadiazine with a fragment of 2-methoxyphenol showed good ferric-reducing properties.

Design, one-pot synthesis, in silico ADMET prediction and molecular docking of novel triazolyl thiadiazine and thiazole derivatives with evaluation of antimicrobial, antioxidant and antibiofilm inhibition activity

Design, one-pot synthesis, in silico ADMET prediction and molecular docking of novel triazolyl thiadiazine and thiazole derivatives with evaluation of antimicrobial, antioxidant and antibiofilm inhibition activity

Synthesis and Anti-Breast Cancer Potency of Mono- and Bis-(pyrazolyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine) Derivatives as EGFR/CDK-2 Target Inhibitors.

The target mono- and bis-(6-pyrazolyltriazolo-thiadiazine) derivatives 4a-c and 6a-d were synthesized using a straightforward protocol via reaction of 3-bromoacetylpyrazole 2 with 4-amino-s-triazole-3-thiols 3a-c and bis(4-amino-5-mercapto-s-triazol-3-yl)alkanes 5a-d, respectively. The bis(6-pyrazolyl-s-triazolo[3,4-b][1,3,4]thiadiazine) derivatives 8a,b and 10 were also constructed by reaction of the triazolo[3,4-b][1,3,4]thiadiazine-3-thiol 4c with the proper dibromo compounds 7a,b and 9, respectively. Structures of the new substances were determined by spectroscopic and analytical data. Compounds 4b, 4c, and 6a showed potent cytotoxicity against MCF-7 (IC50 = 3.16, 2.74, and 0.39 μM, respectively) and were safe against the MCF-10A cells. Compounds 4b, 4c, and 6a also showed promising dual EGFR and CDK-2 inhibition activities, particularly 6a was the most effective (IC50 = 19.6 and 87.9 nM, respectively), better than Erlotinib and Roscovitine. Compound 6a treatment induced EGFR and CDK-2 enzyme inhibition by 97.18% and 94.11%, respectively, at 10 μM (the highest concentration). Compound 6a notably induced cell apoptosis in MCF-7 cells, increasing the cell population by total apoptosis 43.3% compared to 1.29% for the untreated control group, increasing the cell population at the S-phase by 39.2% compared to 18.6% (control).

Potentiating-antibiotic activity and absorption, distribution, metabolism, excretion and toxicity properties (ADMET) analysis of synthetic thiadiazines against multi-drug resistant (MDR) strains.

Thiadiazines are heterocyclic compounds that contain two nitrogen atoms and one sulfur atom in their structure. These synthetic molecules have several relevant pharmacological activities, such as antifungal, antibacterial, and antiparasitic. The present study aimed to evaluate the possible in vitro and in silico interactions of compounds derived from thiadiazines. The compounds were initially synthesized, purified, and confirmed through HPLC methodology. Multi-drug resistant bacterial strains of Staphylococcus aureus 10 and Pseudomonas aeruginosa 24 were used to evaluate the direct and modifying antibiotic activity of thiadiazine derivatives. ADMET assays (absorption, distribution, metabolism, excretion, and toxicity) were conducted, which evaluated the influence of the compounds against thousands of macromolecules considered as bioactive targets. There were modifications in the chemical synthesis in carbon 4 or 3 in one of the aromatic rings of the structure where different ions were added, ensuring a variability of products. It was possible to observe results that indicate the possibility of these compounds acting through the cyclooxygenase 2 mechanism, which, in addition to being involved in inflammatory responses, also acts by helping sodium reabsorption. The amine group present in thiadiazine analogs confers hydrophilic characteristics to the substances, but this primary characteristic has been altered due to alterations and insertions of other ligands. The characteristics of the analogs generally allow easy intestinal absorption, reduce possible hepatic toxic effects, and enable possible neurological and anti-inflammatory action. The antibacterial activity tests showed a slight direct action, mainly of the IJ23 analog. Some compounds were able to modify the action of the antibiotics gentamicin and norfloxacin against multi-drug resistant strains, indicating a possible synergistic action. Among all the results obtained in the study, the relevance of thiadiazine analogs as possible coadjuvant drugs in the antibacterial, anti-inflammatory, and neurological action with low toxicity is clear. Need for further studies to verify these effects in living organisms is not ruled out.

Blocking the major inflammatory pathways by newly synthesized thiadiazine derivatives via in-vivo, in-vitro and in-silico mechanism

A series of new thiadiazine derivatives including 2-(5-alkyl/aryl-6-thioxo-1,3,5-thiadiazinan-3-yl) propanoic acids (a) and 4-methyl-2-(5-alkyl/aryl-6-thioxo-1,3,5-thiadiazinan-3-yl) pentanoic acids (b) were synthesized by reacting primary alkyl/aryl amines with CS2, followed by reaction with formaldehyde and amino acids. The chemical structures of synthesized compounds were confirmed by 13C- NMR and 1H- NMR techniques. The inhibitory potential of major inflammatory enzymes, COX-2 and 5-LOX was examined. Moreover, anti-nociceptive and anti-inflammatory activities were evaluated in the in vivo thermally induced nociceptive, and carrageenan induced paw edema models in mice. The in-vitro results reflect that these compounds exhibited concentration dependent inhibition of COX-2 and 5-LOX. The tested compounds at 50 mg/kg showed significant effect on thermally induced pain, and reduced latency time (seconds) as compared to the vehicle treated animals. Moreover, tested compounds exhibited percent inhibition of paw edema in the carrageenan induced paw edema model in mice. Furthermore, the binding modes of the most active COX-2 and 5-LOX inhibitors were determined through computational methods. The computational study reflects that the docked compounds have high binding affinities for COX-2 and 5-LOX enzymes, which leads to inhibition of these enzymes.

Synthesis and study of the anticancer activity of some new 7H-[1,2,4]triazolo [3,4-b][1,3,4]thiadiazines

The problem of finding effective low-toxic anticancer agents is one of the most important in modern medicine and pharmacy. Despite a large selection of anticancer drugs and a variety of mechanisms of their action, the effectiveness of existing drugs continues to be insufficient. Among the numerous natural and synthetic heterocyclic compounds that exhibit anticancer activity, 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivatives, which are able to initiate different pathways of tumor cell death. Based on this, the synthesis of new derivatives of this class of compounds and the study of their anticancer properties is relevant. The aim of the work is to synthesis of new 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines and study their anticancer activity. Materials and methods. It was used methods of organic synthesis, physical and chemical methods of analysis organic compounds (1H NMR spectroscopy, elemental analysis). Results. In order to obtain new 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines, the interaction implemented of 4-amino-4H-[1,2,4]triazole-3-thiols with the corresponding bromoacetophenones. The reaction proceeds by heating the above reagents in alcohol with the closure of the thiadiazine ring and the formation of 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine systems. The structure of all synthesized compounds was confirmed by 1H NMR spectroscopy and elemental analysis data. The study of the anticancer activity of the synthesized compounds was carried out in the framework of the international scientific program DTP (Developmental Therapeutics Program) of the National Cancer Institute (NCI, Bethesda, Maryland, USA). It was found that the synthesized compounds exhibited different levels of anticancer activity. The most active among the tested substances was compound 3j with an average GP value of 28.73. The most sensitive to it were the lines of melanoma MDA-MB-435 and SK-MEL-2, kidney cancer A498 and RXF 393, CNS cancer SNB-75, and non-small cell lung cancer NCI-H522. The secondary stage of studies of this compound confirmed its high anticancer activity against most cancer cell lines. Conclusions. As a result of the interaction of 4-amino-4H-[1,2,4]triazole-3-thiols with the relevant bromoacetophenones, a series of new triazolo[3,4-b][1,3,4]thiadiazines was not described in the literature was synthesized. Testing the synthesized compounds for the antitumor activity made it possible to isolate 1 highly active compound with a pronounced anticancer effect, which in terms of activity approaches or exceeds the known drugs 5-fluorouracil (5-FU) and cisplatin, as well as an anticancer agent, curcumin.

Discovery of ( ±)-3-(1H-pyrazol-1-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazine derivatives with promising in vitro anticoronavirus and antitumoral activity.

A new series of ( ±)-(3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-7-yl)(phenyl)methanones were efficiently synthesized starting from 4-amino-5-hydrazinyl-4H-1,2,4-triazole-3-thiol 1, acetyl acetone 2, various aromatic and heterocyclic aldehydes 3 and phenacyl bromides 4. All the newly synthesized compounds were tested for their antiviral and antitumoral activity. It was shown that subtle structural variations on the phenyl moiety allowed to tune biological properties toward antiviral or antitumoral activity. Mode-of-action studies revealed that the antitumoral activity was due to inhibition of tubulin polymerization.Graphic abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s11030-021-10258-8.

Synthesis of Two Isomeric Thiadiazine and Thiazole Derivatives from a Hydrazonoyl Halide

Thiadiazine and thiazoles have attracted importance due to their broad applicability as biologically active compounds. New thiadiazines and thiazoles are prepared via the simple reaction of an α-haloketohydrazonoyl with thiocarbohydrazone derivatives in a basic medium under reflux. A S-alkylated intermediate forms through nucleophile substitution involving the hydrazonoyl halogen and thiocarbohydrazone thiol. In situ cyclization via the condensation between the carbonyl and NH2 or NH moieties of the intermediate forms 1,3,4-thiadiazine and thiazole derivatives, respectively. This method employs inexpensive, commercially available reagents and facile reaction conditions to afford novel thiadiazine/thiazole derivatives in good yields.

Synthesis and Biological Activity of 3-(substitutedphenyl)-6-(4-methoxy phenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine: Part II

Background: Fungal infections are opportunistic infections that become a serious problem for human health. Objective: Considering the antifungal potential of the triazole nucleus, the study was carried out with the objective of synthesizing some novel triazole derivatives with antifungal potential. Methods: 1,2,4-triazole derivatives were synthesized via a two-step reaction (reported earlier). The first step involves the reaction of substituted benzoic acid with thiocarbohydrazide to form 4- amino-3-(substituted phenyl)-5-mercapto-1, 2, 4-triazole derivatives (1a-1k) while in the second step, synthesized compounds (1a-1k) were then subsequently treated with substituted acetophenone to yield substituted (4-methoxyphenyl-7H-[1, 2, 4] triazolo [3, 4-b][1,3,4] thiadiazine derivatives (2a-2k). All synthesized compounds were characterized by IR, 1H NMR, and Mass spectral data analysis and were screened for their antifungal properties against different fungal strains i.e. Candida tropicalis (ATCC-13803, ATCC-20913), Candida albicans (ATCC-60193), Candida inconspicua (ATCC-16783) and Candida glabrata (ATCC-90030, ATCC-2001). Results: Compound 2d displayed better percentage inhibition (26.29%, 24.81%) than fluconazole (24.44%, 22.96%) against ATCC-16783, ATCC-2001 fungal strains respectively at 100μg/ml. Compound 2f also displayed better percentage inhibition (28.51%) against ATCC-90030 as compared to fluconazone (27.4%) at 200 μg/ml. Similarly, compounds 2e and 2j also exhibited better antifungal properties than fluconazole at 200μg/ml. Compound 2e was found most potent against ATCC-13803 (30.37%) and ATCC-90030 (30.37%) fungal strains as compared to fluconazole (28.14%, 27.4%) at 200 μg/ml respectively whereas compound 2j exhibited better antifungal activity (28.51%) against ATCC-60193 than fluconazole (27.7%) at 200 μg/ml. Conclusion: The results were in accordance with our assertions for triazole derivatives, as all compounds displayed moderate to good antifungal activity.

Identification of novel thiadiazin derivatives as potentially selective inhibitors towards trypanothione reductase from Trypanosoma cruzi by molecular docking using the numerical index poses ratio Pr and the binding mode analysis

Chagas disease is a serious health problem in Central and South America for which effective treatment is not currently available. This illness is caused by the protozoa Trypanosoma cruzi, a species that relies on a thiol-based metabolism to regulate oxidative stress. Trypanothione reductase enzyme plays a central role in the metabolic pathway of the parasite. In this work, a virtual screening of a library of novel thiadiazine derivatives against trypanothione reductase using molecular docking was performed. Four different series of hybrid ligands having in the structure one or two peptoid moieties (series I and II) or the tetrazole ring (series III and IV) were considered. An ad hoc numerical index called poses ratio was introduced to interpret the results of the docking analysis and to establish relevant structure-interaction relationships. In addition, six binding modes were found for the ligands with the highest populated conformational clusters after applying contact-based analysis. The most regular and relevant were binding modes I and II, found mainly for ligands from series I. A subsequent molecular docking on human glutathione reductase enzyme allowed to assess the possible cytotoxicity of the ligands towards human cells. A selective binding profile was found for ligands with interactions in the Hydrophobic cleft, the spermidine and the Z subsites inside the active site of trypanothione reductase. At the end of the study, new thiadiazine-based compounds were identified as plausible candidates to selectively inhibit the parasitic enzyme.Graphic abstract

Effect of Two Novel Substituted Thiazole and Thiadiazine Derivatives on Experimental Type- 1 Diabetes Mellitus

Thiazole and Thiadiazine derivatives are heterocyclic compounds containing nitrogen and sulfur. They have a wide range of medicinal applications. The aim of the present study was to investigate the anti-hyperglycemic and antioxidant properties of two novel thiazole and thiadiazine derivatives using streptozotocin (STZ)-induced diabetic mice. Male mice were divided into eight groups (n=8). Control none-diabetic group (C), diabetic untreated group, three thiazole derivative-treated groups: Diabetic +20mg/kg Thiazole, Diabetic +10mg/kg Thiazole and Diabetic +5 mg/kg Thiazole. Three thiadiazine derivative treated groups as follows: Diabetic +20 mg/kg thiadiazine, Diabetic +10 mg/kg thiadiazine and Diabetic +5 mg/kg thiadiazine. All treatments were given daily via intraperitoneal injection for 18 days. Diabetes was induced by injection of STZ (50 mg/kg) for five days consecutively. At the end of the experiment, blood glucose, insulin, triglycerides, cholesterol and pancreatic superoxide dismutase (SOD) activity were measured. The two synthesized compounds significantly reduced the hyperglycemia and restored pancreatic insulin secretion in the treated diabetic mice. Also, the two compounds lead to a decrease in the serum triglycerides level and to increase in the pancreatic SOD activity in the treated diabetic mice. The results revealed both thiazole and thiadiazine derivatives had a good antidiabetic activity in diabetic animal model of type-1 diabetes. Further studies of these two compounds, especially on the mechanisms of action are required as a further step towards their development as potential anti-diabetic drugs.

Adaptogens: modern realities and prospects for the search of new effective and safe medicines (review of literature and authors’ research)

In present medical practice adaptogens and antihypoxants are a promising, but still insufficiently studied group of medicines. The largest evidence base among plant adaptogens was developed for ginseng, aralia, eleutherococcus, lemongrass, rhodiola, leuzea, sterculia. Antihypoxants, like trimetazidine, meldonium, succinic and -aminobutyric acid medications are included in the clinical guidelines. They have the most pronounced antihypoxic effects in a variety of diseases and pathological conditions, accompanied by impaired energy metabolism in the tissues. But their effect is not always high due to the variety of etiological factors causing hypoxia.
 Tetrahydropyrido[2,1-b][1,3,5]thiadiazine derivatives characterized by various pharmacodynamic effects with low toxicity which opens up prospects for a detailed further study. In animal experiments, the most pronounced adaptogenic and antidepressant effects is exerted by compounds TD-0348 and TD-0479, superior in strength to the antihypoxants used in modern clinical practice, the classic plant adaptogen ginseng.

Impact of Tetrahydropyrido[2,1-b][1,3,5]thiadiazines on L-DOPA Effects in the Tail Suspension Test

Aim.Evaluation of the impact of tetrahydropyrido[2,1-b][1,3,5]thiadiazine derivatives on L-DOPA effects in the tail suspension test.Materials and methods.Some tetrahydropyrido[2,1-b][1,3,5]thiadiazines exhibit a pronounced antidepressant and adaptogenic activity. We selected compounds that demonstrated the most potent antidepressant effect in the Porsolt’s forced swim test. We chose to combine two approaches in the study: estimation of the antidepressant drug impact on levodopa effects and the tail suspension test. Caffeine sodium benzoate, amitriptyline and fluoxetine were chosen as the reference compounds. Studies of the 1,3,5-thiadiazine effects on levodopa activity were undertaken to ground detailed downstream analyses of associated responses in the dopaminergic neurotransmitter system. We measured the rectal temperature in laboratory rats prior to and after tail suspension and the total active time during 5 min in the test.Results.Administration of levodopa at a dose of 150 mg/kg led to a reduction in rectal temperature and the total time of physical activity in rats in the tail suspension test. The dosage of 500 mg/kg led to a temperature increase of 0.7°C prior to and after the stress and a longer maintenance of physical activity. Rats exhibited exophthalmos and polyuria.Levodopa at a 150 mg/kg dosage in combination with caffeine sodium benzoate did not cause a significant increase in the body temperature and prolonged physical activity by 69% in the test vs. the control group. Amitriptyline in combination with levodopa at a dose of 150 mg/kg triggered a temperature increase of 1.3°C prior to and 1.85°C after tail suspension, thus leading to a prolonged physical activity. Levodopa at a dose of 150 mg/kg in combination with fluoxetine led to elevation of the body temperature by 0.6°C prior to and 0.55°C after the stress. The total active time exhibited a declining trend.The substance TD-0348 reveals an antidepressant activity. Physical active time increased by 32% in the test vs. the control group. Temperature elevation by 1.15°C prior to and 1.25°C after the stress suggests activation of the autonomic nervous system. TD-0470 in combination with levodopa (150 mg/kg) led to a rectal temperature elevation by 0.4°C prior to and 0.7°C after tail suspension. Physical activity was prolonged compared to the levodopa-treated group (150 mg/ kg). TD-0479 led to a temperature elevation by 0.85°C prior to and 0.95°C after the stress and caused polyuria. Treatment with TD-0164 did not provide sufficient data to suggest an impact on dopamine metabolism.Conclusions.The compounds TD-0348, TD-0470 and TD-0479 affect physiological processes in experimental rats in response to treatment with L-DOPA at a dose of 150 mg/kg, which suggests the autonomic nervous system (ANS) activation. TD-0470 exhibits antidepressant properties. Treatment with TD-0164 does not provide sufficient data to evaluate its dopamine-related effects.

Design, Synthesis, Molecular Docking Study and Anti-Hepatocellular Carcinoma Evaluation of New Bis-Triazolothiadiazines.

The reaction of bis(4-amino-4H-1,2,4-triazole-3-thiol) with hydrazonoyl halides and α-halo-ketones gave a new series of bis-1,2,4-triazolo[3,4-b]thiadiazine derivatives. The structure of the new products was established on the basis of their elemental and spectral data (mass, 1H NMR, 13C NMR and IR) and an alternate method. Several of the synthesized products were subjected to in vitro anticancer screening against human hepatocellular carcinoma (HepG-2) and the results showed that compounds 16, 14 and 12 have promising activities (IC50 value of 24.8±9.1, 28.3±0.5, and 31±2.9μM, respectively) compared with Harmine reference drug (IC50 value of 22.4±1.11 μM). Moreover, molecular docking studies were performed to analyze the binding modes of the discovered hits into the active site of DYRK1A using iGEMDOCK.