Evaluation of thiopyrano[2,3-d]thiazole derivatives as potential anticonvulsant agents.

Anticonvulsant drug discovery has achieved significant progress; however, pharmacotherapy of epilepsy continues to be a challenge for modern medicine and pharmacy. To expand the chemical space of heterocycles as potential antiepileptic agents, herein we report on the synthesis and evaluation of anticonvulsant properties of a series of thiopyrano[2,3-d]thiazoles. The studied heterocycles are characterized by satisfactory drug-likeness and pharmacokinetics properties, calculated in silico using SwissADME. The anticonvulsant activity of thiopyrano[2,3-d]thiazole derivatives was evaluated in vivo using the subcutaneous pentylenetetrazole test. Three hits, that is, compounds 12, 14, and 16, that caused a pronounced anticonvulsant effect were identified. Derivatives 12, 14, and 16 positively affected the latent period of onset of clonic seizures, number of seizures, mortality rate, and duration of the seizure period of animals under experimental conditions. The anticonvulsant properties of compound 14 were equivalent to the effect of the reference drug, sodium valproate. All hit compounds are characterized by satisfying toxicity properties in the human lymphocytes and HEK293 cell line. The most active hit 14 possesses a potential affinity with the GABAA receptor in the molecular docking study and forms a stable complex in the molecular dynamics experiments equal to diazepam. Preliminary SAR results were obtained and discussed based on screening data.

1,4-Naphthoquinone Motif in the Synthesis of New Thiopyrano[2,3-d]thiazoles as Potential Biologically Active Compounds.

A series of 11-substituted 3,5,10,11-tetrahydro-2H-benzo[6,7]thiochromeno[2,3-d][1,3]thiazole-2,5,10-triones were obtained via hetero-Diels-Alder reaction of 5-alkyl/arylallylidene/-4-thioxo-2-thiazolidinones and 1,4-naphthoquinones. The structures of newly synthesized compounds were established by spectral data and a single-crystal X-ray diffraction analysis. According to U.S. NCI protocols, compounds 3.5 and 3.6 were screened for their anticancer activity; 11-Phenethyl-3,11-dihydro-2H-benzo[6,7]thiochromeno[2,3-d]thiazole-2,5,10-trione (3.6) showed pronounced cytotoxic effect on leukemia (Jurkat, THP-1), epidermoid (KB3-1, KBC-1), and colon (HCT116wt, HCT116 p53-/-) cell lines. The cytotoxic action of 3.6 on p53-deficient colon carcinoma cells was two times weaker than on HCT116wt, and it may be an interesting feature of the mechanism action.

Molecular design, synthesis and anticancer activity of new thiopyrano[2,3-d]thiazoles based on 5-hydroxy-1,4-naphthoquinone (juglone).

A series of 11-substituted 9-hydroxy-3,5,10,11-tetrahydro-2H-benzo[6,7]thiochromeno[2,3-d][1,3]thiazole-2,5,10-triones 3.1-3.13 were synthesized via hetero-Diels-Alder reaction of 5-ene-4-thioxo-2-thiazolidinones and 5-hydroxy-1,4-naphthoquinone (juglone). The structure of newly synthesized compounds was established by means of spectral data and a single-crystal X-ray diffraction analysis. The synthesized compounds were tested on a panel of cell lines representing different types of cancer as well as normal and pseudonormal cells and peripheral human blood lymphocytes. Compound 3.10 was found to be the most active derivative, exhibiting a cytotoxic effect similar to doxorubicin's one (IC50 ranged from 0.6 to 5.98 µM), but less toxic to normal and pseudonormal cells. All synthesized compounds were able to interact with DNA, although their anticancer activity did not correlate with the potency of interaction with DNA. The status of p53 in colorectal cancer cells correlated with the activity of the synthesized derivatives 3.1, 3.7, and 3.10. Compound 3.10 did not have an acute toxic effect on the body of С57BL/6 mice, unlike the well-known anticancer drug doxorubicin, which was used as a positive control. The injection of 3.10 (20 mg/kg) to mice had no effect on the counts of leukocytes, erythrocytes, platelets and hemoglobin level in their blood, in contrast to doxorubicin, which caused anemia and leukopenia, indicating bio-tolerance of 3.10in vivo.

Synthesis and Evaluation on Anticonvulsant and Antidepressant Activities of Naphthoquinone Derivatives Containing Pyrazole and Pyrimidine Fragments.

Novel heterocyclic dichloronaphthoquinone derivatives have been synthesized by chlorine atom substitution in 2,3-dichloro-1,4-naphthoquinone to pyrazole or pyrimidine fragments. The structures of these compounds have been confirmed by FT-IR, ESI-MS, 1H?NMR, 13C-NMR and elementary analysis. Synthesized compounds were evaluated for their anticonvulsant action in a pentylenetetrazole (PTZ)-convulsion model and antidepressant activity in the forced swimming test (FST). All naphthoquinone derivatives at a dose 100 mg/kg indicated anticonvulsant effect in PTZ-induced test at 3 h and 24 h after oral administration. In addition, these compounds possessed prolonged antidepressant properties significantly reducing the duration of immobility time when compared to the reference drug amitriptyline.

Fluorine-containing block/branched polyamphiphiles forming bioinspired complexes with biopolymers.

Colloidal-chemical characteristics of block/branched cationic and non-ionic polyamphiphiles containing poly(fluorine-alkyl methacrylate) (poly(FMA)) block and their intermolecular complexes with biopolymers were studied. The dependences of their surface activity and micelle size on the length of hydrophobic and hydrophilic blocks, as well as the length of side fluorine-alkyl branches were established. Poly(FMA)-block-poly(DMAEMA) was used for formation of interpolyelectrolyte complexes with plasmid DNA (pDNA) via their electrostatic interaction. Novel non-viral polyplexes were tested as gene delivery systems for mammalian cells. The results of DLS, TEM and MALDI-ToF studies demonstrated disaggregation of lysozyme (LYZ) aggregates in the presence of poly(FMA)-block-poly(NVP) and formation of the polyamphiphile…LYS complex possessing antibacterial action.