Synthesis of 1,2,4-Oxadiazin-5(6)-One Derivatives and Their Biological Investigation as Monoamine Oxidase Inhibitors.

Monoamine oxidase (MAO) plays a key role in the pathogenesis of central nervous system disorders, and MAO inhibitors have been used in the treatment of depression and Parkinson's disease. In the search for new classes of MAO inhibitors, the present study investigated a series of 1,2,4-oxadiazin-5(6)-one derivatives. This study provides the first optimization of the reaction conditions for the condensation of amidoximes with alkyl 2-halocarboxylates to yield the desired 1,2,4-oxadiazin-5(6)-ones.

Pharmacological Properties of Sulfonamide Derivatives, New Inhibitors of Carbonic Anhydrase.

Selective blocking of individual isoforms of carbonic anhydrase (CA) is now one of the main directions in the development of its inhibitors. The new 1,2,4-oxadiazole-containing sulfonamides B12 and B13 predominantly block CA II and CA IX. The study of acute toxicity of B12 and B13 showed their safety.

Monoamine oxidase inhibition properties of 2,1-benzisoxazole derivatives.

Monoamine oxidase (MAO) are flavoenzymes that metabolize neurotransmitter, dietary and xenobiotic amines to their corresponding aldehydes with the production of hydrogen peroxide. Two isoforms, MAO-A and MAO-B, are expressed in humans and mammals, and display different substrate and inhibitor specificities as well as different physiological roles. MAO inhibitors are of much therapeutic value and are used for the treatment of neuropsychiatric and neurodegenerative disorders such as depression, anxiety disorders, and Parkinson's disease.

5-(Sulfamoyl)thien-2-yl 1,3-oxazole inhibitors of carbonic anhydrase II with hydrophilic periphery.

Hydrophilic derivatives of an earlier described series of carbonic anhydrase inhibitors have been designed, prepared and profiled against a panel of carbonic anhydrase isoforms, including the glaucoma-related CA II. For all hydrophilic derivatives, computational prediction of intraocular permeability routes showed the predominance of conjunctival rather than corneal absorption. The potentially reactive primary or secondary amine periphery of these compounds makes them suitable candidates for bioconjugation to polymeric drug carriers.

Diversely substituted sulfamides for fragment-based drug discovery of carbonic anhydrase inhibitors: synthesis and inhibitory profile.

A series of sulfamide fragments has been synthesised and investigated for human carbonic anhydrase inhibition. One of the fragments showing greater selectivity for cancer-related isoforms CA IX and XII was co-crystalized with CA II showing significant potential for fragment periphery evolution fragment growth and linking. These opportunities will be identified in the future the screening of this fragment structure for co-operative carbonic anhydrase binding with other structurally diverse fragments.

1,2,4-Oxadiazole/2-Imidazoline Hybrids: Multi-target-directed Compounds for the Treatment of Infectious Diseases and Cancer.

Replacement of amide moiety with the 1,2,4-oxadiazole core in the scaffold of recently reported efflux pump inhibitors afforded a novel series of oxadiazole/2-imidazoline hybrids. The latter compounds exhibited promising antibacterial activity on both Gram-positive (, ) and Gram-negative (, ) strains. Furthermore, selected compounds markedly inhibited the growth of certain drug-resistant bacteria.

Pyridazinone-substituted benzenesulfonamides display potent inhibition of membrane-bound human carbonic anhydrase IX and promising antiproliferative activity against cancer cell lines.

An expanded set of pyridazine-containing benzene sulfonamides was investigated for inhibition of four human carbonic anhydrase isoforms, which revealed a pronounced inhibition trend toward hCA IX, a cancer-related, membrane-bound isoform of the enzyme. Comparison of antiproliferative effects of these compounds against cancer (PANC-1) and normal (ARPE-19) cells at 50 μM concentration narrowed the selection of compounds to the eight which displayed selective growth inhibition toward the cancer cells. More detailed investigation in concentration-dependent mode against normal (ARPE-19) and two cancer cell lines (PANC-1 and SK-MEL-2) identified two lead compounds one of which displayed a notable cytotoxicity toward pancreatic cancer cells while the other targeted the melanoma cells.

[Dissection of the internal carotid artery in a patient with connective tissue dysplasia having risk variants of several candidate genes].

Spontaneous dissection of the vessels of the neck is one of the main causes of ischemic stroke in young patients under 45 years of age. According to morphological studies, dissection of the vessels of the neck can be based on dysplastic changes in the arterial wall in arteriopathies, Marfan syndrome, Ehlers-Danlos syndrome, undifferentiated connective tissue dysplasia. The article presents a case of spontaneous dissection of the internal carotid artery in a 30-year-old patient with clinical manifestations of undifferentiated connective tissue dysplasia and carriage of homozygous variants of candidate genes: 4G/4G of the PAI-1 (-675, 4G/5G), T/T of the MTHFR C677T, 5A/5A of the MMP-3 (-1171 5A/6A) and A/A of the MMP-9 (8202A/G).

Novel monoamine oxidase inhibitors based on the privileged 2-imidazoline molecular framework.

Series of structurally diverse 2-imidazoline derivatives have been synthesized by condensation of substituted aldehydes with ethylenediamine, Pd-catalyzed N-arylation of 2-imidazolines and by the formation of 1,2,4-oxadiazoles and benzoxazepines from 2-imidazoline-containing precursors. The 2-imidazoline derivatives were evaluated as potential inhibitors of human monoamine oxidase (MAO) A and B. Among the 2-imidazolines, good potency inhibitors were discovered with compound 9p (IC = 0.

[Cerebral vascular syndrome of connective tissue dysplasia as a cause of subarachnoid hemorrhage in young patients].

Aim: To clarify the role of connective tissue dysplasia (CTD) in the development and course of intracranial arterial aneurysm (IAA) and arteriovenous malformation (AVM) in young patients.

Material And Methods: The first stage of the study was a prospective 7-year follow-up of 549 patients with CDT signs, aged from 18 to 45 years, mean 23.51±8.

1,3-Oxazole-based selective picomolar inhibitors of cytosolic human carbonic anhydrase II alleviate ocular hypertension in rabbits: Potency is supported by X-ray crystallography of two leads.

Two lead 1,3-oxazole-based carbonic anhydrase inhibitors (CAIs) earlier identified as selective, picomolar inhibitors of hCA II (a cytosolic target for treatment of glaucoma) have been investigated further. Firstly, they were found to be conveniently synthesized on multigram scale, which enables further development. These compounds were found to be comparable in efficacy to dorzolamide eye drops when applied in the eye drop form as well.

Primary mono- and bis-sulfonamides obtained via regiospecific sulfochlorination of N-arylpyrazoles: inhibition profile against a panel of human carbonic anhydrases.

A diverse set of mono- and bis-sulfonamide was obtained via a direct, chemoselective sulfochlorination of readily available yet hitherto unexplored N-arylpyrazole template. Biochemical profiling of compounds thus obtained against a panel of human carbonic anhydrases (CA I, CA II, CA IV and CA VII) revealed a number of leads that are promising from the isoform selectivity prospective and exhibit potent inhibition profile (from nanomolar to micromolar range). The observed SAR trends have been rationalized by docking of selected compounds into the active site of all four isoforms.

Human carbonic anhydrase inhibitory profile of mono- and bis-sulfonamides synthesized via a direct sulfochlorination of 3- and 4-(hetero)arylisoxazol-5-amine scaffolds.

Three distinct series of isoxazole-based primary mono- and bis-sulfonamides have been synthesized via direct sulfochlorination, each of them delivering nanomolar inhibitors of human carbonic anhydrase. Certain pronounced SAR trends have been established and rationalized by in silico docking. These findings expand the structure-activity knowledge base for heterocycle-containing sulfonamide carbonic anhydrase inhibitors and further validate the power of direct electrophilic sulfochlorination as a means of introducing the pharmacophoric primary sulfonamide group into structurally diverse aromatic precursors.

Probing the 'bipolar' nature of the carbonic anhydrase active site: aromatic sulfonamides containing 1,3-oxazol-5-yl moiety as picomolar inhibitors of cytosolic CA I and CA II isoforms.

A series of potent inhibitors of human carbonic anhydrase (CA) isoforms I and II has been prepared via a direct, chemoselective sulfochlorination of a range of 1,3-oxazolyl benzenes and thiophenes, followed by primary sulfonamide synthesis. The latter functionality is a known zinc-binding group (ZBG) responsible for anchoring the inhibitors to the CA's zinc metal ion. The compound's periphery as well as the overall scaffold geometry was designed to enable optimal interactions with the two distinct sides of the enzyme's active site, one of which is lined with hydrophobic residues and while the other is predominantly hydrophilic.

[Chemobiokinetics of sarcolysin and its peptides with glutaminic acid].

A 14C study of chemobiokinetics of sarcolysin and its peptides of glutaminic acid, dosage and routes of administration was conducted in intact rats and those bearing Walker's carcinoma. Similar in shape for peptides, kinetic curves differed from those found for sarcolysin. The rates of absorption and excretion of sarcolysin peptides in intraperitoneal and, particularly, oral administration were lower than those of sarcolysin.

Methylation of thymine and uracil with free methyl cations formed due to beta-decay of tritiated methane: possible implication in mutagenesis and carcinogenesis.

Exposure of solid thymine and uracil at room temperature to free methyl cations, produced due to beta-decay of tritiated methane, resulted in formation of their 1-, O2-, 3-, O4-, and 6-methyl derivatives. In addition, uracil formed a 5-methyl derivative (thymine); tritium-containing thymine and uracil were also detected. Both thymine and uracil formed predominantly unidentified products which resulted presumably from their oligomerization.

[DNA alkylation and repair in female rats subjected to methylnitrosourea exposure at different ages].

Three- and fourteen-month old female rats received a single intravenous injection of 50 mg/kg 14C-methylnitrosourea. Peculiarities of DNA purines alkylation and repair in different organs were studied. The difference in initial methylpurine levels between the two groups appeared insignificant and did not correlate with the rate of tumor frequency registered in chronic experiments using the same mode of treatment.

[Effect of dioxadet on tumors transplanted to the brain].

A newly-developed antitumor drug Dioxadet is capable of passing the blood-brain barrier. The specific activity of rat brain tissue ranged 8-55% of that of blood at different periods after intraperitoneal injection of 14C-labelled Dioxadet. Dioxadet treatment of mice and rats bearing intracranially-transplanted L1210 leukemia and glioma 35 was followed by a 38-48 and 29% increase in survival, respectively.

Persistence of methylated purines in the DNA of various rat fetal and maternal tissues and carcinogenesis in the offspring following a single transplacental dose of N-methyl-N-nitrosourea.

Formation and loss of methylated purines in DNA of various fetal and maternal tissues were measured up to 7 days following intravenous administration of N-[14C]methyl-N-nitrosourea to rats on the 21st day of gestation. Methylation products were detected in all tissues examined, the level in maternal liver being higher than in other tissues. The concentrations of 7-methylguanine and 3-methyladenine decreased faster in fetal than in corresponding maternal tissues, due to a higher rate of DNA synthesis in fetal tissues, as determined by incorporation of labelled thymidine.