Ligand-based virtual screening and biological evaluation of inhibitors of Mycobacterium tuberculosis H37Rv.

Novel antimycobacterial compounds are needed to expand the existing toolbox of therapeutic agents, which sometimes fail to be effective. In our study we extracted, filtered, and aggregated the diverse data on antimycobacterial activity of chemical compounds from the ChEMBL database version 24.1. These training sets were used to create the classification and regression models with PASS and GUSAR software. The IOC chemical library consisting of approximately 200,000 chemical compounds was screened using these (Q)SAR models to select novel compounds potentially having antimycobacterial activity. The QikProp tool (Schrödinger) was used to predict ADME properties and find compounds with acceptable ADME profiles. As a result, 20 chemical compounds were selected for further biological evaluation, of which 13 were the Schiff bases of isoniazid. To diversify the set of selected compounds we applied substructure filtering and selected an additional 10 compounds, none of which were Schiff bases of isoniazid. Thirty compounds selected using virtual screening were biologically evaluated in a REMA assay against the M. tuberculosis strain H37Rv. Twelve compounds demonstrated MIC below 20 µM (ranging from 2.17 to 16.67 µM) and 18 compounds demonstrated substantially higher MIC values. The discovered antimycobacterial agents represent different chemical classes.

A Two-Step Approach to a Hexacyclic Lamellarin Core via 1,3-Dipolar Cycloaddition of Isoquinolinium Ylides to Nitrostilbenes.

The 1,3-dipolar cycloaddition reaction of isoquinolinium ylides to nitrostilbenes provides an approach to 1,2-diarylpyrrolo[2,1-a]isoquinolinium-3-carboxylates and then to a complete hexacyclic lamellarin core.

Cytostatic Activity of Combretastatin A-4 Derivatives in an In Vitro System.

Cytostatic activity of combretastatin A-4, its 11 analogues, and paclitaxel (Taxacad) was evaluated in vitro on human tumor cells A549 (lung adenocarcinoma) and PC-3 (prostate adenocarcinoma) in order to find the active and stable compound as a promising antitumor agent. 5-(4-Methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-isoxazole (compound 123124) and 3-(3,4,5-trimethoxyphenyl)-4-(4-methoxyphenyl)-isoxazole (compound 29310186) demonstrated the highest cytostatic activity (IC50≈8×10-9 М). The activity of two other cytotoxic compounds (2E)-1-(7-methoxy-2H-1,3-benzodioxol-5-yl)-3-(4-methoxyphenyl)prop-2-en-1-one (compound 104815) and 4-(3-amino-4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-pyrazole hydrochloride (compound 198732) was close to that of Taxacad: IC50 65×10-9 and 80×10-9 М, respectively, and are also promising active components for the development of antitumor drugs.

SOCIAL AND ECONOMIC ASPECTS OF SIMULTANEOUS OPERATIONS ON ABDOMINAL ORGANS.

The article presents an analysis of 107 cases of simultaneous operations of big volume with main stage as gastric resections (gastrectomy) or large intestine resections and mean volume interferences as cholecystectomy and removal of abdominal hernias. It was stated, that simultaneous operations compared with two steps treatment of combined surgical diseases obtained the high economical efficacy. This efficacy was determined by a single - stage routine presurgical examination, single anesthetic management, less medical expenses for medication and laboratory - instrumental studies in postoperative period, significant shortening the terms of hospitalization and disability terms. The authors proposed formulas to evaluate the economiс efficacy of simultaneous operations in system of paid medical service and system of rendering medical aid using paid medical insurance. The efficacy of large operations was 40 766 rubles and in case of mean volume interventions - 25 382 rubles for the paid medical system. The economical efficacy of simultaneous operations of large and mean volume was the same in the system of obligatory medical insurance. It consisted of 19 737,5 or 22 920,1 rubles and depended on the degree of operative anaesthetic risk of the second intervention in two steps treatment of patients.

Clastogenic and anticlastogenic activity of glucocorticoid hormones hydrocortisone and its synthetic analogs prednisolone and dexamethasone.

Clastogenic and anticlastogenic activity of glucocorticoid hormones hydrocortisone, prednisolone, and dexamethasone was studied by counting chromosome aberrations in Crepis capillaris test system. Hydrocortisone in a concentration of 12.5 mg/ml produced a clastogenic effect and increased the number of chromosome aberrations in comparison with spontaneous level. Hydrocortisone (6.25 and 3.13 mg/ml), prednisolone (15, 7.5, and 3.75 mg/ml), and dexamethasone (1, 0.5, 0.25, and 0.125 mg/ml) exhibited an anticlastogenic effect and reduced ethyl methanesulfonate-induced mutagenesis.

Synthesis and antineoplastic properties of (1H-1,2,3-triazol-1-yl)furazans.

A method of 3-amino-4-[5-aryl(heteroaryl)-1H-1,2,3-triazol-1-yl)]furazan synthesis was optimized. Condensation of these compounds with 2,5-dimethoxytetrahydrofuran resulted in a series of previously unknown 4-[5-aryl(heteroaryl)-1H-1,2,3-triazol-1-yl)]-3-(pyrrol-1-yl)furazans. All target compounds were evaluated for both antimitotic microtubule destabilizing effect in a phenotypic sea urchin embryo assay and cytotoxicity in a panel of 60 human cancer cell lines. Pyrrolyl derivatives of triazolylfurazans were determined as antiproliferative compounds. The most potent microtubule targeting compounds 7a and 7e are of interest for further trials as antineoplastic agents.

[Placental changes in type 1 diabetes mellitus].

Pathological immune complexes (PIC) are revealed in high percent (100%) of cases by placental immunomorphological studies in insulin-dependent tissue. This leads to the development of an immunopathological process in the placental tissue. Parallel electron microscopy shows that some placental vessels are in close contact with the basal membrane of syncytiotrophoblast. PIC deposition in the area of confluence of the basal membranes of a syncytiotrophoblast and the vascular endothelium, which act as filters, results in the destruction of the basal membranes to rupture formation, causing the transplacental transport of substances together with immune complexes in the form of endocytotic vacuoles from the intervillous lacuna directly to the vessel. Active proliferation of vascular endotheliocyes leads to typical angiopathy as the body's defense reaction.

[Clastogenic, aneugenic, pro- and antioxidant properties of some neurotropic preparations].

In experimental and clinical investigations, assessment was made of mutagenous, antimutagenous, pro- and antiradical activity of some neurotropic preparations--cerebrolysin, encephabol (pyritinol), nootropil (piracetam), actovegin and cavinton (vinpocetine). In chemical, fermentative and cellular model systems, cerebrolysin inhibited generation of superoxide anion-radical, nitrogen monoxide and final products of degradation of fatty acids. Other preparations showed both anti- and prooxidant effect. The most pronounced anticlastogenic activity during expriments on C. capillaries had a cerebrolysin. Encephabol had the most prooxidant effect and low anticlastogenic activity. The ability of such preparations as ceredrolysin and encephabol to decrease erythrocyte high level with micronuclei in peripheric blood of patients with infantile cerebral palsy (spastic diplegia) was clinically investigated. The modifying effect of preparations was not univalent: it was cerebrolysin that decreased intensivity of aneu- and clastogenesis in patients in a greater degree than encephabol. A protective effect of these preparations was pronounced on the 10th day in group of the boys, and on the 20th day in the group of the girls.

Clastogenesis and aneugenesis in children with cerebral palsy.

The genetic system in children with cerebral palsy was studied by the method of registration of chromosome aberrations and micronuclei in peripheral blood lymphocytes and erythrocytes. A high level of chromosome aberrations and micronuclei in the peripheral blood cells was revealed. A significant reduction of the integral antioxidant capacity of the blood and plasma was detected by coulombometric titration with electrogenerated bromine in patients with all forms of cerebral palsy. Aneugenic and antianeugenic effects of glutamate were studied in experiments on mice. Biphasic effect of glutamate was revealed: it exhibited aneugenic effect in high doses and antianeugenic in low doses. Impairment of the genome stability in children with cerebral palsy is believed to be caused by increased generation of endomutagens under conditions of disease and reduction of the genome antimutagenic defense system.

[Clinical, tomographic and immunogenetic study of patients with infantile cerebral palsy].

A neurovisual and immunogenetic study of patients with different forms of cerebral palsy was conducted. Morphological peculiarities of each form were described. A frequent combination of pathology of cerebrospinal fluid spaces and periventricular area with disruption of neuronal migration and development of brain mass and volume was found. HLA-typing revealed a significant association of the disease with antigen B13. An association of cerebral palsy with particular genetically determined vulnerability of fetal brain to lesions disrupting genetic program for neuroontogenesis is suggested.

[Genoprotective human blood activity and its mechanisms]. / Genoprotektornaia aktivnost' krovi cheloveka i ee mekhanizmy.

Anticlastogenic properties of plasma and proteins (albumin and gamma-globulin) of the human blood were studied using seeds of Crepis capillaris (chromosome aberration assay). Antimutagen p-amino-benzoic acid was used as a comparative reagent. Anticlastogenic activity dependent of processing conditions of the biosubstrate used; for the pre-processing and combined processing anticlastogenic effect was higher than for post-processing, the processing properties of the blood being higher than those of the blood proteins. Anticlastogenic potential of biosubstrates did not depend on mutation inductor. Complex-formimg properties of plasma and blood albumen have been revealed using spectrop-hotometry through the substantial spectral displacement--relative to the expected spectrum--for the mixture of biosubstrata and mutagens. Using chemoluminescence, all plasma, albumin and gamma-globulin concentrations have been shown to enhance generation of hydroxyl radical of the Fenton reagent, especially for albumin in 1.0 g/l concentration. The general trend for all experiments was that the said substances diminished the stimulating effect as their concentrations grew. Peroxidation of yolk lipoproteids showed that only high concentrations of blood's plasma and albumen have antioxidizing properties. gamma-Globulin did not reveal any ability to inhibit lipid peroxidation of yolk lipoproteids. Complex-forming mechanisms of blood's albumen and antioxidizing property of human plasma and proteins have been proved to form the blood's anticlastogenic potential.

Purine receptor agonists protect the genome of plant and animal cells from clastogen damage.

Purine receptor agonists adenosine, cyclohexyladenosine, phenylisopropyladenosine, dimethylaminopurine riboside, ATP, and ADP reduced the level of chromosome aberrations and the number of micronuclei induced by ethylmethane sulfonate and cyclophosphamide in plants (Crepis capillaris) and mice. Possible mechanisms of the protective effect of these ligands are discussed.

[Some aspects of microsurgical decompression of neurovascular formations of the spinal canal in lumbar osteochondrosis]. / Nekotorye aspekty mikrokhirurgiheskoi dekompressii nervno-sosudistykh obrazovanii pozvonochnogo kanala pri poiasnichnom osteokhondroze.

Microsurgical techniques have been developed for decompression of neurovascular formations of the vertebral canal in lumbar osteochondrosis. Surgical policy has been proposed in relation to the site of hernial prolapse by the disk diameter. The use of this policy provides the minimal traumatism of surgical interventions in posterolateral hernias in particular.

Synthetic utilization of polynitroaromatic compounds. 1. S-derivatization of 1-substituted 2,4,6-trinitrobenzenes with thiols.

Reactions of 1-R-2,4,6-trinitrobenenes (R = alkyl, protected aldehyde, aminocarbonyl, cyano groups, or isoxazole ring) with thiol salts were investigated. In most cases, these reactions gave a mixture of minor para and major ortho substitution products. Reactions of N,N-disubstituted 2,4,6-trinitrobenzamides with S-,O-, and N-nucleophiles afforded products of substitution of the p-nitro group exclusively. 1-Cyano-2,4,6-trinitrobenzene was found to be the most reactive and the least selective: all three nitro groups can be substituted using an excess of thiol salts. 2-R-4, 6-dinitrobenzamides showed no regioselectivity under similar conditions to yield 1:1 mixtures of para and ortho isomers.

Preparation of trifluoromethylpyridine libraries.

S-Alkylation followed by heterocyclization of trifluoromethyl-3-cyano-2(1H)-pyridinethiones was used for preparation of libraries of S-alkyl trifluoromethylpyridines and thieno[2,3-b]pyridines. The S-alkylation (in water--DMF mixtures) was successful for all 18 alkylating agents employed (yields typically > 50%). S-Alkyl derivatives were further converted to corresponding thieno[2,3-b]pyridines via heterocyclization in base conditions (yields > 65%). Structures of new compounds were elucidated by a combination of IR and 1H NMR spectroscopy and elemental analysis and were confirmed by means of single-crystal X-ray diffraction analysis.