[Curare-Like Camphor Derivatives and Their Biological Activity].

The synthesis and evaluation of muscle relaxant activity of series of dimeric camphor derivatives are described. Compounds in which the quaternary nitrogen atoms are separated by aromatic chain exhibited the highest efficiency as muscle relaxant. It was shown the screening of a charged atom and counter-ion does not have a significant role on the activity of the studied agents.

Synthesis of N-heterocyclic amides based on (+)-camphoric acid and study of their antiviral activity and pharmacokinetics.

Efficient conditions for the synthesis of nitrogen-containing heterocyclic derivatives of (1R,3S)(+)-camphoric acid were selected. A series of heterocyclic compounds based on (+)-camphoric acid bearing pharmacophoric fragments was synthesized using the developed methodology. The compounds were tested for their antiviral activity against SARS-CoV-2 and H1N1 influenza viruses, and efficient inhibitors were identified that are of significant interest for further studies. The stability of the compounds and pharmaco-kinetics of the leader compound were studied when administered intragastrically and intramuscularly to mice at a dose of 200 mg kg-1 using the HPLC-MS/MS method.

[The use of the andragogic model of education at different stages of studying the "forensic medicine" discipline].

The technology of education for adult subjects, i.e. the scientifically-sound system of andragogic principles for the education of adults (both teachers and learners), is considered. Putting these principles into practice leads with a high degree of probability to the achievement of the sought goals of education. These principles as well as the andragogic educational model itself are recommended for a wider application to the system of education for senior students, junior physicians, and resident medical practitioners with a view to improving the efficacy of the educational process.

[Treatment of esophageal varices bleeding with the use of transformable probes].

Construction of the original transformable esophageal probe is thoroughly described. The innovated construction suggests lesser traumatisation by insertion and spiral expansion, together with secure compression hemostasis. Unlike the traditionally used obturating Blackmore probe, the spiral transformable original construction leaves the esophageal lumen open for further endoscopic hemostatic procedures. The feature provides exclusive advantages of the original construction.

N-Heterocyclic borneol derivatives as inhibitors of Marburg virus glycoprotein-mediated VSIV pseudotype entry.

There is currently no approved antiviral therapy for treatment of Marburg virus disease (MVD). Although filovirus infection outbreaks are quite rare, the high mortality rates in such outbreaks make the development of anti-filoviral drugs an important goal of medical chemistry and virology. Here, we performed screening of a large library of natural derivatives for their virus entry inhibition activity using pseudotype systems. The bornyl ester derivatives containing saturated N-heterocycles exhibited the highest antiviral activity. It is supposed that compounds with specific inhibitory activity toward MarV-GP-dependent virus entry will inhibit the rVSIV-ΔG-MarV-GP pseudotype much more efficiently than the control rVSIV-ΔG-G pseudotype. At the same time, the compounds similarly inhibiting both pseudotypes will likely affect rVSIV capsid replication or the cellular mechanisms common to the entry of both viruses. Borneol itself is not active against both pseudotypes and is nontoxic, whereas its derivatives have varying toxicity and antiviral activity. Among low-toxic borneol derivatives, six compounds turned out to be relatively specific inhibitors of MarV-GP-mediated infection (SC > 10). Of them, compound 6 containing a methylpiperidine moiety exhibited the highest virus-specific activity. Notably, the virus-specific activity of this compound is twice as high as that of the reference.

Synthesis and in vitro study of novel borneol derivatives as potent inhibitors of the influenza A virus.

Herein, we present the design and synthesis of a series of novel heterocyclic derivatives of (-)-borneol and (-)-isoborneol as potent inhibitors of the influenza A virus. All compounds were tested for their toxicity against MDCK cells and for virus-inhibiting activity against the influenza virus A/Puerto Rico/8/34 (H1N1). Compounds 7, 16 and 26 containing a morpholine fragment exhibited the highest efficiency as agents inhibiting the replication of the influenza virus A(H1N1) with selectivity indices of 82, 45 and 65, correspondingly. Derivatives 9 (SI = 23) and 18 (SI = 25) containing a 1-methylpiperazine motif showed moderate antiviral activity. Structure-activity analysis of this new series of borneol derivatives revealed that a 1,7,7-trimethylbicyclo[2.2.1]heptan scaffold is required for the antiviral activity.

Broad range of inhibiting action of novel camphor-based compound with anti-hemagglutinin activity against influenza viruses in vitro and in vivo.

Influenza virus continues to remain one of the leading human respiratory pathogens causing significant morbidity and mortality around the globe. Due to short-term life cycle and high rate of mutations influenza virus is able to rapidly develop resistance to clinically available antivirals. This makes necessary the search and development of new drugs with different targets and mechanisms of activity. Here we report anti-influenza activity of camphor derivative 1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene-aminoethanol (camphecene). In in vitro experiments it inhibited influenza viruses A(H1, H1pdm09, H3 and H5 subtypes) and B with EC50's lying in micromolar range. Due to low cytotoxicity it resulted in high selectivity indices (74-661 depending on the virus). This effect did not depend on susceptibility or resistance of the viruses to adamantane derivatives amantadine and rimantadine. The compound appeared the most effective when added at the early stages of viral life cycle (0-2h p.i.). In direct hemagglutinin inhibition tests camphecene was shown to decrease the activity of HA's of influenza viruses A and B. The activity of camphecene was further confirmed in experiments with influenza virus-infected mice, in which, being used orally by therapeutic schedule (once a day, days 1-5 p.i.) it decreased specific mortality of animals infected with both influenza A and B viruses (highest indices of protection 66.7% and 88.9%, respectively). Taken together, these results are encouraging for further development of camphecene-based drug(s) and for exploration of camphor derivatives as highly prospective group of potential antivirals.

An anticancer drug prospidine: failure to reveal antimitotic and clastogenic action on regenerating mouse liver.

Prospidine is an anticancer drug used in oncological practice in the USSR. It is characterized by only a slight toxicity and the absence of such side-effect as the hemopoiesis suppression. The mechanism of tumor growth inhibition by prospidine is still open to question. The present study was undertaken to reveal the potential mutagenic properties of prospidine, using regenerating mouse liver as rapidly proliferating cell system. Animals were given a single (900 or 1500 mg/kg) or daily (200 mg/kg for 9 days) injections of prospidine before or after partial hepatectomy. The mitotic activity, the duration of the cell cycle periods and the frequency of chromosome aberrations in ana-telophase were determined. The data show that unlike other alkylating drugs prospidine fails to suppress cell proliferation or to induce marked chromosome-breaking effects. The only mild effect observed was some prophase and prometaphase prolongation.

[In vitro systems for the primary search for biologically active substances with carcinostatic action]. / Sistemy in vitro dlia pervichnogo poiska biologicheski aktivnykh veshchestv s kantserostaticheskim deistviem.

Improvement and development of new methods for primary screening of antitumour drugs in vitro are based on the data on the points open to injury in the tumour cell metabolism and on the evidence of the known carcinostatic drug mechanism. Further development of the primary screening methods should proceed, probably, in two main directions. Further improvement of the methods for cloning tumour cells in the semifluid nutrient media is of great interest. On the whole the creation of new test systems is a significant trend of the scientific screening.

[Effect of the alkylating agent dipin on the induced proliferation of hepatocytes. I. The kinetics of the cell population]. / Vliianie alkiliruiushchego agenta dipina na indutsirovannuiu proliferatsiiu gepatotsitov. I. Kinetika kletochnoi populiatsii.

The alkylating drug dipin was injected to mice 2 hours before a partial hepatectomy. Liver regeneration was characterized by a decrease of the intensity of 3H-thymidine label, an increase of the labeled cell index, absence of mitoses, constant number of binuclear cells. The analysis of these data has shown that dipin causes a sharp (more than by 2 times) increase of the S-period and prolonged (up to 6--20 days) blocking of cells in the G2-period. No phenomenon of unbalanced growth was recorded. No changes in duration of prereplicative period, or in the volume of proliferative pool were recorded. The increase of mitotic cycle periods resulted in the cell population synchronization: by the end of the second ay more than a half of hepatocytes were in S-period, by the end of the third day about 80% of cells passed to G2-period.

[Tomizine--a new inhibitor of folate metabolism enzymes possessing an antitumor activity]. / Tomizin--novyi ingibitor fermentov folievogo obmena, obladaiuschii protivoopukholevoi aktivnost'iu

In the experiments on enzymic systems functioning in the metabolism of folic acid and on transplantable tumors in animals the preparation thomizine (chlorohydrate 4-methoxy-6-aminopyrimido (4,5-b) (1,4) thiazine) was worked out. Thomizine, as well as the known antimetabolite of folic acid-methotrexate, suppresses the activity of dihydrofolate reductase, but contrary to it suppresses FAP enzymic system, inhibiting aminopterin in the organism. Thomizine differes from methotrexate by another spectrum of antitumor effect, selective suppression of the tumor tissue growth, compared with the normal in vitro, it does not inhibit leucopoiesis, shows less toxicity and insignificant cumulative properties.

Kinetics of cellular proliferation in regenerating mouse liver pretreated with the alkylating drug dipin.

The effect of prior exposure to the alkylating drug 1,4-Bis[N,N'-di(ethylene)-phosphamide] piperazine (Dipin) on the cell cycle progression in a regenerating mouse liver is reported, using cytological, autoradiographical and DNA-cytophotometrical methods. In Dipin-treated animals 3H-TdR pulse labelled nuclei appeared 22 h after the partial hepatectomy, followed by a rapid rise in labelling index to a very high level between 43-54 h, and then by a gradual decline to 72 h. Four injections of 3H-thymidine at 16 h intervals resulted in 89% labelling of hepatocytes at 72 h. The DNA-synthesis time was assessed by DNA photometry combined with 3H-TdR autoradiography on the same nucleus. The DNA-content in Dipin-pretreated nuclei was doubled after 26 h, approximately three times longer than in the controls. Mitoses were completely absent during the first 2-4 days. They were observed subsequently for up to 2 months but with varying frequency. The frequency of binucleated hepatocytes remained constant during liver regeneration. Hence, pretreatment of resting liver with Dipin altered the kinetics of cell proliferation following partial hepatectomy. Delay in division resulted primarily from an increase in the DNA-synthesis time and a prolonged block of the transition from G2 to mitosis. No changes in the duration of the prereplicative period and in the size of the proliferative pool were noticed. The increase of the mitotic cycle time led to synchronization of the cell population. About a half of the hepatocytes were seen in the S phase by the end of the second day and by the end of the third day about 80% of the cells had passed into the G2 phase.