Design, synthesis and biological evaluation of 4-aminoquinoline-guanylthiourea derivatives as antimalarial agents.

Guanylthiourea (GTU) has been identified as an important antifolate antimalarial pharmacophore unit, whereas, 4-amino quinolones are already known for antimalarial activity. In the present work molecules carrying 4-aminoquinoline and GTU moiety have been designed using molecular docking analysis with PfDHFR enzyme and heme unit. The docking results indicated that the necessary interactions (Asp54 and Ile14) and docking score (-9.63 to -7.36 kcal/mmol) were comparable to WR99210 (-9.89 kcal/mol). From these results nine molecules were selected for synthesis. In vitro analysis of these synthesized compounds reveal that out of the nine molecules, eight show antimalarial activity in the range of 0.61-7.55 µM for PfD6 strain and 0.43-8.04 µM for PfW2 strain. Further, molecular dynamics simulations were performed on the most active molecule to establish comparative binding interactions of these compounds and reference ligand with Plasmodium falciparum dihydrofolate reductase (PfDHFR).

Guanylthiourea derivatives as potential antimalarial agents: Synthesis, in vivo and molecular modelling studies.

Guanylthiourea (GTU) derivatives were identified as possible anti-malarial agents, recently, using in vitro studies on Plasmodium falciparum. This article gives an account of the in vivo anti-malarial activity of GTU derivatives against experimental rodent malaria. A total of 20 synthesized GTU derivatives were evaluated for in vivo antimalarial activity, out of which six showed encouraging results; one compound appeared to have curative potential. Molecular docking and molecular dynamics analysis were carried out to understand the molecular level interactions.

Design and synthesis of guanylthiourea derivatives as potential inhibitors of Plasmodium falciparum dihydrofolate reductase enzyme.

A new class of compounds based on S-benzylated guanylthiourea has been designed as potential PfDHFR inhibitors using computer aided methods (molecular electrostatic potential, molecular docking). Several compounds in this class have been synthesized starting from guanylthiourea and alkyl bromides. In vitro studies showed that two compounds from this class are active with the IC50 value of 100 µM and 400 nM.

[Neurophysiological analysis of the effects of antihypoxic versus psychotropic agents]. / Neirofiziologicheskii analiz deistviia antigipoksantov v sravnenii s psikhotropnymi sredstvami.

The Fourie EEG spectral analysis of thr sensomotor cortex and dorsal hypocampus in freely moving rats could reveal the common pharmacological EEG effects of different antihypoxic agents (gutimin, amtizole, emoxipine, and 3-OPK). All the agents decreased the total EEG power (they all reduced the absolute power in all frequency bands) and simultaneously enhanced (2 relative power. The former suggests that there was a decrease in the energetic level of bioelectric fluctuations, which may indicate that the brain reduces its energetic functioning level. The latter means that antihypoxic drugs activate the central nervous system. This effect may normalize EEG activity during hypoxic conditions, which causes the enhancement of slow-wave activity and reduces fast EEG activity. The pharmacological EEG effects of different groups of psychotropic drugs (nootropic drugs, psychostimulants, antidepressants, benzodiazepine tranquilizers, etc.) versus antihypoxants are discussed.

[The effect of gutimine and amtizol on the K, Na-pump activity of the nerve cell]. / Vliianie gutimina i amtizola na aktivnost' K, Na-nasosa nervnoi kletki.

The antihypoxants gutimine and amtisole, its cyclic derivative of 3.5-diamino-1,thia-2,4-diazole were tested for their effects on the activity of one of the most power-consuming functions of a nerve cell--on the activity of the K, Na-pump during normoxia. Gutimine was found to decrease K, Na-pump activity in the Retzius neurone by an average of 70% presumably due to its inhibitory effects of leakage currents. The experiments suggest that the preventive protective effect of gutimine is displayed at the membranous level. Amtisole was found to unchange the functional activity of the K, Na-pump in the Retzius neurone.

[The use of sodium gamma-oxybutyrate and gutimine for decreasing metabolic disorders in the heart, caused by exotoxic shock in acetic acid poisoning]. / Primenenie gamm-oksibutirata natriia i gutimina dlia umen'sheniia metabolicheskikh narushenii v serdtse, vyzvannykh ékzotoksicheskim shokom pri otravlenii ukusnoi kislotoi.

Exotoxic shock was simulated in non-linear rat males anesthetized with barbital after intragastric administration of 70% acetic acid at a dose of 4 ml/kg using a gastric tube. Energy metabolism and the rate of lipid peroxidation were studied in heart muscle during the decompensated and terminal periods of exotoxic shock. Sodium hydroxybutyrate (200 mg/kg) and gutimine (75 mg/kg), administered alone within 30 min after the poisoning, prolonged the period before manifestation of the decompensated and terminal steps of the shock; these drugs decreased the rate of metabolic impairments in the myocardium by decreasing the rates of adenine nucleotide catabolism, of glycolysis, lipolysis and lipid peroxidation.

[Effect of using gutimine in the pre-ischemic period on myocardial phospholipids during reperfusion]. / Vliianie primeneniia gutimina v predyshemicheskom periode na fosfolipidy miokarda vo vremia reperfuzii.

Physico-chemical properties of phospholipids were studied in heart muscle at postischemic period after preventive treatment with gutimine. Two administrations of the drug, as compared with its three times treatment, during the preischemic period contributed to development of stable adaptive antiischemic and antireperfusion responses involving alterations in fatty acid composition of phospholipids as demonstrated by an increase in content of arachidonic acid in all the phospholipid fractions studied as well as in total content of monoenic acids in lysophosphatidyl choline and phosphatidyl serine and of polyenic acids in lysophosphatidyl choline, phosphatidyl serine and phosphatidyl ethanolamine.

[An electromyographic method for determining the antihypoxic activity of preparations]. / Elektromiograficheskii metod opredeleniia protivogipoksicheskoi aktivnosti preparatov.

To measure drug antihypoxic activity, an electromyographic method was worked out. The main idea of the method is to estimate the influence of these substances on the amplitude of slow electric waves of smooth muscles on an isolated strip of rat small intestine in situ. This parameter whose value directly depends on tissue pO2 was recorded under the conditions of artificial ischemia of the intestinal strip. Circulatory hypoxia was simulated by the clamping of mesentery vessels, and the time was determined, during which the amplitude of slow electric waves reduced to 1/3 of the initial value in control animals and rats treated beforehand with the drugs under study. Antihypoxic activity of the drugs was calculated as difference in these time intervals between experiment and control, given in per cent.

[The action of amtizol and gutimin on the respiratory metabolism of the neuron]. / Deistvie amtizola i gutimina na dykhatel'nyi metabolizm neirona.

The effects of antihypoxants gutimine and amtisole on oxygen consumption by the intact nerve cell of the invertebrate and the activity of NADN-DH and SDH-dependent ways of oxidation in the cell were studied. Under normoxia gutimine inhibited the nerve cell respiration and decreased the activity of NADN-DN and SDH-dependent ways of oxidation by 15% and 5% respectively. Amtisole activated the neuron respiration increasing the activity of NADN-DH-dependent way of oxidation. Both antihypoxants, despite the fact that they refer to the same class of compounds, have different mechanisms of action on the neuron metabolism. Gutimine appears to be a pharmacological agent, protector, amtisole as an initiator of the active adaptative reorganization of the intracellular metabolism.

[Ultrastructural features of heart insufficiency and its correction during the post-asphyxia period]. / Ul'trastrukturnye priznaki serdechnoi nedostatochnosti i ee korrektsiia v postasfiksicheskom periode.

The ultrastructure of myocardium was studied in the experiments on rats during 24 hours after 6-min mechanical asphyxia with following clinical death. It has been established that the contractile cardiac apparatus of myocytes lesions on the intracellular edema background is the main while energy production process impairs insignificantly. The effectiveness of anti-hypoxia, membrane stability and protease inhibiting preparations for prevention of postresuscitation myocardium lesion was examined. The contrykal protective action, suppressing the proteolytic ferment hyperactivity was determined.

[Action of gutimine on the redox status of flavin and pyridine nucleotides in intact neurons]. / Deistvie gutimina na redoks-sostoianie flavinovykh i piridinovykh nukleotidov intaktnykh neironov.

Redox-reactions of flavine (FN) and pyridine (PN) nucleotides of the cell to guthimine were studied by the method of fluorescent microscopy without using any stains. The comparison was made of the kinetics of fluorescence intensity of FN and PN of the Retzius intact neuron under the action of guthimine, oxaloacetate, nembutal and succinate. It is suggested that guthimine may activate the switching of oxidative metabolism of the cell over to a more energitically profitable way.

[Effect of gutimine derivatives on the metamorphosis of Rana temporaria tadpoles]. / O vliianii proizvodnykh gutiminovogo riada na metamorfoz golovastikov Rana temporaria.

A one-time addition of gutimine (0.5 g/l), amtizol (0.2 g/l), and unithiol (0.25 g/l) to the medium at early stages of tadpole development was shown to inhibit metamorphosis only upon addition of unithiol. Repeated addition of gutimine, amtizol, and unithiol to the medium leads to reliable delay in metamorphosis. The delay is more pronounced at addition of the compounds to the medium at late stages of tadpole development (beginning at 40 stage). This suggests that the studied compounds may have anti-thyroid activity. All drugs under study induce the skin clearing.

[Radiation protection of mice with hypoxic gas mixtures after administration of anti-hypoxic agents]. / Radiozashchita myshei gipoksicheskimi gazovymi smesiami na fone vvedeniia antigipoksantov.

It is shown that such substances as gutimine, antizol and mexamine increases the resistance of animals to short-term breathing of gas mixtures containing 6 and 5% oxygen. Even if some of them decrease the degree of radioprotective effect of hypoxia, they afford the possibility to safe use of breathing mixtures with lower oxygen content than endured by intact animals, with the resulting increase in radioprotection. Thus the antihypoxic substances can be tested during hypoxiradiotherapy of human tumors.

[Infraslow activity and temperature of the brain during tests with emotional tension]. / Sverkhmedlennaia aktivnost' i temperatura mozga pri testakh émotsional'nogo napriazheniia.

Infraslow electrical activity and brain temperature were recorded with implanted electrodes and differential thermocouples in rabbits. Stimulation of gyrus cinguli increased the amplitude of infraslow activity and reduced its frequency. Stimulation of the hypothalamus entailed both changes of the infraslow activity and raise of the brain temperature. The effects of stimulation were altered after administration of antihypoxants.

[Metabolic effect of gutimine on the myocardial tissue in blood loss]. / Metabolicheskii éffekt gutimina v tkani miokarda pri krovopotere.

A rate of hemorrhage accounted for 31 mg/kg in 80 adult dogs premedicated with promedol and atropine. After circular-hemic hypoxia caused by the hemorrhage, single intravenous administration of gutimine (35-40 mg/kg) transformed the carbohydrate metabolism in heart muscle: activated glycolysis and accelerated the rate of its products oxidation, maintained the free amino acids concentration at the level similar to that of intact animals, reduced the rate of creatine phosphate synthesis.

[Dynamics of changes in the neuronal function of the central nervous system under prolonged stimulations]. / Dinamika izmenenii funktsional'nogo sostoianiia neironov tsentral'noi nervnoi sistemy pri dlitel'nykh razdrazheniiakh.

Mechanisms involved in long-term stimulation of the c. n. s. neurons of different degrees of complexity (cats, molluscs,) were studied. The hypoxic effect and prolonged transmembrane depolarization of a single neuron were used as long-term stimulation. The pattern of electrophysiological properties of neurons was investigated with microelectrode technique, fixation of potential and intracellular dialysis. The experiments showed that the hypoxic effect converted the neuron from the state of excitation into the state of depolarization inhibition. This reaction of the neuron was shown to be connected with the primary activation followed by a slow inactivation of the channels of input current.