New Adamantane-Containing Edaravone Conjugates as Potential Neuroprotective Agents for ALS Treatments.

Currently, there are no effective drugs for the treatment of amyotrophic lateral sclerosis (ALS). Only two drugs-edaravone and riluzole-have been approved, but they have very limited efficacy. The aim of this work was to modify the structural core of the Edaravone-phenylpyrazolone moiety and combine it with aminoadamantane pharmacophore in order to expand the spectrum of its action to a number of processes involved in the pathogenesis of ALS. New conjugates of edaravone derivatives with 1-aminoadamantanes combined with alkylene or hydroxypropylene spacers were synthesized, and their biological activity was investigated. Compounds were found that could inhibit lipid peroxidation and calcium-related mitochondrial permeability, block fast sodium currents of CNS neurons, and reduce aggregation of the mutated form of the FUS-protein typical to ALS. So, the proposed modification of the edaravone molecule has allowed the obtaining of new original structures that combine some prospective therapeutic mechanisms against key chains of the pathogenesis of ALS. The identified lead compounds can be used for further optimization and development of new promising drugs on this basis for the treatment of ALS.

Derivatives of 9-phosphorylated acridine as butyrylcholinesterase inhibitors with antioxidant activity and the ability to inhibit ß-amyloid self-aggregation: potential therapeutic agents for Alzheimer's disease.

We investigated the inhibitory activities of novel 9-phosphoryl-9,10-dihydroacridines and 9-phosphorylacridines against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CES). We also studied the abilities of the new compounds to interfere with the self-aggregation of ß-amyloid (Aß42) in the thioflavin test as well as their antioxidant activities in the ABTS and FRAP assays. We used molecular docking, molecular dynamics simulations, and quantum-chemical calculations to explain experimental results. All new compounds weakly inhibited AChE and off-target CES. Dihydroacridines with aryl substituents in the phosphoryl moiety inhibited BChE; the most active were the dibenzyloxy derivative 1d and its diphenethyl bioisostere 1e (IC50 = 2.90 ± 0.23 µM and 3.22 ± 0.25 µM, respectively). Only one acridine, 2d, an analog of dihydroacridine, 1d, was an effective BChE inhibitor (IC50 = 6.90 ± 0.55 µM), consistent with docking results. Dihydroacridines inhibited Aß42 self-aggregation; 1d and 1e were the most active (58.9% ± 4.7% and 46.9% ± 4.2%, respectively). All dihydroacridines 1 demonstrated high ABTS•+-scavenging and iron-reducing activities comparable to Trolox, but acridines 2 were almost inactive. Observed features were well explained by quantum-chemical calculations. ADMET parameters calculated for all compounds predicted favorable intestinal absorption, good blood-brain barrier permeability, and low cardiac toxicity. Overall, the best results were obtained for two dihydroacridine derivatives 1d and 1e with dibenzyloxy and diphenethyl substituents in the phosphoryl moiety. These compounds displayed high inhibition of BChE activity and Aß42 self-aggregation, high antioxidant activity, and favorable predicted ADMET profiles. Therefore, we consider 1d and 1e as lead compounds for further in-depth studies as potential anti-AD preparations.

Variations of Redox Balance in Different Stages of Childhood Immune Thrombocytopenic Purpura.

BACKGROUND: Few previous studies indicated the role of oxidative stress in the pathogenesis of childhood idiopathic thrombocytopenic purpura (ITP), but there are little data regarding changes in redox balance in different forms of the disease, and changes after therapeutic procedures. We aimed to investigate the values of pro-oxidants and antioxidative capacity in various forms of ITP before and after the applying therapy. MATERIALS AND METHODS: The research included 102 children, classified into the following groups: (1) newly diagnosed ITP (ndITP), (2) persistent ITP, (3) chronic ITP (chITP), and (4) control groups: (A) healthy control and (B) previously experienced ITP-healthy children who had been suffering from ITP earlier. During the clinical assessment, a blood sample was taken from the patients, from which the value of pro-oxidants (index of lipid peroxidation measured as TBARS, nitrites [NO2 -], as measurement of nitric oxide [NO] production, superoxide anion radical [O2 -], and hydrogen peroxide [H2O2]) and the capacity of antioxidant protection (activity of superoxide dismutase and catalase, and quantity of reduced glutathione) were determined spectrophotometrically. RESULTS: Our results demonstrated that values of pro-oxidants, especially reflected through the TBARS and O2 -, were the highest in the ndITP and exacerbated chITP groups. Also, the activity of the endogenous antioxidative defense system was the lowest in these groups. Intravenous immunoglobulin therapy in the ndITP group exerted the most prominent effect on the redox balance. CONCLUSION: It can be concluded that severity and exacerbation of the ITP are closely related to the redox status.

Effect of CYP2D6*4, CYP2D6*10 polymorphisms on the safety of treatment with timolol maleate in patients with glaucoma.

OBJECTIVES: Timolol maleate is used for the treatment of glaucoma and metabolized by cytochrome CYP2D6 in the liver. The aim of this study was the evaluation of the influence of CYP2D6*4 and CYP2D6*10 gene polymorphisms on the safety of medications containing 0.5% of timolol maleate as glaucoma treatment in patients with primary open-angle glaucoma (POAG). METHODS: 105 patients with POAG were prescribed glaucoma medications, containing 0.5% timolol maleate. The safety of glaucoma treatment was determined by electrocardiography (ECG) (to assess heart rate (HR) and PQ interval) and blood pressure (BP) measurements. The real-time polymerase chain reaction method was used for the detection of single nucleotide polymorphisms (SNP). RESULTS: The risk of adverse drug reactions was higher in patients with the CYP2D6*4 GA genotype compared with GG: mean HR change at 1 month (2.88 ± 4.68 and 6.44 ± 5.57, p<0.001) and 6 months (5.14 ± 8.93 and 7.88 ± 5.65, p<0.001), mean PQ interval change at 1 (0.01 ± 0.031 and 0.02 ± 0.022, p=0.003) and 6 months (0.01 ± 0.032 and 0.02 ± 0.024, p=0.003). The risk of adverse drug reactions was higher in patients with the CYP2D6*10 CT genotype compared with CC: mean HR change at 1 month (2.94 ± 4.65 and 6.34 ± 5.66, p<0.001) and 6 months (5.20 ± 8.90 and 7.78 ± 5.75, p<0.001), mean PQ interval change at 1 (0.01 ± 0.032 and 0.02 ± 0.021, p=0.014) and 6 months (0.01 ± 0.033 and 0.02 ± 0.022, p=0.014). CONCLUSIONS: CYP2D6*4 and CYP2D6*10 gene polymorphisms may affect a higher risk of timolol-induced bradycardia and increased PQ interval of treatment medications containing 0.5% of timolol maleate in patients with POAG.

CYP2C9 gene polymorphisms influence on antihypertensive effectiveness and hypouricemic effect of losartan among patients with arterial hypertension: an observational study.

OBJECTIVES: CYP2C9 gene polymorphic variants can decrease the effects of losartan, reducing active metabolite (E-3174) formation. Study aims to determine the influence of *2 (+430C>T; rs799853) and *3 (+1075A>C; rs1057910) CYP2C9 gene polymorphic variants on the hypotensive and uricosuric effect of losartan on patients with arterial hypertension. METHODS: Eighty one patients with stage 1-2 arterial hypertension newly diagnosed with ABMP were enrolled in the study. Physicians started losartan treatment and then we measured urine concentration of E-3174/losartan to estimate CYP2C9 activity. After 3-month losartan treatment we compared effectiveness of the therapy with ABPM and plasma uric acid level between carriers of CYP2C9 *1/*1 and CYP2C9 gene polymorphic variants (*2 and *3). RESULTS: Carriage of CYP2C9*2 and CYP2C9*3 alleles reduced the hypotensive effect of losartan (p<0.001, OR=8.13 (95% CI, 2.75-23.97)). Analysis of the ABPM data revealed that blood pressure was significantly higher in patients with polymorphic genotypes. There was no significant difference in uric acid level in plasma and losartan and its metabolite concentration in urine between genotypes. CONCLUSIONS: Carriage of low function polymorphic variants of the CYP2C9 gene (*2 and *3) reduced the hypotensive effect of losartan according to ABPM and don't affect uric acid level in plasma and E-3174/losartan in urine.

Conjugates of Methylene Blue with Cycloalkaneindoles as New Multifunctional Agents for Potential Treatment of Neurodegenerative Disease.

The development of multi-target-directed ligands (MTDLs) would provide effective therapy of neurodegenerative diseases (ND) with complex and nonclear pathogenesis. A promising method to create such potential drugs is combining neuroactive pharmacophoric groups acting on different biotargets involved in the pathogenesis of ND. We developed a synthetic algorithm for the conjugation of indole derivatives and methylene blue (MB), which are pharmacophoric ligands that act on the key stages of pathogenesis. We synthesized hybrid structures and performed a comprehensive screening for a specific set of biotargets participating in the pathogenesis of ND (i.e., cholinesterases, NMDA receptor, mitochondria, and microtubules assembly). The results of the screening study enabled us to find two lead compounds (4h and 4i) which effectively inhibited cholinesterases and bound to the AChE PAS, possessed antioxidant activity, and stimulated the assembly of microtubules. One of them (4i) exhibited activity as a ligand for the ifenprodil-specific site of the NMDA receptor. In addition, this lead compound was able to bypass the inhibition of complex I and prevent calcium-induced mitochondrial depolarization, suggesting a neuroprotective property that was confirmed using a cellular calcium overload model of neurodegeneration. Thus, these new MB-cycloalkaneindole conjugates constitute a promising class of compounds for the development of multitarget neuroprotective drugs which simultaneously act on several targets, thereby providing cognitive stimulating, neuroprotective, and disease-modifying effects.

Pharmacological sequestration of mitochondrial calcium uptake protects against dementia and ß-amyloid neurotoxicity.

All forms of dementia including Alzheimer's disease are currently incurable. Mitochondrial dysfunction and calcium alterations are shown to be involved in the mechanism of neurodegeneration in Alzheimer's disease. Previously we have described the ability of compound Tg-2112x to protect neurons via sequestration of mitochondrial calcium uptake and we suggest that it can also be protective against neurodegeneration and development of dementia. Using primary co-culture neurons and astrocytes we studied the effect of Tg-2112x and its derivative Tg-2113x on ß-amyloid-induced changes in calcium signal, mitochondrial membrane potential, mitochondrial calcium, and cell death. We have found that both compounds had no effect on ß-amyloid or acetylcholine-induced calcium changes in the cytosol although Tg2113x, but not Tg2112x reduced glutamate-induced calcium signal. Both compounds were able to reduce mitochondrial calcium uptake and protected cells against ß-amyloid-induced mitochondrial depolarization and cell death. Behavioral effects of Tg-2113x on learning and memory in fear conditioning were also studied in 3 mouse models of neurodegeneration: aged (16-month-old) C57Bl/6j mice, scopolamine-induced amnesia (3-month-old mice), and 9-month-old 5xFAD mice. It was found that Tg-2113x prevented age-, scopolamine- and cerebral amyloidosis-induced decrease in fear conditioning. In addition, Tg-2113x restored fear extinction of aged mice. Thus, reduction of the mitochondrial calcium uptake protects neurons and astrocytes against ß-amyloid-induced cell death and contributes to protection against dementia of different ethology. These compounds could be used as background for the developing of a novel generation of disease-modifying neuroprotective agents.

Minocycline as heart conditioning agent in experimental type 2 diabetes mellitus - an antibacterial drug in heart protection.

Cardiovascular diseases, and among them certainly myocardial infarction, remain leading cause of death worldwide. Diabetes increases risk of occurrence as well as adverse outcome of myocardial infarction. Conditioning maneuvers are the most attractive method for alleviating both the consequences of ischemia and reperfusion. Minocycline is a tetracycline derivative which exerts antioxidant, anti-inflammatory, and anti-apoptotic effects. The aim of this study was to assess the protective ability of preconditioning and postconditioning of isolated hearts from healthy and rats with experimentally induced type 2 diabetes with minocycline on functional recovery and redox status after ischemia and reperfusion. The hearts from healthy and diabetic rats were excised and retrogradely perfused according to the Langendorff technique. Using sensor in the left ventricle, the cardiodynamic parameters were recorded and in the samples of the coronary venous effluent oxidative stress biomarkers were analyzed. Minocycline was injected directly into the coronary vessels, in preconditioning 5 min before global ischemia, and in postconditioning during the first 5 min of reperfusion. Results of this study clearly show beneficial effects of minocycline applied both before ischemia and in the first minutes of reperfusion fashion in both healthy and diabetic rat hearts. The most prominent protective effect regarding oxidative stress is related to the decreased production of superoxide anion radical due postconditioning with minocycline in diabetic hearts. Cardiodynamic parameters were significantly improved in minocycline conditioned groups. Superoxide anion radical stands out as the most susceptible to changes induced by minocycline.

Conjugation of Aminoadamantane and γ-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional Ligands.

A new series of conjugates of aminoadamantane and γ-carboline, which are basic scaffolds of the known neuroactive agents, memantine and dimebon (Latrepirdine) was synthesized and characterized. Conjugates act simultaneously on several biological structures and processes involved in the pathogenesis of Alzheimer's disease and some other neurodegenerative disorders. In particular, these compounds inhibit enzymes of the cholinesterase family, exhibiting higher inhibitory activity against butyrylcholinesterase (BChE), but having almost no effect on the activity of carboxylesterase (anti-target). The compounds serve as NMDA-subtype glutamate receptor ligands, show mitoprotective properties by preventing opening of the mitochondrial permeability transition (MPT) pore, and act as microtubule stabilizers, stimulating the polymerization of tubulin and microtubule-associated proteins. Structure-activity relationships were studied, with particular attention to the effect of the spacer on biological activity. The synthesized conjugates showed new properties compared to their prototypes (memantine and dimebon), including the ability to bind to the ifenprodil-binding site of the NMDA receptor and to occupy the peripheral anionic site of acetylcholinesterase (AChE), which indicates that these compounds can act as blockers of AChE-induced ß-amyloid aggregation. These new attributes of the conjugates represent improvements to the pharmacological profiles of the separate components by conferring the potential to act as neuroprotectants and cognition enhancers with a multifunctional mode of action.

Amiridine-piperazine hybrids as cholinesterase inhibitors and potential multitarget agents for Alzheimer's disease treatment.

We synthesized eleven new amiridine-piperazine hybrids 5a-j and 7 as potential multifunctional agents for Alzheimer's disease (AD) treatment by reacting N-chloroacetylamiridine with piperazines. The compounds displayed mixed-type reversible inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Conjugates were moderate inhibitors of equine and human BChE with negligible fluctuation in anti-BChE activity, whereas anti-AChE activity was substantially dependent on N4-substitution of the piperazine ring. Compounds with para-substituted aromatic moieties (5g, 5h, and bis-amiridine 7) had the highest anti-AChE activity in the low micromolar range. Top-ranked compound 5h, N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-9-yl)-2-[4-(4-nitro-phenyl)-piperazin-1-yl]-acetamide, had an IC50 for AChE = 1.83 ± 0.03 µM (Ki = 1.50 ± 0.12 and αKi = 2.58 ± 0.23 µM). The conjugates possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. In agreement with analysis of inhibition kinetics and molecular modeling studies, the lead compounds were found to bind effectively to the peripheral anionic site of AChE and displace propidium, indicating their potential to block AChE-induced ß-amyloid aggregation. Similar propidium displacement activity was first shown for amiridine. Two compounds, 5c (R = cyclohexyl) and 5e (R = 2-MeO-Ph), exhibited appreciable antioxidant capability with Trolox equivalent antioxidant capacity values of 0.47 ± 0.03 and 0.39 ± 0.02, respectively. Molecular docking and molecular dynamics simulations provided insights into the structure-activity relationships for AChE and BChE inhibition, including the observation that inhibitory potencies and computed pKa values of hybrids were generally lower than those of the parent molecules. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters comparable to those of amiridine and therefore acceptable for potential lead compounds at the early stages of anti-AD drug development.

The Long-Term Effect of Medically Enhancing Melanin Intrinsic Bioenergetics Capacity in Prematurity.

BACKGROUND: The ability of the human body to produce metabolic energy from light modifies fundamental concepts of biochemistry. OBJECTIVE: This review discusses the relationships between the long-accepted concept is that glucose has a unique dual role as an energy source and as the main source of carbon chains that are precursors of all organic matter. The capability of melanin to produce energy challenges this premise. METHODS: The prevalent biochemical concept, therefore, needs to be adjusted to incorporate a newly discovered state of Nature based on melanin's ability to dissociate water to produce energy and to re-form water from molecular hydrogen and oxygen. RESULTS AND DISCUSSION: Our findings regarding the potential implication of QIAPI-1 as a melanin precursor that has bioenergetics capabilities. CONCLUSION: Specifically, we reported its promising application as a means for treating retinopathy of prematurity (ROP). The instant report focuses on the long-term treatment medical effects of melanin in treating ROP.

Updated Understanding of the Degenerative Disc Diseases - Causes Versus Effects - Treatments, Studies and Hypothesis.

BACKGROUND: In this review we survey medical treatments and research strategies, and we discuss why they have failed to cure degenerative disc diseases or even slow down the degenerative process. OBJECTIVE: We seek to stimulate discussion with respect to changing the medical paradigm associated with treatments and research applied to degenerative disc diseases. METHOD PROPOSAL: We summarize a Biological Transformation therapy for curing chronic inflammations and degenerative disc diseases, as was previously described in the book Biological Transformations controlled by the Mind Volume 1. PRELIMINARY STUDIES: A single-patient case study is presented that documents complete recovery from an advanced lumbar bilateral discopathy and long-term hypertrophic chronic rhinitis by application of the method proposed. CONCLUSION: Biological transformations controlled by the mind can be applied by men and women in order to improve their quality of life and cure degenerative disc diseases and chronic inflammations illnesses.

Effects of Simvastatin on the Metabolism of Fatty Acids in Combined Secondary Prevention of Coronary Heart Disease: Dosage and Gender Differences between the Effects.

BACKGROUND: Statins are currently used for secondary prevention of Coronary Heart Disease (CHD), as the lipid-lowering therapy with them is proven safe and effective. OBJECTIVE: The purpose of this research is to investigate the dose-dependent effect of statins used for secondary prevention of coronary heart disease, as well as mechanisms of quantitative and qualitative changes in lipoproteins, fatty acids and cholesterol in the blood and tissues of people of both sexes. METHODS: In a clinical trial (n=125, of which 89 patients belong to group 1 and 36 to group 2) and an experiment on laboratory animals (n = 100), simvastatin reduced the total level of fatty acids in blood plasma, when given in the amount that was within the therapeutic dose range. RESULTS: This effect was achieved through a drug-induced improvement in the capacity of hepatic cells to absorb Low-density (LDL) and Very-low-density (VLDL) lipoproteins. CONCLUSION: Considering the formation of saturated fatty acids, statin performed better in males. With Omega-3 polyunsaturated fatty acids involved, changes in lipoproteins, cholesterol and fatty acids (liver and myocardium) were similar to those caused by small doses of a statin drug. Effects of the combination of bisoprolol and acetylsalicylic acid were completely different from those caused by the use of statin.

The Role of Melanin to Dissociate Oxygen from Water to Treat Retinopathy of Prematurity.

BACKGROUND: Retinopathy of Prematurity (ROP) is a potentially blinding disorder that commonly afflicts premature infants who are born prior to 31weeks of gestation or with a body weight less than 1250 grams (about 2.75 pounds). Another risk factor is excessive oxygen in incubators, which can lead to blindness. A compounding factor is that survival rates for premature infants are rising with concomitantly more cases of ROP. We have reported an unsuspected intrinsic property of melanin to dissociate water. This capability can be considered an alternative treatment option for adult and neonatal diseases. It is known that exogenous surfactant administration suppresses bronchopulmonary dysplasia and consequent death, randomized, controlled trials with various respiratory interventions did not show any significant reductions in morbidity and mortality rates. During a descriptive study about the three leading causes of blindness in the world, the ability of melanin to transform light energy into chemical energy through the dissociation of water molecule was unraveled. Initially, during 2 or 3 years; we tried to link together our findings with the widely accepted metabolic pathways already described in molecular pathway databases, which have been developed to collect and organize the current knowledge on metabolism scattered across a multitude of scientific evidence. OBSERVATIONS: The current report demonstrates the main problems that afflict premature babies with an emphasis on the growth of abnormal vessels in the retina, the explanation for which is unknown until date. We also reported a case of a baby who suffered digestive and respiratory problems with a brain haemorrhage that was successfully treated by laser photocoagulation. We hypothesise that most likely this effect was due to the melanin level and melanin itself produces oxygen via dissociating with water molecules. CONCLUSION: We postulate that the intrinsic effect of melanin may easily convert visible and invisible light into chemical energy via a water dissociation reaction similar to the one in plant's chlorophyll, and markedly elevated with diagnosis and treatment of the complications related to premature babies.

Conjugates of methylene blue with γ-carboline derivatives as new multifunctional agents for the treatment of neurodegenerative diseases.

We studied the inhibitory activity of methylene blue (MB) γ-carbolines (gC) conjugates (MB-gCs) against human erythrocyte acetylcholinesterase (AChE), equine serum butyrylcholinesterase (BChE), and a structurally related enzyme, porcine liver carboxylesterase (CaE). In addition, we determined the ability of MB-gCs to bind to the peripheral anionic site (PAS) of Electrophorus electricus AChE (EeAChE) and competitively displace propidium iodide from this site. Moreover, we examined the ability of MB-gCs to scavenge free radicals as well as their influence on mitochondrial potential and iron-induced lipid peroxidation. We found that MB-gCs effectively inhibited AChE and BChE with IC50 values in the range 1.73-10.5 µM and exhibited low potencies against CaE (9.8-26% inhibition at 20 µM). Kinetic studies showed that MB-gCs were mixed-type reversible inhibitors of both cholinesterases. Molecular docking results showed that the MB-gCs could bind both to the catalytic active site and to the PAS of human AChE and BChE. Accordingly, MB-gCs effectively displaced propidium from the peripheral anionic site of EeAChE. In addition, MB-gCs were extremely active in both radical scavenging tests. Quantum mechanical DFT calculations suggested that free radical scavenging was likely mediated by the sulfur atom in the MB fragment. Furthermore, the MB-gCs, in like manner to MB, can restore mitochondrial membrane potential after depolarization with rotenone. Moreover, MB-gCs possess strong antioxidant properties, preventing iron-induced lipid peroxidation in mitochondria. Overall, the results indicate that MB-gCs are promising candidates for further optimization as multitarget therapeutic agents for neurodegenerative diseases.

A Novel Non-invasive Effective Method for Potential Treatment of Degenerative Disc Disease: A Hypothesis.

The pathophysiology of the intervertebral discs plays a significant role in the people's life quality. There is not adequate research done in the pathogenesis and treatment of intervertebral disc degeneration. Alternately, self-educated physiology offers a novel and noninvasive method to reverse the degenerated discs. In this single case study, report attempts have been made to highlight the effect of the self-educative physiology, on magnetic resonance imaging investigations, of progressive healing, on the degenerated intervertebral discs. Based on this novel method, an effort has been made to review literature on the degeneration of intervertebral discs and available mode of treatments and then to propose a hypothesis for the biochemical mechanisms of healing. The idea is that transforming growth factor-ß1 from seminal plasma secretions may contribute to releasing the osteogenic protein- 1 which induces nucleus pulposus and annulus fibrosus cells in intervertebral discs for repairs. In addition, the patient's medical history is presented with background information.

The Dopaminergic Dysfunction and Altered Working Memory Performance of Aging Mice Lacking Gamma-synuclein Gene.

BACKGROUND: It was previously shown that inactivation of gamma-synuclein which is a small soluble neuronal protein affects psycho-emotional status and cognitive abilities in knock-out mice. OBJECTIVE: Determine the role of gamma-synuclein inactivation on memory performance in aging animals. METHOD: We used the passive avoidance test and acute amphetamine administration in aging gammasynuclein knock-out mice. RESULTS: As a result, we found moderate aging-unlinked deficit of dopaminergic neurotransmitter system of gamma-synuclein knock-out mice. At the same time, the evidence of progressive synaptic vesicle trafficking machinery impairment was obtained. CONCLUSION: Therefore most likely these dysfunctions are associated with a reduction in the highefficient learning performance in tests that require intact working memory.

Novel conjugates of aminoadamantanes with carbazole derivatives as potential multitarget agents for AD treatment.

A new group of compounds, promising for the design of original multitarget therapeutic agents for treating neurodegenerative diseases, based on conjugates of aminoadamantane and carbazole derivatives was synthesized and investigated. Compounds of these series were found to interact with a group of targets that play an important role in the development of this type of diseases. First of all, these compounds selectively inhibit butyrylcholinesterase, block NMDA receptors containing NR2B subunits while maintaining the properties of MK-801 binding site blockers, exert microtubules stabilizing properties, and possess the ability to protect nerve cells from death at the calcium overload conditions. The leading compound C-2h has been shown the most promising effects on all analyzed parameters. Thus, these compounds can be regarded as promising candidates for the design of multi-target disease-modifying drugs for treatment of AD and/or similar neuropathologies.

Securinine Derivatives as Potential Anti-amyloid Therapeutic Approach.

BACKGROUND: Oxidative stress and amyloid deposition are tightly interconnected pathological features of Alzheimer disease. In this respect, both amyloid production and aggregation may be stimulated by oxidative stress and also the increase of pathogenic ß-amyloid and its aggregated form lead to oxidative stress progression. Therefore, the search for potential drugs with both antioxidant and antiaggregation properties are of great interest. METHODS: In this study, we described the stereospecific synthesis of alkaloid securinine aminoderivatives. RESULTS: We showed that the newly synthesized compounds possess antioxidant and metal-chelating properties. Indeed, we report that one compound has inhibitory effects towards µ-amyloid aggregation. CONCLUSION: Based on these results, aminoderivatives of securinine scaffold are promising compounds for development of new drugs for the treatment of neurodegenerative diseases.