Development and study of the stability of comenic acid solutions

Introduction. The article presents the development of solutions based on the comenic acid substance. The criteria of the studied compositions that affect their stability during storage are evaluated within the framework of the Quality-by-Design concept. The optimal compositions of comenic acid solutions have been established.Aim. The purpose of the study is to develop solutions based on the comenic acid substance and determine the most stable variants of execution.Materials and methods. The study of comenic acid solutions was carried out by using a laboratory pH meter PB-11-P11 (SARTORIUS, Germany) and a liquid/ion chromatograph "Stayer" ("Akvilon" JSC, Russia).Results and discussion. The study made it possible to determine the most stable compositions of solutions based on the comenic acid substance and to establish optimal indicators of their stability criteria. It was found that solutions of comenic acid are the most stable in the pH range: from 4.0 to 6.0. At the same time, regardless of the studied methods of neutralization of comenic acid, solutions are unstable at concentrations of 25 mg/ml or more.Conclusion. As a result of the study, the optimal compositions of solutions based on the comenic acid substance were determined. A comparative analysis of excipients that increase the solubility of comenic acid in aqueous solvents is performed. The stability criteria of the studied solutions are established and their values for ensuring the stability of the developed drug are determined.

New approaches to the design of analgesic medicinal substances

A gamma-pyrone derivative, comenic acid, activates the opioid-like receptor-mediated signaling pathway that modulates the NaV1.8 channels in the primary sensory neuron membrane. These channels are responsible for generation of the nociceptive signal; gamma-pyrones can therefore have a great therapeutic potential as analgesics, and this effect deserves a deeper understanding. The novelty of our approach to the design of a medicinal substance is based on a combination of the data obtained on living neurons using very sensitive physiological methods and the results of quantum-chemical calculations. This approach allows to correlate the molecular structure of gamma-pyrones with their ability to evoke a physiological response of the neuron. Comenic acid can bind two calcium cations. One of them is chelated by the carbonyl and the hydroxyl functional groups, while another one forms the salt bond with the carboxylate anion. Calcium-bound gamma-pyrones are fundamentally different in electrostatic properties from the free gamma-pyrone molecules. These two calcium ions are the key elements involved in ligand-receptor binding. It is very likely ion-ionic interactions between these cations and anionic functional groups of the opioid-like receptor that activate the latter. The calculated intercationic distance of 9.5 Å is a structural criterion for effective ligand-receptor binding of calcium-bound gamma-pyrones.

Synthesis of new ferulic/lipoic/comenic acid-melatonin hybrids as antioxidants and Nrf2 activators via Ugi reaction

Aim: Oxidative stress has been implicated in the pathogenesis of many neurodegenerative diseases, and particularly in Alzheimer’s disease. Results: This work describes the Ugi multicomponent synthesis, antioxidant power and Nrf2 pathway induction in antioxidant response element cells of ( E)- N-(2-((2-(1 H-indol-3-yl)ethyl)amino)-2-oxoethyl)- N-(2-(5-(benzyloxy)-1 H-indol-3-yl)ethyl)-3-(4-hydroxy-3-methoxyphenyl)acryl amides 8a–d, N-(2-((2-(1 H-indol-3-yl)ethyl)amino)-2-oxoethyl)- N-(2-(5-(benzyloxy)-1 H-indol-3-yl)ethyl)-5-(1,2-dithiolan-3-yl)pentanamides 8e–h and N-(2-((2-(1 H-indol-3-yl)ethyl)amino)-2-oxoethyl)- N-(2-(5-(benzyloxy)-1 H-indol-3-yl)ethyl)-5-hydroxy-4-oxo-4 H-pyran-2-carboxamides 8i,j. Conclusion: We have identified compounds 8e and 8g, showing a potent antioxidant capacity, a remarkable neuroprotective effect against the cell death induced by H2O2 in SH-SY5Y cells, and a performing activation of the Nrf2 signaling pathway, as very interesting new antioxidant agents for pathologies that curse with oxidative stress.

Нелинейная динамика паттернов импульсной активности ноцицептивных нейронов при коррекции повреждающего болевого воздействия

A bifurcation analysis of a nociceptive neuron model was performed to study how the firing activity pattern changes when an antinociceptive response to damaging pain stimulation arises in rat dorsal ganglia. Ectopic train activity was found to arise in the model. Suppression of train activity was demonstrated to proceed solely through modification of the activation gating structure of the Na _ V 1.8 slow sodium channel in response to comenic acid, which exerts an analgesic effect and is an active ingredient of the new nonopioid analgesic Anoceptin.

Synthesis and Biological Activity of Novel Comenic Acid Derivatives Containing Isoxazole and Isothiazole Moieties

Methyl 5-hydroxy-4-oxo-4 H-pyran-2-carboxylate was synthesized by esterification of methanol with comenic acid under acidic catalysis. The obtained ester was alkylated with 3-(chloromethyl)-5-phenylisoxazole and 4,5-dichloro-3-(chloromethyl)isothiazole to afford corresponding conjugates containing isoxazole and isothiazole moieties which then were transformed into water-soluble Li-salts. During the bioassays of synthesized isoxazole and isothiazole derivatives of comenic acid in mixtures with first-line antitumor drug Temobel (Temozolomid) used in brain tumors chemotherapy, a synergetic effect was observed.