Adsorption Behavior of an Adamantane Derivative on Metal Clusters – DFT Simulation Studies

Investigation of the adsorption properties of 3-(adamantan-1-yl)-4-phenyl-1-[(4-phenylpiperazin-yl)methyl]-1H-1,2,4-triazole-5(4H)-thione (APT) with metal clusters (mC: Ag, Au and Cu) are reported using DFT method. APT is found to form stable cluster with transition metal clusters of copper, silver and gold. The drug-cluster complexation energy is slightly more for the gold nanocluster-drug complex. Dipole moment of the drug-gold cluster is found to be higher than that of the other systems. SERS studies demonstrate improved Raman signals for multiple wavenumbers of all APT-metal cluster complexes. Different spectroscopic, chemical and electronic properties are also investigated.

Antibiofilm Effect of Adamantane Derivative against Staphylococcus aureus

Currently, one of the most urgent problems in clinical practice is the antibiotic therapy ineffectiveness at chronic diseases treatment caused by biofilms-forming microorganisms. One of the ways to its solution is the search for new compounds with antibiofilm activity which can prevent the adhesion of microorganisms, disrupt the structure of the biofilm matrix and affect the Quorum sensing system. The aim of the study was to investigate adamantane derivative 1-[4-(1-adamantyl) phenoxy]-3-(N-benzyl,N-dimethylamino)-2-propanol chloride (KVM-97) antimicrobial activity mechanism against Staphylococcus aureus biofilms. Methods. The ability of the adamantane derivative KVM-97 to prevent S. aureus biofilm formation and to destroy previously formed biofilms has been tested on polystyrene plates by gentian violet sorption on these structures, followed by desorption with organic solvent and use of resazurin (redox indicator). The S. aureus cells viability in mature biofilms was evaluated with specific dyes for living (acridine orange) and dead (propidium iodide) cells. Lowry method was used to assess the effect of KVM-97 on the matrix components for the total protein contents determination, the polysaccharides were detected spectrophotometrically (using phenol and sulfuric acid), Bap-protein – by test with Congo red. Persisters’ subpopulation was detected by activation of the SOS response in bacteria when exposed to high concentrations of antimicrobial substances. Results. It was found that KVM-97 (the compound with the adamantyl radical) showed an antibiofilm effect against S. aureus, decreasing biofilm biomass: at the biofilm formation stage – by 22.5% and 75.0%, while in case of 2-day biofilms treatment – by 34.5% and 32.4% at 0.5 MIC and 5.0 MIC respectively. Compound KVM-97 was able to reduce the number of metabolically active S. aureus cells only at the stage of biofilm formation (reduction by 92.7 and 95.8% at 2.0 and 5.0 MIC). Obtained results indicated that this adamantane-containing compound did not affect the protein and polysaccharides contents of S. aureus biofilms matrix. The changes of Bap-protein level caused by KVM-97 were not statistically significant (p>0.05). It was shown that KVM-97 did not prevent the formation of metabolically inactive persister cells; their share was 0.71% of the control. Conclusions. Thus, adamantane-containing compound KVM-97 is able to prevent S. aureus biofilm formation, causing significant biofilms’ mass reduction, as well as lowering the viable cells number in them and destroying already formed biofilms. Its antibiofilm effects are not associated with matrix protein and polysaccharides synthesis impairments. Further thorough investigations are needed to establish the effect of this compound on eDNA synthesis, the Quorum sensing system, and the ica and arg genes expression of S. aureus responsible for biofilm formation.

New Antiarrhythmic Agent to Stabilize Functional Activity of Rat Heart Sinus Node Cardiomyocytes

Introduction: The aim of this study was to explore the antiarrhythmic activity of the new antiarrhythmic drug, succinic acid ester of 5-hydroxyadamantane-2-one (ADK-1110) and its effect on the functional activity of rat heart sinus node. Materials and methods: Experiments were performed on 80 non-linear white awake male rats weighing 200 g, using calcium chloride and aconitine arrhythmia models. The ECG was recorded from all the animals in the II standard lead before the start of the experiment. The effect of ADK-1110 on the electrical activity characteristics of rat heart sinus node pacemakers in vitro was studied on 26 outbred Wistar rats of both sexes with a body weight of 160 to 200 g, using the microelectrode technique. Results and discussion: The compound significantly exceeds the known reference drugs in terms of the antiarrhythmic index. The agent also surpasses our previously proposed adamantane derivative ADK-1100 on calcium chloride model and is not inferior to the aconitine one. The electrophysiological analysis of the sinus node pacemaker cardiomyocytes characteristics in vitro under the influence of ADK-1110 revealed that the compound expands the area occupied by true pacemakers. Discussion: The obtained data indicate the presence of properties of antiarrhythmics of classes I, III, and IV in ADK-1110. The indicated functional remodeling stabilizes the functional activity of the central part of the sinus node. Conclusion: ADK-1110 stabilizes the functional activity of the central part of the sinus node. ADK-1110 also has a cerebrovascular anti-ischemic property.

Lipophilic Guanylhydrazone Analogues as Promising Trypanocidal Agents: An Extended SAR Study

In this report, we extend the SAR analysis of a number of lipophilic guanylhydrazone analogues with respect to in vitro growth inhibition of Trypanosoma brucei and Trypanosoma cruzi. Sleeping sickness and Chagas disease, caused by the tropical parasites T. brucei and T. cruzi, constitute a significant socioeconomic burden in low-income countries of sub-Saharan Africa and Latin America, respectively. Drug development is underfunded. Moreover, current treatments are outdated and difficult to administer, while drug resistance is an emerging concern. The synthesis of adamantane-based compounds that have potential as antitrypanosomal agents is extensively reviewed. The critical role of the adamantane ring was further investigated by synthesizing and testing a number of novel lipophilic guanylhydrazones. The introduction of hydrophobic bulky substituents onto the adamantane ring generated the most active analogues, illustrating the synergistic effect of the lipophilic character of the C1 side chain and guanylhydrazone moiety on trypanocidal activity. The n-decyl C1-substituted compound G8 proved to be the most potent adamantane derivative against T. brucei with activity in the nanomolar range (EC50=90 nM). Molecular simulations were also performed to better understand the structure-activity relationships between the studied guanylhydrazone analogues and their potential enzyme target.

The study of the effects of the combination of Himantane and Piribedil on a model of MPTP-induced parkinsonian syndrome in C57BL/6 mice

The effectiveness of hemantane, an original adamantane derivative, in combination with the dopamine receptor agonist piribedil on the model of acute parkinsonian syndrome induced by a single intraperitoneal injection of 30 mg/kg neurotoxicin-1, induced by a single intraperitoneal injection of 30 mg/kg neurotoxin 1-methyl-4-phenyl-tetrahydropyridine (MPTP) in C57BL/6 mice. Rigidity was assessed by stride length, oligokinesia and impaired coordination in the “rotarod test’’, effect on the catalepsy model caused by 0.1 mg/kg haloperidol. It has been established that the combination of hemantane and piribedil reduces the manifestations of parkinsonian syndrome, significantly exceeding in efficiency of each of the drugs separately.