Background: Heterocyclic compounds and their fused analogs, which contain pharmacophore fragments such as pyridine, thiophene and pyrimidine rings, are of great interest due to their broad spectrum of biological activity. Chemical compounds containing two or more pharmacophore groups due to additional interactions with active receptor centers usually enhance biological activity and can even lead to a new type of activity. The search for new effective neurotropic drugs in the series of derivatives of heterocycles containing pharmacophore groups in organic, bioorganic and medical chemistry is a serious problem. Methods: Modern methodology of drugs involves synthesis, physicochemical study, molecular modeling and selection of active compounds through virtual screening and experimental evaluation of the biological activity of new chimeric compounds with pharmacophore fragments. For the synthesis of new compounds, classical organic methods were used and developed. For the evaluation of neurotropic activity of new synthesized compounds, some biological methods were used according to indicators characterizing anticonvulsant, sedative and antianxiety activity as well as side effects. For docking analysis, various soft ware packages and methods were used. Results: As a result of multistep reactions, 11 new, tri- and tetracyclic heterocyclic systems were obtained. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures as well as some psychotropic effects. The biological assays evidenced that nine of the eleven studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of the compounds is low, and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity, it was found that the selected compounds have an activating behavior and anxiolytic effects on the “open field” and “elevated plus maze” (EPM) models. The data obtained indicate the anxiolytic (antianxiety) activity of the derivatives of tricyclic thieno[2,3-b]pyridines and tetracyclic pyridothieno[3,2-d]pyrimidin-8-ones, especially pronounced in compounds 3b–f and 4e. The studied compounds increase the latent time of first immobilization on the “forced swimming” (FS) model and exhibit antidepressant effects; compounds 3e and 3f especially exhibit these effects, similarly to diazepam. Docking studies revealed that compounds 3c and 4b bound tightly in the active site of γ-aminobutyric acid type A (GABA_A) receptors with a value of the scoring function that estimates free energy of binding (∆G) at −10.0 ± 5 kcal/mol. Compound 4e showed the best affinity ((∆G) at −11.0 ± 0.54 kcal/mol) and seems to be an inhibitor of serotonin (SERT) transporter. Compounds 3c–f and 4e practically bound with the groove of T4L of 5HT_1A and blocked it completely, while the best affinity observed was in compound 3f ((∆G) at −9.3 ± 0.46 kcal/mol). Conclusions: The selected compounds have an anticonvulsant, activating behavior and anxiolytic effects and at the same time exhibit antidepressant effects.

Store-operated calcium entry (SOCE) constitutes a fine-tuning mechanism responsible for the replenishment of intracellular stores. Hippocampal SOCE is regulated by store-operated channels (SOC) organized in tripartite complex TRPC6/ORAI2/STIM2. It is suggested that in neurons, SOCE maintains intracellular homeostatic Ca2+ concentration at resting conditions and is needed to support the structure of dendritic spines. Recent evidence suggests that positive modulators of SOC are prospective drug candidates to treat Alzheimer’s disease (AD) at early stages. Although STIM2 and ORAI2 are definitely involved in the regulation of nSOC amplitude and a play major role in AD pathogenesis, growing evidence suggest that it is not easy to target these proteins pharmacologically. Existing positive modulators of TRPC6 are unsuitable for drug development due to either bad pharmacokinetics or side effects. Thus, we concentrate the review on perspectives to develop specific nSOC modulators based on available 3D structures of TRPC6, ORAI2, and STIM2. We shortly describe the structural features of existing models and the methods used to prepare them. We provide commonly used steps applied for drug design based on 3D structures of target proteins that might be used to develop novel AD preventing therapy.

Background: Pseudomonas aeruginosa is one of the most dangerous superbugs in the list of bacteria for which new antibiotics are urgently needed, which was published by World Health Organization. P. aeruginosa is an antibiotic-resistant opportunistic human pathogen. It affects patients with AIDS, cystic fibrosis, cancer, burn victims and people with prosthetics and implants. P. aeruginosa also forms biofilms. Biofilms increase resistance to antibiotics and host immune responses. Because of biofilms, current therapies are not effective. It is important to find new antibacterial treatment strategies against P. aeruginosa . Biofilm formation is regulated through a system called quorum sensing. Thus disrupting this system is considered a promising strategy to combat bacterial pathogenicity. It is known that quercetin inhibits Pseudomonas aeruginosa biofilm formation, but the mechanism of action is unknown. In the present study, we tried to analyse the mode of interactions of LasR with quercetin. Results: We used a combination of molecular docking, molecular dynamics (MD) simulations and machine learning techniques for the study of the interaction of the LasR protein of P. aeruginosa with quercetin. We assessed the conformational changes of the interaction and analysed the molecular details of the binding of quercetin with LasR. We show that quercetin has two binding modes. One binding mode is the interaction with ligand binding domain, this interaction is not competitive and it has also been shown experimentally. The second binding mode is the interaction with the bridge, it involves conservative amino acid interactions from LBD, SLR, and DBD and it is also not competitive. Experimental studies show hydroxyl group of ring A is necessary for inhibitory activity, in our model the hydroxyl group interacts with Leu177 during the second binding mode. This could explain the molecular mechanism of how quercetin inhibits LasR protein. Conclusions: This study may offer insights on how quercetin inhibits quorum sensing circuitry by interacting with transcriptional regulator LasR. The capability of having two binding modes may explain why quercetin is effective at inhibiting biofilm formation and virulence gene expression. List of abbreviations: PDB Protein data bank MD Molecular Dynamics PCA Principal Component Analysis PC Principal Component SLR Short Linker Region BLAST Basic local alignment search tool DBI David-Bouldin Index psF pseudo-F statistic

The reaction of 2-phenyl-4-(4-benzoyloxyarylidene)-5(4H)-oxazolones the corresponding amino acids with hydrochlorides of methyl esters afforded N,O-dibenzoyl-α,β-dehydrotyrosylpeptides methyl esters. From the latter, O-benzoyl protecting group was removed with 3-(dimethylamino)-1-propylamine. Antiradical and anticholinesterase activity of the synthesized α,β-dehydrotyrosylpeptides were studied.

The use of O-benzoyl protection in the synthesis of N-benzoyl-α,β-dehydrotyrosine benzylamide, and the corresponding 4-imidazolone was studied. The reaction of 4-(4-benzoyloxybenzylidene)oxazol-5(4H)-one with benzylamine proceeds with the retention of the O-benzoyl protecting group. The latter is removed with 2-(dimethylamino)-1-ethylamine or 3-(dimethylamino)-1-propylamine. In the case of the cyclization of N,O-dibenzoyl-α,β-dehydrotyrosine benzylamide with 1,1,1,3,3,3-hexamethyldisilazane into (Z)-3-benzyl-5-(4-hydroxybenzylidene)-2-phenyl-3,5-dihydro-4H-imidazol-4-one leads to elimination of the O-benzoyl protection. The antiradical and anticholinesterase properties of the synthesized compounds were studied.

The piperazine derivative N-(2,6-difluorophenyl)-2-(4-phenylpiperazin-1-yl)propanamide (cmp2) has emerged as a potential transient receptor potential cation channel, subfamily C, member 6 (TRPC6) modulator, offering a promising pathway for Alzheimer’s disease (AD) therapy. Our recent findings identify cmp2 as a novel compound with synaptoprotective effects in primary hippocampal cultures and effective blood–brain barrier (BBB) penetration. In vivo studies demonstrate that cmp2 (10 mg/kg, intraperitoneally) restores synaptic plasticity deficits in 5xFAD mice. This study further shows cmp2’s selectivity towards tetrameric TRPC6 channel in silico. Acute administration of cmp2 is non-toxic, with no indications of chronic toxicity, and Ames testing confirms its lack of mutagenicity. Behavioral assays reveal that cmp2 improves cognitive functions in 5xFAD mice, including increased novel object recognition, better passing of the Morris water maze, and improved fear memory, as well as upregulation of motor function in beam walking tests. These findings suggest that cmp2 holds promise as a candidate for AD treatment.