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1,3,5-triazine derivatives are useful compounds with potential applications in various branches of chemical industry, including pharmaceutical chemistry, cosmetic chemistry, photochemistry, and organic chemistry. Due to the growing environmental requirements on conducting efficient, economical, and safe syntheses, development of new methods for synthesizing organic compounds is highly desirable. In this publication, we present a protocol for the synthesis of 1,3,5-triazine derivatives using a sonochemical approach. In as little as 5 min, it is possible to obtain most of the investigated compounds with a yield of over 75%. An undeniable advantage of this method, besides its short time, is the use of water as the solvent. Furthermore, we provide examples that the sonochemical method may be more versatile than the competing microwave method. Analysis conducted using the DOZN TM 2.0 tool revealed that in terms of the 12 principles of green chemistry, the developed sonochemical method is 13 times "greener" than the classical one. Additionally, it has been demonstrated that the investigated molecules are attractive for their application as drug-like compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

According to WHO, infectious diseases are still a significant threat to public health. The combine effects of antibiotic resistance, immunopressure, and mutations within the bacterial and viral genomes necessitates the search for new molecules exhibiting antimicrobial and antiviral activities. Such molecules often contain cyclic guanidine moiety. As part of this work, we investigated the selected antimicrobial and antiviral activity of compounds from the cyclic arylguanidine group. Molecules were designed using molecular modeling and obtained using microwave radiation (MW) and sonochemical ()))) methods, in accordance with the previously developed pathways. The obtained compounds were screened for the ability to inhibit the growth of Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, and Cryptococcus neoformans. The capacity to block the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the host cell was probed using a bioluminescence immunoassay. The cytotoxicity and hemolytic properties of the most active molecules were also evaluated. The N-[2-(naphthalen-1-yl)ethyl]-5-phenyl-1,4,5,6-tetrahydro-1,3,5-triazin-2-amine 12j showed a high inhibition of Staphylococcus aureus and Cryptococcus neoformans (MIC ≤ 0.25 µg/mL), with no cytotoxic nor hemolytic effect (CC 50 , HC 10  > 32 µm/mL). The CO-ADD platform identified many potentially useful molecules. A particularly rich population was examined in the database of the N.D. Zelinsky Institute of Organic Chemistry, in which 2517 active molecules (MIC ≤ 32 mg/mL) were found, of which about 10% are active at very low concentrations (MIC ≤ 1 mg/mL)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Przemyslaw Zareba reports financial support was provided by Cracow University of Technology Faculty of Chemical Engineering and Technology. Przemyslaw Zareba reports equipment, drugs, or supplies was provided by AGH University of Science and Technology Academic Computer Centre Cyfronet. Przemyslaw Zareba reports equipment, drugs, or supplies was provided by University of Queensland. Sylwia Wnorowska reports financial support was provided by Medical University of Lublin., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

In this study, we have developed a new ultrasonic synthesis method of dibenzoepines using olanzapine and quetiapine, which are well-known drugs for the treatment of schizophrenia and bipolar disorder. The method is based on the N -alkylation reaction of the piperazine fragment in tricyclic compounds with methyl iodide or 2-(2-chloroethoxy)ethanol as the alkylating agent, respectively. The synthesis reactions were carried out in an ultrasonic bath with solvents such as acetonitrile or dimethylformamide in the presence of potassium or sodium carbonate or sodium hydroxide and metal-free, ecological phase transfer catalyst at a temperature of 40-50 °C. This allowed us to obtain olanzapine in 1 h (Y = 67%), and quetiapine in 3 h (Y = 72%). An ultrasonic reactor (Qsonica Q700) was used in the synthesis of olanzapine and made it possible to shorten the reaction time to 10 min and obtain 90% yield with very high purity. The developed method allows obtaining compounds in mild conditions and in a short time, thanks to which the process is more ecological than others described in the literature., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jolanta Jaskowska reports financial support was provided by 10.13039/501100006520Cracow University of Technology. Jolanta Jaskowska has patent #PL239444 (B1) issued to Assignee., (© 2023 The Authors.)

New derivatives of the known antipsychotic drug olanzapine have been obtained as potential compounds with anticancer activity in two metabolically different breast cancer cell lines: MCF-7 and triple negative MDA-MB-231. The compounds were obtained under phase transfer catalysis (PTC) in the presence of microwave irradiation (MW) or ultrasound (")))"), evaluating the effect of solvents such as dimethylformamide, water, or choline chloride/urea (natural deep eutectic solvent, NaDES). In the best option, the compounds were obtained within 2 minutes with a yield of 57-86% in MW. Two of the obtained compounds which have a naphthalimide moiety and a pentyl (7) or hexyl chain (8) show pronounced cytotoxicity. Interestingly, neither olanzapine nor desmethylolanzapine (DOLA), which was one of the substrates for the synthesis reaction, showed any significant activity in the study., Competing Interests: The authors declare no competing interests., (This journal is © The Royal Society of Chemistry.)

Memory impairments constitute a significant problem worldwide, and the COVID-19 pandemic dramatically increased the prevalence of cognitive deficits. Patients with cognitive deficits, specifically memory disturbances, have underlying comorbid conditions such as schizophrenia, anxiety, or depression. Moreover, the available treatment options have unsatisfactory effectiveness. Therefore, there is a need to search for novel procognitive and anti-amnesic drugs with additional pharmacological activity. One of the important therapeutic targets involved in the modulation of learning and memory processes are serotonin receptors, including 5-HT 1A , 5-HT 6 , and 5-HT 7 , which also play a role in the pathophysiology of depression. Therefore, this study aimed to assess the anti-amnesic and antidepressant-like potential of JJGW08, a novel arylpiperazine alkyl derivative of salicylamide with strong antagonistic properties at 5-HT 1A and D 2 receptors and weak at 5-HT 2A and 5-HT 7 receptors in rodents. First, we investigated the compound's affinity for 5-HT 6 receptors using the radioligand assays. Next, we assessed the influence of the compound on long-term emotional and recognition memory. Further, we evaluated whether the compound could protect against MK-801-induced cognitive impairments. Finally, we determined the potential antidepressant-like activity of the tested compound. We found that JJGW08 possessed no affinity for 5-HT 6 receptors. Furthermore, JJGW08 protected mice against MK-801-induced recognition and emotional memory deficits but showed no antidepressant-like effects in rodents. Therefore, our preliminary study may suggest that blocking serotonin receptors, especially 5-HT 1A and 5-HT 7 , might be beneficial in treating cognitive impairments, but it requires further investigation.

Depression, anxiety, and schizophrenia may coexist in psychiatric patients. Moreover, these disorders are very often associated with cognitive impairments. However, pharmacotherapy of these conditions remains challenging due to limited drug effectiveness or numerous side effects. Therefore, there is an urgent need to develop novel multimodal compounds that can be used to treat depression, anxiety, and schizophrenia, as well as memory deficits. Thus, this study aimed to evaluate the potential antidepressant-like, anxiolytic-like, antipsychotic-like effects, and anti-amnesic properties, of the novel arylpiperazine derivative of salicylamide, JJGW07, with an affinity towards serotonin 5-HT 1A , 5-HT 2A , and 5-HT 7 and dopamine D 2 receptors. Firstly, we investigated the compound's affinity for 5-HT 6 receptors and its functional activity by using in vitro assays. JJGW07 did not bind to 5-HT 6 receptors and showed antagonistic properties for 5-HT 1A , 5-HT 2A , 5-HT 7 , and D 2 receptors. Based on the receptor profile, we performed behavioral studies in mice to evaluate the antidepressant-like, anxiolytic-like, and antipsychotic-like activity of the tested compound using forced swim and tail suspension tests; four-plate, marble-burying, and elevated plus maze tests; and MK-801- and amphetamine-induced hyperlocomotion tests, respectively. JJGW07 revealed antidepressant-like properties in the tail suspension test, anxiolytic-like effects in the four-plate and marble-burying tests, and antipsychotic-like activity in the MK-801-induced hyperlocomotion test. Importantly, the tested compound did not induce catalepsy and motor impairments or influence locomotor activity in rodents. Finally, to assess the potential procognitive and anti-amnesic properties of JJGW07, we used passive avoidance and object recognition tests in mice. JJGW07 demonstrated positive effects on long-term emotional memory and also ameliorated MK-801-induced emotional memory impairments in mice, but showed no procognitive properties in the case of recognition memory. Our results encourage the search for new compounds among salicylamide derivatives, which could be model structures with multitarget mechanisms of action that could be used in psychiatric disorder therapy.

Cardiovascular diseases remain one of the leading causes of death worldwide. Unfortunately, the available pharmacotherapeutic options have limited effectiveness. Therefore, developing new drug candidates remains very important. We selected six novel arylpiperazine alkyl derivatives of salicylamide to investigate their cardiovascular effects. Having in mind the beneficial role of α 1 -adrenergic receptors in restoring sinus rhythm and regulating blood pressure, first, using radioligand binding assays, we evaluated the affinity of the tested compounds for α-adrenergic receptors. Our experiments revealed their high to moderate affinity for α 1 - but not α 2 -adrenoceptors. Next, we aimed to determine the antiarrhythmic potential of novel derivatives in rat models of arrhythmia induced by adrenaline, calcium chloride, or aconitine. All compounds showed potent prophylactic antiarrhythmic activity in the adrenaline-induced arrhythmia model and no effects in calcium chloride- or aconitine-induced arrhythmias. Moreover, the tested compounds demonstrated therapeutic antiarrhythmic activity, restoring a normal sinus rhythm immediately after the administration of the arrhythmogen adrenaline. Notably, none of the tested derivatives affected the normal electrocardiogram (ECG) parameters in rodents, which excludes their proarrhythmic potential. Finally, all tested compounds decreased blood pressure in normotensive rats and reversed the pressor response to methoxamine, suggesting that their hypotensive mechanism of action is connected with the blockade of α 1 -adrenoceptors. Our results confirm the antiarrhythmic and hypotensive activities of novel arylpiperazine derivatives and encourage their further investigation as model structures for potential drugs.

Schizophrenia is a chronic mental illness, which remains difficult to treat. A high resistance to the available therapies, their insufficient efficacy, and numerous side effects are the reasons why there is an urgent need to develop new antipsychotics. This study aimed to assess the antipsychotic-like effects of JJGW08, a novel arylpiperazine alkyl derivative of salicylamide, in rodents. First, considering the JJGW08 receptor profile, we investigated the compound's intrinsic activity towards dopamine D 2 and serotonin 5-HT 1A , 5-HT 2A , and 5-HT 7 receptors using functional assays. Next, we assessed the effect of JJGW08 on MK-801- and amphetamine-induced hyperlocomotion, its risk of inducing catalepsy and impairing motor coordination, as well as the anxiolytic-like effects in the four-plate and marble burying tests in mice. Finally, we investigated the antipsychotic-like properties of JJGW08 in rats using MK-801-induced hyperlocomotion and prepulse inhibition tests. We found that JJGW08 showed antagonistic properties at dopamine D 2 and serotonin 5-HT 1A , 5-HT 2A , and 5-HT 7 receptors. However, the effect on the 5-HT 2A and 5-HT 7 receptors was very weak. Moreover, the tested compound showed an antipsychotic-like effect in MK-801- and amphetamine-induced hyperlocomotion but not in a prepulse inhibition test in rats. Notably, JJGW08 demonstrated anxiolytic-like properties in both behavioral tests. Importantly, the compound did not induce catalepsy or motor coordination impairment in mice at antipsychotic-like doses. Our study suggests it is worth searching for new potential antipsychotics among arylpiperazine alkyl derivatives of salicylamide.

Considering the key functions of the 5-HT 7 receptor, especially in psychiatry, and the fact that effective and selective 5-HT 7 receptor ligands are yet to be available, in this work, we designed and synthesized novel 1,3,5-triazine derivatives particularly based on the evaluation of the effect of substituents at aromatic rings on biological activity. The tested compounds showed high affinity to the 5-HT 7 receptor, particularly ligands N 2 -(2-(5-fluoro-1H-indol-3-yl)ethyl)-N 4 -phenethyl-1,3,5-triazine-2,4,6-triamine 2 ( K i = 8 nM) and N 2 -(2-(1H-indol-3-yl)ethyl)-N 4 -(2-((4-fluorophenyl)amino)ethyl)-1,3,5-triazine-2,4,6-triamine 12 ( K i = 18 nM) which showed moderate metabolic stability, and affinity to the CYP3A4 isoenzyme. As for the hepatotoxicity evaluation, the tested compounds showed moderate cytotoxicity only at concentrations above 50 µM. Compound 12 exhibited less cardiotoxic effect than 2 on Danio rerio in vivo model.

The chemotype of arylsulfonamide derivatives of cyclic arylguanidines is a source of molecules with valuable biological activities, including antimicrobial and antitumor properties. The methods of the synthesis presented in the literature are characterized with low selectivity and high environmental nuisance. In this publication, we present a developed alternative and earlier undescribed pathway C, for the synthesis of arylsulfonamide derivatives of cyclic arylguanidines (N-(1H-arylimidazol-2-yl)arylsulfonamides and N-(1,4-dihydroquinazolin-2-yl)arylsulfonamides), including reaction between 2-(methylsulfanyl)-benzimidazole or 2-(methylsulfanyl)-3,4-dihydroquinazoline with arylsulfonamides. We also optimized previously reported methods; A (reaction of 2-aminobenzimidazole or 2-amino-3,4-dihydroquinazoline with arylsulfonyl chlorides) and B (reaction of dimethyl-(arylsulfonyl)carbonodithioimidate with aryldiamines). The conducted research allowed achieving two independent ecological and quick methods of obtaining the desired products. We used ecological methods of ultrasound-assisted or microwave synthesis, solvent-free reactions and a"green" reaction environment. In both pathways, it has proven advantageous to use H 2 O as the solvent and K 2 CO 3 (1 or 3 equivalent) as the basic agent. In the sonochemical variant, the efficiency reached B: 37-89 %, C: 90 % in 60 min (P = 80 W and f = 40 kHz), while in the microwave synthesis it was B: 38-74 %, C: 63-85 % in 0.5-4 min (P = 50 W). Path A led to a complementary substitution product (i.e. 1-(arylsulfonyl)-1H-benzimidazol-2-amine or 1-(arylsulfonyl)-1,4-dihydroquinazolin-2-amine). We obtained a small group of compounds that were tested for cytotoxicity. The 10f (N-(1,4-dihydroquinazolin-2-yl)naphthalene-1-sulfonamide) showed cytotoxic activity towards human astrocytoma cell line 1321 N1. The calculated IC 50 value was 8.22 µM at 24 h timepoint (doxorubicin suppressed 1321 N1 cell viability with IC 50 of 1.1 µM). The viability of the cells exposed to 10f for 24 h dropped to 48.0 % compared to vehicle control, while the cells treated with doxorubicin experienced decline to 47.5 %. We assessed its potential usefulness in pharmacotherapy in the ADMET study, confirming its ability to cross the blood-brain barrier (Pe = 5.0 ± 1.5 × 10 -6 cm/s) and the safety of its potential use in terms of DDI and hepatotoxicity., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Przemyslaw Zareba reports financial support was provided by National Science Centre Poland. Przemyslaw Zareba reports equipment, drugs, or supplies was provided by AGH University of Science and Technology Academic Computer Centre CYFRONET., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Serotonin 5-HT 1A and 5-HT 7 receptors play an important role in the pathogenesis and pharmacotherapy of depression. Previously identified N -hexyl trazodone derivatives, 2-(6-(4-(3-chlorophenyl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3- a ]pyridin-3(2 H )-one hydrochloride ( 7a·HCl ), with high affinity for 5-HT 1A R and 2-(6-(4-([1,1'-biphenyl]-2-yl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3- a ]pyridin-3(2 H )-one hydrochloride ( 7b·HCl ), a dual-acting 5-HT 1A /5-HT 7 receptor ligand, were prepared with a new microwave-assisted method. The protocol for the synthesis of 7a and 7b involved reductive alkylation under a mild reducing agent. We produced the final compounds with yield of 56-63% using ethanol or 51-56% in solvent-free conditions in 4 min. We then determined the 5-HT 7 R binding mode for compounds 7a and 7b using in silico methods and assessed the preliminary ADME and safety properties (hepatotoxicity and CYP3A4 inhibition) using in vitro methods for 7a·HCl and 7b·HCl . Furthermore, we evaluated antidepressant-like activity of the dual antagonist of 5-HT 1A /5-HT 7 receptors ( 7b·HCl ) in the forced swim test (FST) in mice. The 5-HT 1A R ligand ( 7a·HCl ) with a much lower affinity for 5-HT 7 R compared to that of 7b·HCl was tested comparatively. Both compounds showed antidepressant activity, while 5-HT 1A /5-HT 7 double antagonist 7b·HCl showed a stronger and more specific response.

A new ligand for 5-HT1A and 5-HT7 receptors, an arylpiperazine salicylamide derivative with an inflexible spacer, is investigated to identify preferred fragments capable of creating essential intermolecular interactions in different solvates. To fully identify and characterize the obtained crystalline materials, various methods including powder and single-crystal X-ray diffraction, solid-state NMR, and thermal analysis were employed, supplemented by periodic ab initio calculations. The molecular conformation in different solvates, types, and hierarchy of intermolecular interactions as well as the crystal packing were investigated to provide data for future research focused on studying protein-ligand interactions. Based on various methods of crystal structure analysis, including the interaction energy calculation and programs using an artificial neural network, a salicylamide fragment was found to be crucial for intermolecular contacts, mostly of dispersion and electrostatic character. A supramolecular 2D kite-type layer of {4,4} topology was found to form in crystals. The closed voids between layers contain disordered solvents, very weakly interacting with the molecule and the layer. It has been postulated that the separation of the layers might be influenced by an increase in temperature or the size of the solvent; hence, only methanol and ethanol hemi-solvates could be obtained from a series of various alcohols.

New pharmaceutically acceptable salts of trazodone (trazodone hydrogen bromide and trazodone 1-hydroxy-2-naphthonic acid) for the treatment of central nervous system disorders are synthesized and described. Although trazodone salts are poorly crystalline, single-crystal X-ray diffraction data for trazodone 1-hydroxy-2-naphthonic acid were collected and analyzed as well as compared to the previously described crystal structure of commercially available trazodone hydrochloride. The powder samples of all new salts were characterized by Fourier transform infrared spectroscopy, X-ray diffraction and 13 C solid-state nuclear magnetic resonance spectroscopy. Spectroscopic studies were supported by gauge including projector augmented wave (GIPAW) calculations of carbon chemical shielding constants. The main goal of our research was to find salts with better physicochemical properties and to make an attempt to associate them with both the anion structure and the most prominent interactions exhibited by the protonated trazodone cation. The dissolution profiles of trazodone from tablets prepared from various salts with lactose monohydrate were investigated. The studies revealed that salts with simple anions show a fast release of the drug while the presence of more complex anion, more strongly interacting with the cation, effects a slow-release profile of the active substance and can be used for the preparation of the tables with a delay or prolonged mode of action.

Developing new and selective 5-HT 7 R ligands may have a key impact on the treatment of central nervous system diseases including depression. We have found that indoleaminotriazine core fused with alkyl aryl moiety exhibits high affinity and selectivity to 5-HT 7 R. SAR analysis demonstrated that the ethyl or ethoxy group (5c 5-HT 7 R K i  = 8 nM; 5d 5-HT 7 R K i  = 55 nM) is the optimal carbon linker between triazine and aryl moiety. The results of the molecular dynamics simulations show stable interaction with E7.34 upon binding to a 5-HT 7 R. Compounds 5c and 5d were tested for early ADMET parameters. Compounds are not hepatotoxic and exhibit moderate potential interaction with other drugs metabolized by CYP3A4 or CYP2D6., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Trazodone, a well-known antidepressant drug widely used throughout the world, works as a 5-hydroxytryptamine (5-HT 2 ) and α 1 -adrenergic receptor antagonist and a serotonin reuptake inhibitor. Our research aimed to develop a new method for the synthesis of trazodone and its derivatives. In the known methods of the synthesis of trazodone and its derivatives, organic and toxic solvents are used, and the synthesis time varies from several to several dozen hours. Our research shows that trazodone and its derivatives can be successfully obtained in the presence of potassium carbonate as a reaction medium in the microwave field in a few minutes. As a result of the research work, 17 derivatives of trazodone were obtained, including compounds that exhibit the characteristics of 5-HT 1A receptor ligands. Molecular modeling studies were performed to understand the differences in the activity toward 5-HT 1A and 5-HT 2A receptors between ligand 10a (2-(6-(4-(3-chlorophenyl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2 H )-one) (5-HT 1A K i = 16 nM) and trazodone. The docking results indicate the lack of the binding of ligand 10a to 5-HT 2A R, which is consistent with the in vitro studies. On the other hand, the docking results for the 5-HT 1A receptor indicate two possible binding modes. Crystallographic studies support the hypothesis of an extended conformation.

The complexes of selected long-chain arylpiperazines with homology models of 5-HT 1A , 5-HT 2A , and 5-HT 7 receptors were investigated using quantum mechanical methods. The molecular geometries of the ligand-receptor complexes were firstly optimized with the Our own N-layered Integrated molecular Orbital and molecular Mechanics (ONIOM) method. Next, the fragment molecular orbitals method with an energy decomposition analysis scheme (FMO-EDA) was employed to estimate the interaction energies in binding sites. The results clearly showed that orthosteric binding sites of studied serotonin receptors have both attractive and repulsive regions. In the case of 5-HT 1A and 5-HT 2A two repulsive areas, located in the lower part of the binding pocket, and one large area of attraction engaging many residues at the top of all helices were identified. Additionally, for the 5-HT 7 receptor, the third area of destabilization located at the extracellular end of the helix 6 was found.