Evaluation of Physicochemical Properties of Ipsapirone Derivatives Based on Chromatographic and Chemometric Approaches.

Drug discovery is a challenging process, with many compounds failing to progress due to unmet pharmacokinetic criteria. Lipophilicity is an important physicochemical parameter that affects various pharmacokinetic processes, including absorption, metabolism, and excretion. This study evaluated the lipophilic properties of a library of ipsapirone derivatives that were previously synthesized to affect dopamine and serotonin receptors. Lipophilicity indices were determined using computational and chromatographic approaches. In addition, the affinity to human serum albumin (HSA) and phospholipids was assessed using biomimetic chromatography protocols. Quantitative Structure-Retention Relationship (QSRR) methodologies were used to determine the impact of theoretical descriptors on experimentally determined properties. A multiple linear regression (MLR) model was calculated to identify the most important features, and genetic algorithms (GAs) were used to assist in the selection of features. The resultant models showed commendable predictive accuracy, minimal error, and good concordance correlation coefficient values of 0.876, 0.149, and 0.930 for the validation group, respectively.

A new synthetic ultrasound-assisted method for dibenzoepines.

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.

Eco-friendly synthesis of new olanzapine derivatives and evaluation of their anticancer potential.

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.

Click chemistry as a method for the synthesis of steroid bioconjugates of bile acids derivatives and sterols.

Six steroid conjugates of bile acids and sterol derivatives have been synthesized using the click chemistry method. The azide-alkyne Huisgen cycloaddition of the propionyl ester of lithocholic, deoxycholic and cholic acid with azide derivatives of cholesterol and cholestanol gave new bile acid-sterol conjugates linked with a 1,2,3-triazole ring. Previously, sterols were converted to bromoacetate substituted derivatives by reaction with bromoacetic acid bromide in anhydrous dichloromethane. These compounds were then converted to azide derivatives using sodium azide. The propiolic esters of lithocholic, deoxycholic and cholic acids were obtained by reaction with propiolic acid in the presence of p-toluenesulfonic acid. Additionally, two of these steroids: methyl 3α-propynoyloxy-12α-acetoxy-5ß-cholane-24-oate and methyl 3α-propynoyloxy-7 α,12α-diacetoxy-5ß-cholane-24-oate were also obtained and characterized for the first time. All conjugates were obtained in good yields using an efficient synthesis method. The structures of all conjugates and the four substrates were confirmed by spectral (1H- and 13C NMR, FT-IR) analysis, mass spectrometry (ESI-MS), and PM5 semiempirical methods. The pharmacotherapeutic potential of the synthesized compounds was estimated based on the in silico Prediction of Activity Spectra for Substances (PASS) method. The cytotoxicity of the compounds was in vitro evaluated in a hemolytic assay using human erythrocytes as a cell model. The in silico and in vitro study results indicate that the selected compound possesses an interesting biological activity and can be considered as potential drug design agent. Additionally, molecular docking was performed for the selected conjugate.

Design, Synthesis and Biological Evaluation of Novel 1,3,5-Triazines: Effect of Aromatic Ring Decoration on Affinity to 5-HT7 Receptor.

Considering the key functions of the 5-HT7 receptor, especially in psychiatry, and the fact that effective and selective 5-HT7 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-HT7 receptor, particularly ligands N2-(2-(5-fluoro-1H-indol-3-yl)ethyl)-N4-phenethyl-1,3,5-triazine-2,4,6-triamine 2 (Ki = 8 nM) and N2-(2-(1H-indol-3-yl)ethyl)-N4-(2-((4-fluorophenyl)amino)ethyl)-1,3,5-triazine-2,4,6-triamine 12 (Ki = 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.

Design and synthesis of new potent 5-HT7 receptor ligands as a candidate for the treatment of central nervous system diseases.

Owing to their multifunctional pharmacological profiles (including dual 5-HT1A/5-HT7 action), arylpiperazine derivatives are widely used for treating central nervous system diseases including the depression or neuropathic pain. Herein we describe the design, synthesis and evaluation of biological activity of novel 5-HT7 ligands derived of 2,4,6-triamino-1,3,5-triazine. The studied compounds showed affinity and high selectively towards 5-HT7 receptor with the two most active compounds 34 (Ki = 61 nM), 22 (Ki = 109 nM) showing good metabolic stability and moderate affinity to CYP3A4 isoenzyme. Compound 22 had high hepatotoxicity at a concentration below 50 µM, while compound 34 showed low hepatotoxicity even at a concentration above 50 µM.

Radioligand and computational insight in structure - Activity relationship of saccharin derivatives being ipsapirone and revospirone analogues.

Schizophrenia and depression are diseases that significantly impede human functioning in society. Current antidepressant drugs are not fully effective. According to literature data, the effect on D2R or 5-HT1AR can effectively reduce the symptoms of depression or schizophrenia. Recent research hypothetized that the synergism of both of these receptors can improve the effectiveness of therapy. Ipsapirone, a representative of long-chain arylpiperazines, is a known 5-HT1AR ligand that has antidepressant effect. This compound has no affinity for the D2R. Bearing in mind, we decided to design ligands with improved affinity to D2R and confirmed that in some cases elongation of the carbon linker or arylpiperazine exchange may have beneficial influence on the binding to D2R and 5-HT1AR. Four groups of ligands being ipsapirone analogues with butyl, pentyl, hexyl and stiffened xylene chains were designed. All compounds were obtained in solvent-free reactions supported by a microwave irradiation with an efficiency mainly above 60%. All ligands containing 1-(2-pyrimidinyl)piperazine exhibited high affinity to 5-HT1AR. In this case, chemical modifications within the chain did not affect the affinity to D2R. In the case of ligands containing 1-phenylpiperazine, 1-(3-trifluoromethylphenyl)piperazine, 1-(1-naphthyl)piperazine, and 1-(4-chlorophenyl)piperazine, elongation of carbon linker increases of affinity to D2R. For ligands containing 1- (2-pyridyl) piperazine, and 1-(2,3-dichlorophenyl)piperazine, we observed an opposite effect. For ligands containing 1-phenylpiperazine, 1-(2-methoxyphenyl)piperazine and 1-(2-pyridyl)piperazine, chain elongation had no effect on 5-HT1AR binding. In turn of ligands containing 1-(3-trifluoromethylphenyl)piperazine and 1- (2,3-dichlorophenyl)piperazine, we observed that elongation of carbon linker has a positive influence to 5-HT1AR. Molecular modelling was used to support the SAR study.

Aminotriazines with indole motif as novel, 5-HT7 receptor ligands with atypical binding mode.

Developing new and selective 5-HT7R 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-HT7R. SAR analysis demonstrated that the ethyl or ethoxy group (5c 5-HT7R Ki = 8 nM; 5d 5-HT7R Ki = 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-HT7R. 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.

Design, synthesis and biological evaluation of novel serotonin and dopamine receptor ligands being 6-bromohexyl saccharine derivatives.

Due to numerous side effects of current antidepressants, the search for new, safer bioactive compounds is still a valid research topic in medical chemistry. In our research we decided to synthesize and determine SAR for new hexyl arylpiperazines (LACPs) derivated with saccharin moiety. High biological activity has been explained using molecular modelling methods. The compounds obtained show high affinity for the 5-HT1A (compound 18, Ki = 4 nM - antagonist mode) and D2 (compound 15, Ki = 7 nM - antagonist mode) receptor, and in some cases also 5-HT7 receptor (compound 17, Ki = 20 nM). A preliminary ADME analysis showed that the compounds exhibit CNS drugability properties. We have proved that carbon-chain lengthening may have a beneficial effect on increasing the activity towards serotonin and dopamine receptors.