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Innovative eco-friendly methods based on natural deep eutectic solvents (NaDES) coupled with ultrasound-assisted extraction were employed for chokeberry anthocyanins extractions. Nine different NaDES composed of choline chloride as a hydrogen bond acceptor and organic acids (lactic, citric, malic), sugars (glucose, fructose), polyols (glycerol, 1,2-propanediol, sorbitol), and an amide (urea) as hydrogen bond donors were screened. Malic acid-containing NaDES was selected for optimization extraction conditions (time, temperature, water in NaDES) by response surface methodology. Optimal conditions for simultaneously maximizing the anthocyanins extraction (cyanidin-3-O-glucoside, cyanidin-3-O-galactoside, cyanidin-3-O-arabinoside, total anthocyanins) were 42.7 °C, 90 min, and 40 % (w/w) water in NaDES. In the next stage of this study, the possibility to improve anthocyanins extraction at elevated temperatures by incorporating different concentrations of hydroxypropyl-β-cyclodextrin into selected NaDES was investigated. The extraction was improved at hydroxypropyl-β-cyclodextrin concentrations up to 3 % (w/w). To clarify the interaction of NaDES components and anthocyanins, a molecular dynamic simulation was conducted.

Recent findings unveil the pharmacological modulation of imidazoline I

I2 receptors (I2-IR) are widely distributed in the central nervous system. I2-IR ligands are associated with a neuroprotective effect but, as I2-IR structure remains unknown, the discovery of better and more selective ligands is necessary to understand the pharmacological and molecular implications of I2-IR. Recently, we described a new imidazoline-structure family which showed high affinity and selectivity for I2-IR. In vivo studies in mice indicated a neuroprotective role and revealed beneficial effects in behaviour and cognition with a murine model of neurodegeneration, senescence-accelerated prone mouse (SAMP8). Herein, we report a novel non-imidazoline-structure of bicyclic α-iminophosphonates family with high affinities for I2-IR. In vivo studies in 5X-FAD mice (a transgenic representative model of AD) and SAMP8 mice (a model of neurodegeneration linked to aging) showed an improvement in behaviour and cognition, a reduction of AD hallmarks and of neuroinflammation markers for the mice treated with the lead compound B06. After evaluating several pathways associated with neurodegeneration, we demonstrated that CaN pathway plays a critical role on the neuroprotective effects of I2-IR ligands on SAMP8 mice model. To rule out warnings of the novel family, we calculated DMPK and physicochemical properties for the novel bicyclic α-iminophosphonates. As well, we carried out drug metabolism, safety studies and in vivo pharmacokinetics for lead compound B06. In summary, we present a novel family of I2-IR ligands, its effectiveness in in vivo models and the possible neuroprotective molecular mechanism mediated by them. This highlights that the modulation of I2-IR by bicyclic α-iminophosphonates may open a new therapeutic venue for unmet neurodegenerative conditions.

Drug discovery and development is a very challenging, expensive and time-consuming process. Impressive technological advances in computer sciences and molecular biology have made it possible to use computer-aided drug design (CADD) methods in various stages of the drug discovery and development pipeline. Nowadays, CADD presents an efficacious and indispensable tool, widely used in medicinal chemistry, to lead rational drug design and synthesis of novel compounds. In this article, an overview of commonly used CADD approaches from hit identification to lead optimization was presented. Moreover, different aspects of design of multitarget ligands for neuropsychiatric and anti-inflammatory diseases were summarized. Apparently, designing multi-target directed ligands for treatment of various complex diseases may offer better efficacy, and fewer side effects. Antipsychotics that act through aminergic G protein-coupled receptors (GPCRs), especially dopamine D2 and serotonin 5-HT2A receptors, are the best option for treatment of various symptoms associated with neuropsychiatric disorders. Furthermore, multi-target directed cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitors are also a successful approach to aid the discovery of new anti-inflammatory drugs with fewer side effects. Overall, employing CADD approaches in the process of rational drug design provides a great opportunity for future development, allowing rapid identification of compounds with the optimal polypharmacological profile. Proces otkrića i razvoja lekova je veoma zahtevan, skup i dugotrajan. Veliki tehnološki napredak u molekularnoj biologiji i kompjuterskim naukama je omogućio primenu metoda kompjuterski potpomognutog dizajniranja lekova (CADD) u različitim fazama procesa otkrića i razvoja lekova. Danas CADD predstavlja efikasnu i nezamenljivu alatku, koja se široko koristi u medicinskoj hemiji za racionalni dizajn i sintezu novih jedinjenja. U ovom preglednom radu biće prikazani CADD pristupi koji se najčešće koriste od procesa identifikacije hit jedinjenja do optimizacije lead jedinjenja. Pored toga, biće predstavljeni različiti aspekti u dizajnu višeciljnih liganada za neuropsihijatrijske i inflamatorne bolesti. Pokazano je da su ova jedinjenja veoma efikasna u lečenju složenih bolesti zbog veće efikasnosti i manje neželjenih efekata koje izazivaju. Antipsihotici koji deluju preko aminergičnih G-protein spregnutih receptora (GPCR), posebno preko dopaminskih D2 i serotoninskih 5-HT2A receptora, predstavljaju najbolju opcija za lečenje različitih simptoma povezanih sa neuropsihijatrijskim poremećajima. Pored toga, dizajn i sinteza dualnih inhibitora ciklooksigenaze-2 (COX-2) i 5lipoksigenaze (5-LOX) takođe predstavlja uspešan pristup u otkrivanju novih antiinflamatornih lekova sa manje neželjenih efekata. Na kraju se može zaključiti da primena CADD metoda u procesu racionalnog dizajniranja lekova pruža značajnu priliku za dalji napredak jer omogućava brzu identifikaciju jedinjenja sa optimalnim polifarmakološkim profilom.

Imidazoline I

Temeljna potreba za kretanjem i tjelesnom aktivnosti u suvremenom životu postaje zapostavljena te se zadovoljstvo, zabava i užitak pronalaze u različitim pasivnim sadržajima i aktivnostima. Outdoor aktivnosti i tjelesna rekreacija ističu se kao zaboravljene temeljne ljudske potrebe koje je važno vratiti u središte pozornosti. S obzirom na to, u ovom je radu opisano planinarenje kao oblik sportske rekreacije u prirodi čija pravilna primjena ima važnu ulogu, a njena kvalitetna upotreba ovisi o svijesti i odgovornosti svakog pojedinca. Boravak i aktivnosti u planinama imaju dugoročne koristi za tjelesni, socijalni, emocionalni i kognitivni razvoj djece i mladih. Mnogi stručnjaci složili su se kako je upravo priroda ono što nedostaje generaciji koju prati dinamičan i brz tehnološki napredak, ali nedovoljan broj istraživanja s fokusom na djecu pokazuje kako se ova tema još ne shvaća dovoljno ozbiljnom. Provedena istraživanja u Hrvatskoj se koncentriraju više na motorički razvoj i sportsku aktivnost djece, a manje na samo planinarenje s djecom što se ovim radom nastoji korigirati. Planinarenje kao rekreacijska aktivnost s ciljem razvijanja ekološke svijesti i svijesti o zdravom životu, ostvarivo je i lako dostupno rješenje kako bi se osigurala veća tjelesna aktivnost djece. U ovom radu je prikazano na koji način zainteresirati djecu za planine te im omogućiti siguran i uspješan izlet u svrhu očuvanja tjelesnog i duhovnog zdravlja, a najvažnije, razvijanja osjećaja poštovanja za prirodu i sve što nam ona daje.

A wide range of neuropsychological disorders is caused by serotonin 5-HT2A receptor (5-HT2AR) malfunction. Therefore, this receptor had been frequently used as target in CNS drug research. To design novel potent 5-HT2AR antagonists, we have combined ligand-based and target-based approaches. This study was performed on wide range of structurally diverse antagonists that were divided into three different clusters: clozapine, ziprasidone, and ChEMBL240876 derivatives. By performing the 50 ns long molecular dynamic simulations with each cluster representative in complex with 5-HT2A receptor, we have obtained virtually bioactive conformations of the ligands and three different antagonist-bound, inactive, conformations of the 5-HT2AR. These three 5-HT2AR conformations were further used for docking studies and generation of the bioactive conformations of the data set ligands in each cluster. Subsequently, selected conformers were used for 3D-Quantitative Structure Activity Relationship (3D-QSAR) modelling and pharmacophore analysis. The reliability and predictive power of the created model was assessed using an external test set compounds and showed reasonable external predictability. Statistically significant variables were used to define the most important structural features required for 5-HT2A antagonistic activity. Conclusions obtained from performed ligand-based (3D-QSAR) and target-based (molecular docking and molecular dynamics) methods were compiled and used as guidelines for rational drug design of novel 5-HT2AR antagonists. Communicated by Ramaswamy H. Sarma

Imidazoline I2 receptors (I2-IR), widely distributed in the CNS and altered in patients that suffer from neurodegenerative disorders, are orphans from a structural point of view, and new I2-IR ligands are urgently required for improving their pharmacological characterization. We report the synthesis and three-dimensional quantitative structure−activity relationship (3D-QSAR) studies of a new family of bicyclic α-iminophosphonates endowed with relevant affinities for human brain I2-IR. Acute treatment in mice with a selected compound significantly decreased Fas-associated protein with death domain (FADD) in the hippocampus, a key signaling mediator of neuroprotective actions. Additionally, in vivo studies in the familial Alzheimer’s disease 5xFAD murine model revealed beneficial effects in behavior and cognition. These results are supported by changes in molecular pathways related to cognitive decline and Alzheimer’s disease. Therefore, bicyclic α-iminophosphonates are tools that may open new therapeutic avenues for I2-IR, particularly for unmet neurodegenerative conditions., We strongly acknowledge the advice of Dr Andrés G. Fernández (our mentor in the CaixaImpulse 2018 program) for unvaluable advice. This study was supported by the Ministerio de Economía y Competitividad of Spain (SAF2016-3307) and the Basque Government (IT1211- 19). The project leading to these results has received funding from “la Caixa” Foundation (ID 100010434) under agreement CI18-00002. This activity has received funding from the European Institute of Innovation and Technology (EIT). This body of the European Union receives support from the European Union’s Horizon 2020 research and innovation programme. C.G.-F, F. V., C. E., S. R-A., A. B. and M. P. belong to 2017SGR106 (Generalitat de Catalunya). J. A. G.-S. is a member emeritus of the Institut d’Estudis Catalans. Financial support was provided for F. V. (University of Barcelona, APIF_2017), S. R.-A. (Generalitat de Catalunya, 2018FI_B_00227), A. B. (Institute of Biomedicine UB_2018), C. M. (Marie Sklodowska-Curie Actions Individual Fellowships H2020-MSCA-IF-2016, ID747487), and E. H.-H. (Consejería de Innovación, Investigación y Turismo del Gobierno de las Islas Baleares y del Fondo Social Europeo, FPI/2102/2018). MR, TD and KN kindly acknowledge Ministry of Science and Technological Development of the Republic of Serbia, Project Contract No. 172033, and HORISON2020- COST-Action CA18133 ERNEST: European Research Network on Signal Transduction.

Permeability assessment of small molecules through the blood-brain barrier (BBB) plays a significant role in the development of effective central nervous system (CNS) drug candidates. Since in vivo methods for BBB permeability estimation require a lot of time and resources, in silico and in vitro approaches are becoming increasingly popular nowadays for faster and more economical predictions in early phases of drug discovery. In this work, through application of in vitro parallel artificial membrane permeability assay (PAMPA-BBB) and in silico computational methods we aimed to examine the passive permeability of eighteen compounds, which affect serotonin and dopamine levels in the CNS. The data set was consisted of novel six human dopamine transporter (hDAT) substrates that were previously identified as the most promising lead compounds for further optimisation to achieve neuroprotective effect, twelve approved CNS drugs, and their related compounds. Firstly, PAMPA methods was used to experimentally determine effective BBB permeability (Pe) for all studied compounds and obtained results were further submitted for quantitative structure permeability relationship (QSPR) analysis. QSPR models were built by using three different statistical methods: stepwise multiple linear regression (MLR), partial least square (PLS), and support-vector machine (SVM), while their predictive capability was tested through internal and external validation. Obtained statistical parameters (MLR- R2pred=-0.10; PLS- R2pred=0.64, r2m=0.69, r/2m=0.44; SVM- R2pred=0.57, r2m=0.72, r/2m=0.55) indicated that the SVM model is superior over others. The most important molecular descriptors (H0p and SolvEMt_3D) were identified and used to propose structural modifications of the examined compounds in order to improve their BBB permeability. Moreover, steered molecular dynamics (SMD) simulation was employed to comprehensively investigate the permeability pathway of compounds through a lipid bilayer. Taken together, the created QSPR model could be used as a reliable and fast pre-screening tool for BBB permeability prediction of structurally related CNS compounds, while performed MD simulations provide a good foundation for future in silico examination.

2-Imidazoline-containing compounds constitute a valuable class of agents that modulate α2- adrenergic receptors and often show a high affinity for imidazoline I2-receptors (I2-IR). Moreover, 2- imidazolines are an important class of heterocyclic scaffolds found in natural product chemistry, coordination chemistry, and homogeneous catalysis. To meet the demand for 2-imidazolinecontaining compounds, different synthetic approximations were developed. In this work, we describe an efficient and user-friendly synthetic process involving the combination of isocyanidebased multicomponent reaction and microwave heating without the need of anhydrous atmosphere or additional solvents that generates unprecedented (2-imidazolin-4-yl)phosphonates [1]. We assessed the pharmacological profile and selectivity of the prepared compounds upon I2-IR. Owing to the outstanding high I2-IR affinity of one of the prepared compounds and high selectivity devoid to the α2-adrenoceptor of other compounds, markedly better than any described I2-IR ligand to date, (2-imidazolin-4-yl)phosphonates might be considered as a suitable scaffold for designing novel I2-IR ligands [2]. In addition, we demonstrated the effectiveness of two of the new I2-IR ligands in an in vivo female model for cognitive decline (SAMP8), and we analyzed the pathological biomarkers for neurodegeneration. This study is the first experimental evidence that demonstrates the possibility of using this receptor as a target for cognitive impairment [3]. Note, theoretical studies were carried out for designing compounds with enhanced activity and selectivity upon I2-IR based on created 3D-QSAR model. In this work, green chemistry to access an unprecedented scaffold and promising pharmacological results in the neurodegeneration field walked together. The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery, Barcelona, Spain, 15–17 May 2019

All tested compounds show agonistic activity onserotonin5-HT2areceptors, which activation causes neuronal excitations, behavioral changes and platelet aggregation. The main aims of this study were to create 3D-QSAR(3D-Quantitative structure-activity relationship)model, analyse 3D-structure of the pharmacophore, validate the 3D-QSARmodel, and propose structural modification for novel 5-HT2aagonists.3D-QSAR modeling was applied to 51 agonists of 5-HT2areceptors. Dominant forms at physiologic pHof the examined compounds were optimized using the PM3 method and used for QSAR modeling. Data set was divided in two groups, training set of38 compounds, and test set of 13 compounds. Training set was used to build 3D-QSAR model, while test set was examined for the model validation. PLS (Partial Least Square Regression)method was used to develop 3D-QSAR model. Statistical parameters of the created and validated 3D-QSAR model,R2= 0.93, Q2=0.72, RMSEE=0.178, RMSEP=0.190 and R2 pred=0.63, indicate good prognostic capacity of the model.The3D-QSAR model was applied to analyse pharmacophore and to predict activity of other agonists of serotonin 5-HT2areceptors. Information obtained from the 3D-QSAR study indicated that presence of hydrogen bond donor and steric hot spot at a distance 14.80-15.20Å (v477:O-TIP), hydrophobic region and hydrogen bond donor at a distance of 2.40-2.86Å (v226:DRY-O), hydrogen bond donor and hydrogen bond acceptor at a distance of 1.60-2.00Å (v389:O-N1) and two hydrophobic regions at a distance 9.20-9.60Å (v23:DRY-DRY) are essential for agonistic activity on 5-HT2aserotonin receptors. Ispitivana jedinjenja djeluju kao agonisti serotoninskih 5-HT2areceptora, i dovode do neuralne ekscitacije, promjene ponašanja i agregacije trombocita. Cilj ove studije je bio formiranje 3D-QSAR (3D-Quantitative structure-activity relationship) modela i 3D-strukture farmakofore agonista serotoninskih 5-HT2a receptora, validacija formiranog 3D-QSAR modela i definisanje strukturnih modifikacija za dizajn novih agonista serotoninskih 5-HT2areceptora. Iz literature su preuzete strukture i aktivnosti 51 agoniste 5-HT2areceptora. Definisani su dominantni oblici ispitivanih jedinjenja pri fiziološkom pH i optimizovane njihove konformacije primjenom PM3 (Parameterized Model revision 3) metode. Ispitivana jedinjenja su podijeljena u dvije grupe, trening set sa 38 jedinjenja i test set sa 13 jedinjenja. Trening set je korišćen za formiranje jednačine i građenje 3D-QSAR modela, a test set za validaciju 3DQSAR modela. Pomoću PLS (Partial Least Square Regression) metode kreira se novi 3DQSAR model i računaju statistički parametri modela: R2=0,93, Q2=0,72, RMSEE=0,178, RMSEP=0,190 i R2pred=0,63. Formirani i validirani 3D-QSAR model je dalje upotrijebljen za analizu 3D-strukture farmakofore i za predviđanje aktivnosti novih agonista serotoninskih 5-HT2areceptora. Analizom je utvrđeno da je za ispoljavanje agonističke aktivnosti na nivou 5-HT2a serotoninskih receptora neophodno prisustvo donora vodonične veze i sternog centra na rastojanju 14,80-15,20Å (v477:O-TIP), donora i akceptora vodonične veze na rastojanju 1,60- 2,00Å (v389:O-N1), hidrofobnog centra i donora vodonične veze na rastojanju 2,40-2,86Å (v226:DRY-O) i dva hidrofobna centra na rastojanju 9,20-9,60Å (v23:DRY-DRY).