Nonlinear optical and spectroscopic properties, thermal analysis, and hemolytic capacity evaluation of quinoline-1,3-benzodioxole chalcone.

This article describes the synthesis, characterization (1H NMR, 13C NMR, FT-IR, HRMS and XRD), UV-Vis absorption and fluorescence spectra, theoretical analysis, evaluation of nonlinear optical properties (NLO), thermal analysis and determination of the hemolytic capacity of the compound (E)-N-(4-(3-(benzo[d][1,3]dioxol-5-yl)acryloyl)phenyl)quinoline-3-carboxamide (5). Radiological findings showed that compound 5 crystallized in space group Pca21. Furthermore, theoretical DFT studies performed with the B3LYP and M062X functionals showed good agreement with the experimental results and provided valuable information on the molecular and electronic structure, reactivity, polarizability, and kinematic stability of the compound. Besides, compound 5 did not show any hemolytic effect on human erythrocytes and exhibited strong NLO properties. The TG and DTA thermograms of quinoline-chalcone (5) revealed a multi-step thermal decomposition process with a total mass loss of 83.2%, including water content loss. The DTA curves exhibited endothermic peaks corresponding to decomposition steps, melting point, and thermochemical transition. Additionally, exothermic peaks in the DTA thermograms align with significant mass loss, confirming the compound's melting point and water content, as validated by X-ray diffraction analysis. These results contribute to the advancement of research on compounds with NLO properties and offer a promising avenue for the development of substances potentially applicable to optical devices in the biomedical field.

Crystal structure, quantum chemical insights, and molecular docking studies of Naryl-2-(N-disubstituted) acetamide compounds: potential inhibitors for neurodegenerative enzymes.

The increase in and concern about neurodegenerative diseases continue to grow in an increasingly long-lived world population. Therefore, the search for new drugs continues to be a priority for medicinal chemistry. We present here the synthesis of a series of compounds with acetamide nuclei. Their structures were established using UV-Visible, NMR, HRMS and IR techniques. Furthermore, we report the crystal structures that were obtained from compounds 5a-5d by X-ray diffraction. The compounds were evaluated as potential inhibitors of the monoxidase enzymes; A (MAO-A) and B (MAO-B), and cholinesterases; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) through in silico studies using the induced fit docking (IFD) method and binding free energy (ΔGbind) calculations by the MMGBSA method. Interestingly, compounds 5b, 5c and 5d showed much better ΔGbind than the reference drug Zonisamide. Compound 5c is the best in the series, which indicates a potential selective affinity of our compounds against MAO-B, which could be a promising finding in the search for new drugs for Parkinson's disease treatment. The acetamide crystal exhibits moderate NLO properties suggesting that it could be considered a potential candidate for application in nonlinear optical devices.

Higher heavy metal contamination indoors than outdoors during COVID-19 in Mexico City.

People spend most of their time indoors, especially during the coronavirus disease. Prolonged exposure to heavy metal-contaminated dust can be harmful to human health. The objectives of this study were to identify the contamination level in outdoor and indoor dust, compare contamination in both environments, and assess the human health risk. Two-hundred thirty-nine samples of dust were taken by Mexico City citizens in 38 homes on the weekends of May 2020. Heavy metal concentrations were measured through XRF. The contamination level was set using the contamination factor with a local and global background value, mixed linear models were used to identify indoor and outdoor differences, and USEPA human health risk methodology was used. Pb, Zn, and Cu had the highest contamination levels, followed by Sr and Mn, using both the local and global background values. The Pb, Zn, and Cu contamination was greater indoors, while higher Mn, Sr, and Fe were detected outdoors. According to the outdoor/indoor ratios, the main sources of Ca, Pb, Zn, and Cu must be indoors, while the main sources of Fe, Mn, Sr, Y, and Ti are outdoors. A human health risk was not detected, as the hazard index was lower than one. However, ailments can be developed due to exposure to Pb, Mn, and Fe in children (hazard index > 0.1). A higher risk due to Pb exposition was found indoors. Indoor environments in Mexico City were more contaminated by heavy metals and represented a higher risk to human health than outdoors during the pandemic isolation.

Comprehensive analysis of crystal structure, spectroscopic properties, quantum chemical insights, and molecular docking studies of two pyrazolopyridine compounds: potential anticancer agents.

In this study, two pyrazolo[3,4-b]pyridine derivatives (4a and 4b) were grown using a slow evaporation solution growth technique and characterized by FT-IR, HRMS, 1H/13C NMR spectroscopy, and X-ray crystallography. The 4a and 4b structures crystallized in monoclinic and triclinic systems with space groups P21/n and P1̄, respectively. Theoretical calculations were performed at the DFT/B3LYP level for the optimized geometries. The results were in excellent agreement with the experimental data (spectroscopic and XRD). This investigation encompasses molecular modeling studies including Hirshfeld surface analysis, energy framework calculations, and frontier molecular orbital analysis. Intermolecular interactions within the crystal structures of the compounds were explored through Hirshfeld surface analysis, which revealed the notable presence of hydrogen bonding and hydrophobic interactions. This insight provides valuable information on the structural stability and potential solubility characteristics of these compounds. The research was extended to docking analysis with eight distinct kinases (BRAF, HER2, CSF1R, MEK2, PDGFRA, JAK, AKT1, and AKT2). The results of this analysis demonstrate that both 4a and 4b interact effectively with the kinase-binding sites through a combination of hydrophobic interactions and hydrogen bonding. Compound 4a had the best affinity for proteins; this is related to the fact that the compound is not rigid and has a small size, allowing it to sit well at any binding site. This study contributes to the advancement of kinase inhibitor research and offers potential avenues for the development of new therapeutic agents for cancer treatment.

Multicomponent synthesis and photophysical study of novel α,ß-unsaturated carbonyl depsipeptides and peptoids.

Multicomponent reactions were performed to develop novel α,ß-unsaturated carbonyl depsipeptides and peptoids incorporating various chromophores such as cinnamic, coumarin, and quinolines. Thus, through the Passerini and Ugi multicomponent reactions (P-3CR and U-4CR), we obtained thirteen depsipeptides and peptoids in moderate to high yield following the established protocol and fundamentally varying the electron-rich carboxylic acid as reactants. UV/Vis spectroscopy was utilized to study the photophysical properties of the newly synthesized compounds. Differences between the carbonyl-substituted chromophores cause differences in electron delocalization that can be captured in the spectra. The near UV regions of all the compounds exhibited strong absorption bands. Compounds P2, P5, U2, U5, and U7 displayed absorption bands in the range of 250-350 nm, absorbing radiation in this broad region of the electromagnetic spectrum. A photostability study for U5 showed that its molecular structure does not change after exposure to UV radiation. Fluorescence analysis showed an incipient emission of U5, while U6 showed blue fluorescence under UV radiation. The photophysical properties and electronic structure were also determined by TD-DFT theoretical study.

New NADPH Oxidase 2 Inhibitors Display Potent Activity against Oxidative Stress by Targeting p22phox-p47phox Interactions.

NADPH oxidase (NOX2) is responsible for reactive oxygen species (ROS) production in neutrophils and has been recognized as a key mediator in inflammatory and cardiovascular pathologies. Nevertheless, there is a lack of specific NOX2 pharmacological inhibitors. In medicinal chemistry, heterocyclic compounds are essential scaffolds for drug design, and among them, indole is a very versatile pharmacophore. We tested the hypothesis that indole heteroaryl-acrylonitrile derivatives may serve as NOX2 inhibitors by evaluating the capacity of 19 of these molecules to inhibit NOX2-derived ROS production in human neutrophils (HL-60 cells). Of these compounds, C6 and C14 exhibited concentration-dependent inhibition of NOX2 (IC50~1 µM). These molecules also reduced NOX2-derived oxidative stress in cardiomyocytes and prevented cardiac damage induced by ischemia-reperfusion. Compound C6 significantly reduced the membrane translocation of p47phox, a cytosolic subunit that is required for NOX2 activation. Molecular docking analyses of the binding modes of these molecules with p47phox indicated that C6 and C14 interact with specific residues in the inner part of the groove of p47phox, the binding cavity for p22phox. This combination of methods showed that novel indole heteroaryl acrylonitriles represent interesting lead compounds for developing specific and potent NOX2 inhibitors.

Phenolic Profile and Cholinesterase Inhibitory Properties of Three Chilean Altiplano Plants: Clinopodium gilliesii (Benth.) Kuntze [Lamiaceae], Mutisia acuminata Ruiz & Pav. var. hirsuta (Meyen) Cabrera, and Tagetes multiflora (Kunth) [Asteraceae].

This research aimed to identify the phenolic profile and composition of the aerial parts of three native species used in traditional medicine in the Andean Altiplano of northern Chile: Clinopodium gilliesii (Benth.) Kuntze [Lamiaceae] (commonly known as Muña-Muña), Mutisia acuminata Ruiz & Pav. var. hirsuta (Meyen) Cabrera [Asteraceae] (commonly known as Chinchircoma), and Tagetes multiflora (Kunth), [Asteraceae] (commonly known as Gracilis), as well as to evaluate their potential inhibitory effects against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Polyphenolic enriched-extracts (PEEs) of the species were prepared and analyzed and the main components were quantified using HPLC-DAD. In total, 30 phenolic compounds were identified and quantified in all species, including simple phenolics, hydroxycinnamic acids, flavan-3-ols (monomers and polymers), flavanones, and flavonols. In addition, other main phenolics from the extracts were tentatively identified by ESI-MS-MS high-resolution analysis. T. multiflora extract showed the greatest anti-AChE and BChE activity in comparison with C. gilliesii and M. acuminata extracts, being the anti-AChE and BChE activity weak in all extracts in comparison to galantamine control. To comprise to better understand the interactions between cholinesterase enzymes and the main phenolics identified in T. multiflora, molecular docking analysis was conducted.

Piperonal chalcone derivative incorporating the pyrazolo[3,4-b]pyridine moiety; crystal structure, spectroscopic characterization and quantum chemical investigations.

A single crystal of a piperonal chalcone derivative was obtained, fully characterized, and crystallized by a slow evaporation technique. The synthesized compound was characterized by UV-Visible, FT-IR, HRMS, 1H NMR, and 13C NMR spectroscopic studies and X-ray crystallography, revealing that the crystal belongs to a triclinic crystal system with a P1̄ space group, Z = 2. In the present work, we focus on molecular modeling studies such as Hirshfeld surface analysis, energy framework calculations, frontier molecular orbital analysis, natural bond orbital analysis, and NLO properties of a π-conjugate system combining the chalcone and the pyrazole[3,4-b]pyridine scaffolds to describe the in-depth structural analysis thereof. Good agreement was found between the calculated results and experimental data. In addition, Hirshfeld surface analysis of the crystal structure showed that the intermolecular stabilization in the crystal packing comes mainly from H⋯H bond interactions. The chalcone crystal exhibits significant NLO properties suggesting that it could be considered a potential candidate for application in nonlinear optical devices.

Design, synthesis, theoretical study, antioxidant, and anticholinesterase activities of new pyrazolo-fused phenanthrolines.

Pyrazole-fused phenanthroline compounds were obtained through several synthetic routes. NMR, HRMS, and IR techniques were used to characterize and confirm the chemical structures. Crystal structures were obtained from compounds 3a, 5b, 5j, 5k, and 5n and analyzed using X-ray diffraction. Compounds were evaluated as acetyl (AChE) and butyrylcholinesterase (BChE) inhibitors, and the results showed a moderate activity. Compound 5c presented the best activity against AChE (IC50 = 53.29 µM) and compound 5l against BChE enzyme (IC50 = 119.3 µM). Furthermore, the ability of the synthetic compounds to scavenge cationic radicals DPPH and ABTS was evaluated. Compound 5e (EC50 = 26.71 µg mL-1) presented the best results in the DPPH assay, and compounds 5e, 5f and 5g (EC50 = 11.51, 3.10 and <3 µg mL-1, respectively) showed better ABTS cationic radical scavenging results. Finally, in silico analyses indicated that 71% of the compounds show good oral availability and are within the ranges established by the Lipinski criteria.

Selective TASK-1 Inhibitor with a Defined Structure-Activity Relationship Reduces Cancer Cell Proliferation and Viability.

Chemical structures of selective blockers of TASK channels contain aromatic groups and amide bonds. Using this rationale, we designed and synthesized a series of compounds based on 3-benzamidobenzoic acid. These compounds block TASK-1 channels by binding to the central cavity. The most active compound is 3-benzoylamino-N-(2-ethyl-phenyl)-benzamide or F3, blocking TASK-1 with an IC50 of 148 nM, showing a reduced inhibition of TASK-3 channels and not a significant effect on different K+ channels. We identified putative F3-binding sites in the TASK-1 channel by molecular modeling studies. Mutation of seven residues to A (I118A, L122A, F125A, Q126A, L232A, I235A, and L239A) markedly decreased the F3-induced inhibition of TASK-1 channels, consistent with the molecular modeling predictions. F3 blocks cell proliferation and viability in the MCF-7 cancer cell line but not in TASK-1 knockdown MCF-7 cells, indicating that it is acting in TASK-1 channels. These results indicated that TASK-1 is necessary to drive proliferation in the MCF-7 cancer cell line.

Toward the cholinesterase inhibition potential of TADDOL derivatives: Seminal biological and computational studies.

Alzheimer's disease (AD) is a degenerative neurological disease characterized by gradual loss of cognitive skills and memory. The exact pathogenesis involved still remains unrevealed, but several studies indicate the involvement of an array of different enzymes, underlining the multifactorial character of the disease. Inhibition of these enzymes is therefore a powerful approach in the development of AD treatments, with promising candidates, including acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidase. Interestingly, AChE is the target of a major pesticide family (organophosphates), with several reports indicating an intersection between the pesticide's activity and AD. In this study, various TADDOL derivatives were synthesized and their in vitro activities as AChE/BuChE inhibitors as well as their antioxidant activities were studied. Molecular modeling studies revealed the capability of TADDOL derivatives to bind to AChE and induce inhibition, especially compounds 2b and 3c furnishing IC50 values of 36.78 ± 8.97 and 59.23 ± 5.31 µM, respectively. Experimental biological activities and molecular modeling studies clearly demonstrate that TADDOL derivatives with specific stereochemistry have an interesting potential for the design of potent AChE inhibitors. The encouraging results for compounds 2b and 3c indicate them as promising scaffolds for selective and potent AChE inhibitors.

Dyhidro-ß-agarofurans natural and synthetic as acetylcholinesterase and COX inhibitors: interaction with the peripheral anionic site (AChE-PAS), and anti-inflammatory potentials.

In order to find molecules of natural origin with potential biological activities, we isolate and synthesise compounds with agarofuran skeletons (epoxyeudesmanes). From the seeds of Maytenus disticha and Maytenus magellanica we obtained six dihydro-ß-agarofurans, and by means of the Robinson annulation reaction we synthesised five compounds with the same skeleton. The structures were established on the basis of NMR, IR, and MS. The evaluated compounds showed inhibitory activity on the acetylcholinesterase enzyme and on the COX enzymes. Compound 4 emerged as the most potent in the acetylcholinesterase inhibition assay with IC50 17.0 ± 0.016 µM on acetylcholinesterase (AChE). The compounds evaluated were shown to be selective for AChE. The molecular docking, and the propidium displacement assay suggested that the compounds do not bind to the active site of the enzyme AChE, but rather bind to the peripheral anionic site (PAS) of the enzyme, on the other hand, the natural compound 8, showed the best inhibitory activity on the COX-2 enzyme with an IC50 value of 0.04 ± 0.007 µM. The pharmacokinetic profile calculated in silico using the SWISSADME platform shows that these molecules could be considered as potential drugs for the treatment of neurodegenerative diseases such as AD.

Evaluation of pharmaceutical pictogram comprehension among adults in the Philippines.

BACKGROUND: The use of pharmaceutical pictograms to enhance patients' understanding of drug regimens has been proven effective in many countries. There are two reference systems for pictograms generally used in pharmacy: the United States Pharmacopeia (USP) and International Pharmacy Federation (FIP). This study aimed to evaluate the effectiveness of USP and FIP pictograms among adults in the Philippines by identifying how many pictograms would pass the American National Standards Institute (ANSI) criterion of 85% comprehension, and to describe the factors affecting pictograms' comprehension. METHODS: A descriptive cross-sectional research using a face-to-face interview was performed to evaluate 108 pictograms in 52 Filipino adults enrolled through quota sampling. Descriptive statistics, Mann-Whitney U test (Wilcoxon rank-sum test), univariate linear regression, and multiple linear regression were used to statistically analyze the data collected. RESULTS: Only 17 (16 USP and 1 FIP) out of the 108 pictograms (15.74%) passed the ANSI criterion. The median score of Filipinos was 71 out of 108 pictograms (Interquartile range: 10-96). The multivariate model (R2 = 0.5645, F (4,47) = 15.23) suggested that the score was lower by 5.85 points if the user was female, 21.58 points lower if the participant was below Grade 12 education level, and 1.20 points lower if the patient was greater than 46 years old. Education level was identified as the significant predictor (p-value < 0.0000*, power = 99.98%). The participant with greater than Grade 12 has a higher comprehension score of rank-sum 952.5 (Expected = 689) compared to only 425.5 (Expected = 689). CONCLUSIONS: Since only 17 pictograms passed as stand-alone tool for patient information material, the researchers recommend the use of verbal and written instructions to complement pictograms to enhance comprehension. Furthermore, the government should consider the inclusion of health pictograms in basic health education.

Two New Adenosine Derivatives and their Antiproliferative Properties: An In Vitro Evaluation.

BACKGROUND: Adenosine is a natural nucleoside present in a variety of organs and tissues, where it acts as a modulator of diverse physiological and pathophysiological processes. These actions are mediated by at least four G protein-coupled receptors, which are widely and differentially expressed in tissues. Interestingly, high concentrations of adenosine have been reported in a variety of tumors. In this context, the final output of adenosine in tumorigenesis will likely depend on the constellation of adenosine receptors expressed by tumor and stromal cells. Notably, activation of the A3 receptor can reduce the proliferative capacity of various cancer cells. OBJECTIVE: This study aimed to describe the anti-proliferative effects of two previously synthesized adenosine derivatives with A3 agonist action (compounds 2b and 2f) through in vitro assays. METHODS: We used gastric and breast cancer cell lines expressing the A3 receptor as in vitro models and theoretical experiments for molecular dynamics and determination of ADME properties. RESULTS: The antiproliferative effects of adenosine derivatives (after determining IC50 values) were comparable or even higher than those described for IB-MECA, a commercially available A3 agonist. Among possible mechanisms involved, apoptosis was found to be induced in MCF-7 cells but not in AGS or MDA-MB-231 cells. Surprisingly, we were unable to observe cellular senescence induction upon treatment with compounds 2b and 2f in any of the cell lines studied, although we cannot rule out other forms of cell cycles exit at this point. CONCLUSION: Both adenosine derivatives showed antiproliferative effects on gastric and breast cancer cell lines, and were able to induce apoptosis, at least in the MCF-7 cell line. Further studies will be necessary to unveil receptor specificity and mechanisms accounting for the antiproliferative properties of these novel semi-synthetic compounds.

Factors associated with medication adherence of hypertensive patients in the Philippines: a systematic review.

BACKGROUND: Diseases of the heart and vascular system are the leading cause of mortality in the Philippines. Hypertension, the most important modifiable risk factor, has a prevalence rate of 28% and a control rate of 20%. Despite the proven efficacy of pharmacologic treatment, medication adherence is reported to be as low as 66%. While there are publications that reported factors that affect adherence in Filipinos, there are no existing research that evaluated them systematically. This review is conducted to present and synthesize findings of published literatures. METHODS: Databases-PubMed, Scopus, Wiley Online library, Science Direct, JSTOR, Web of Science, SAGE journals, and Cochrane-were used to search for articles published from 2000 to 2020 that studied medication adherence in adult Filipino hypertensive population. Out of the initial 1514 articles, 15 articles met the criteria and were included in the analysis. The evidence from the included studies was summarized and discussed in a narrative review using the World Health Organization framework for adherence to long-term therapies as the framework. RESULT: The factors that were positively associated with adherence were health care system-related factors: good patient-health provider relationship, accessibility of health services, use of specialty clinics and programs for hypertension, and health insurance. The factors found to be negatively associated with adherence are (1) social economic factors: younger age, single civil status, low educational attainment, and unemployment; (2) patient-related factors: low in health literacy and awareness, knowledge on hypertension, attitude towards hypertension, self-efficacy, and social support; (3) therapy-related factors: inconsistent drug regimen schedule, use of Thiazide and complementary and alternative medicines; (4) condition-related factors: low illness perception, and absence of comorbidities. CONCLUSIONS: Findings should be interpreted with caution because of methodological limitations. Despite this, given that health systems related factors are modifiable, they can be the focus of interventions and future researches to increase medication adherence. Clinicians may also want to screen their Filipino hypertensive patients for factors that are associated to low adherence in order to provide a tailored advice. Longitudinal research studies with heterogeneous samples of hypertensive Filipinos are imperative so that targeted interventions can be developed for the population.

Spirocyclic derivatives as antioxidants: a review.

In recent years, spiro compounds have attracted significant interest in medicinal chemistry due to their numerous biological activities attributed primarily to their versatility and structural similarity to important pharmacophore centers. Currently, the development of drugs with potential antioxidant activities is of great importance since numerous investigations have shown that oxidative stress is involved in the development and progression of numerous diseases such as cancer, senile cataracts, kidney failure, diabetes, high blood pressure, cirrhosis, and neurodegenerative diseases, among others. This article provides an overview of the synthesis and various antioxidant activities found in naturally occurring and synthetic spiro compounds. Among the antioxidant activities reviewed are DPPH, ABTS, FRAP, anti-LPO, superoxide, xanthine oxidase, peroxide, hydroxyl, and nitric oxide tests, among others. Molecules that presented best results for these tests were spiro compounds G14, C12, D41, C18, C15, D5, D11, E1, and C14. In general, most active compounds are characterized for having at least one oxygen atom; an important number of them (around 35%) are phenolic compounds, and in molecules where this functional group was absent, aryl ethers and nitrogen-containing functional groups such as amine and amides could be found. Recent advances in the antioxidant activity profiles of spiro compounds have shown that they have a significant position in discovering drugs with potential antioxidant activities.

Adapting and validating the Rosenberg Self-Esteem Scale for elderly Spanish population.

OBJECTIVES: This study aims to adapt and validate the most common measure of self-esteem, the Rosenberg Self-Esteem Scale (RSES), in the elderly Spanish population based on the initial one-factor model proposed by the author of the scale. DESIGN: The factorial validity of the scale was tested using confirmatory factor analysis. SETTING: The study was carried out in the city of Valencia (Spain). PARTICIPANTS: A total of 231 elderly people with a mean age 72.68 (SD=8.55). MEASUREMENTS: The participants completed the questionnaire RSES for the validation process, sociodemographic data and Mini-Mental State Examination. RESULTS: Confirmatory factor analysis with a five-item structure for the one-factor structure showed good fit indexes (Chi square [5] = 217.20, p < .05; CFI = .965; GFI = .980; RMSEA = .070 [90% confidence interval of RMSEA, .022-.087]), and reliability, as internal consistency, measure with Cronbach's alpha was .732. CONCLUSION: The adaptation of the RSES showed a unifactorial structure with good internal consistency. This reduced adaptation/version of the scale may facilitate clinical practice and be useful in research in older people.

Differential sorting behavior for soluble and transmembrane cargoes at the trans-Golgi network in endocrine cells.

Regulated secretion of neuropeptides and peptide hormones by secretory granules (SGs) is central to physiology. Formation of SGs occurs at the trans-Golgi network (TGN) where their soluble cargo aggregates to form a dense core, but the mechanisms controlling the sorting of regulated secretory cargoes (soluble and transmembrane) away from constitutively secreted proteins remain unclear. Optimizing the use of the retention using selective hooks method in (neuro-)endocrine cells, we now quantify TGN budding kinetics of constitutive and regulated secretory cargoes. We further show that, by monitoring two cargoes simultaneously, it becomes possible to visualize sorting to the constitutive and regulated secretory pathways in real time. Further analysis of the localization of SG cargoes immediately after budding from the TGN revealed that, surprisingly, the bulk of two studied transmembrane SG cargoes (phogrin and VMAT2) does not sort directly onto SGs during budding, but rather exit the TGN into nonregulated vesicles to get incorporated to SGs at a later step. This differential behavior of soluble and transmembrane cargoes suggests a more complex model of SG biogenesis than anticipated.

Tetrahydroquinoline-Isoxazole/Isoxazoline Hybrid Compounds as Potential Cholinesterases Inhibitors: Synthesis, Enzyme Inhibition Assays, and Molecular Modeling Studies.

A series of 44 hybrid compounds that included in their structure tetrahydroquinoline (THQ) and isoxazole/isoxazoline moieties were synthesized through the 1,3-dipolar cycloaddition reaction (1,3-DC) from the corresponding N-allyl/propargyl THQs, previously obtained via cationic Povarov reaction. In vitro cholinergic enzymes inhibition potential of all compounds was tested. Enzyme inhibition assays showed that some hybrids exhibited significant potency to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Especially, the hybrid compound 5n presented the more effective inhibition against AChE (4.24 µM) with an acceptable selectivity index versus BChE (SI: 5.19), while compound 6aa exhibited the greatest inhibition activity on BChE (3.97 µM) and a significant selectivity index against AChE (SI: 0.04). Kinetic studies were carried out for compounds with greater inhibitory activity of cholinesterases. Structure-activity relationships of the molecular hybrids were analyzed, through computational models using a molecular cross-docking algorithm and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) binding free energy approach, which indicated a good correlation between the experimental inhibition values and the predicted free binding energy.