Organohalogen chalcones: design, synthesis, ADMET prediction, molecular dynamics study and inhibition effect on acetylcholinesterase and carbonic anhydrase.

In an effort to discover potential acetylcholinesterase (AChE) and carbonic anhydrase (CA) inhibitors, a novel series of organohalogen chalcone derivatives (12-20, 23-30) was synthesized, and their chemical structures were characterized by spectral analysis. They showed a highly potent inhibition effect on AChE and hCAs (Ki values range from 5.07 ± 0.062 to 65.53 ± 4.36 nM for AChE, 13.54 ± 2.55 to 94.11 ± 10.39 nM for hCA I, and 5.21 ± 0.54 to 57.44 ± 3.12 nM for hCA II). In addition, the chalcone derivatives with the highest inhibitor score docked into the active site of the indicated metabolic enzyme receptors, and their absorption, metabolism, and toxic properties were evaluated according to ADMET's estimation.Compounds 16 and 19 exhibited the highest inhibition score, emerged as lead compounds, and inspired the development of more potent compounds.

Screening and toxicity evaluation of natural compounds as adenosine 2a and 2b receptor ligands: insights from molecular docking, dynamics, and ADMET analysis.

Recent studies suggest that immunological and inflammatory responses in cardiovascular disorders, such as hypertension, myocardial infarction, ischemia injury, heart failure, arrhythmias, and atherosclerosis, may be affected by changes in the adenosine system. Pharmacological modulation of adenosine occurs through its receptor subtypes. In numerous preclinical studies, the activation of adenosine receptor 2A (A2AR) or the blockade of adenosine receptor 2B (A2BR) has shown promising results against cardiovascular diseases. This in silico study aimed to identify potential natural compounds that can activate A2AR or block A2BR without causing toxicity. Natural compounds were screened using COlleCtion of Open Natural ProdUcTs (COCONUT) or Natural Product Activity and Species Source Database (NPASS) databases to find agonists for A2AR or an antagonists/inverse agonists for A2BR. These compounds were then pre-filtered based on their toxicity profiles. The remaining compounds were subjected to molecular docking against A2AR and A2BR followed by molecular dynamics simulations were conducted. Finally, selected compounds' ADMET properties were determined using ADMETlab 2.0 web tool. Ultimately, one novel natural compound with potential agonistic activity (COCONUT IDs: CNP0450901) for A2AR and one antagonist/inverse agonist (rauwolscine) for A2BR were identified.

Development of a Novel Class of Pyridazinone Derivatives as Selective MAO-B Inhibitors.

Sixteen compounds (TR1-TR16) were synthesized and evaluated for their inhibitory activities against monoamine oxidase A and B (MAOs). Most of the derivatives showed potent and highly selective MAO-B inhibition. Compound TR16 was the most potent inhibitor against MAO-B with an IC50 value of 0.17 µM, followed by TR2 (IC50 = 0.27 µM). TR2 and TR16 selectivity index (SI) values for MAO-B versus MAO-A were 84.96 and higher than 235.29, respectively. Compared to the basic structures, the para-chloro substituent in TR2 and TR16 increased the inhibitory activity of MAO-B. TR2 and TR16 were reversible MAO-B inhibitors that were competitive, with Ki values of 0.230 ± 0.004 and 0.149 ± 0.016 µM, respectively. The PAMPA method indicated that compounds TR2 and TR16 had the tendency to traverse the blood-brain barrier. Docking investigations revealed that lead compounds were beneficial for MAO-B inhibition via association with key as well as selective E84 or Y326 residues, but not for MAO-A inhibition via interaction primarily driven by hydrophobic contacts. In conclusion, TR2 and TR16 are therapeutic prospects for the management of multiple neurodegenerative diseases.

Head-to-head bisbenzazole derivatives as antiproliferative agents: design, synthesis, in vitro activity, and SAR analysis.

In the present work, a series of bisbenzazole derivatives were designed and synthesized as antiproliferative agents. The antiproliferative activity of these compounds was investigated using MTT assay. Bisbenzazole derivatives showed significant antiproliferative activity against all the four tested cancer cell lines. Among the various bisbenzazole derivatives, bisbenzoxazole derivatives exhibited the most promising anticancer activity followed by bisbenzimidazole and bisbenzothiazole derivatives. All the derivatives were found to be less toxic as compared to methotrexate (positive control) in normal human cells, indicating selective and efficient antiproliferative activity of these bisbenzazole derivatives. The structure-activity relationships of heteroaromatic systems and linkers present in bisbenzazole derivatives were analyzed in detail. In silico ADMET prediction revealed that bisbenzazole is a drug-like small molecule with a favorable safety profile. Compound 31 is a potential antiproliferative hit compound that exhibits unique cytotoxic activity distinct from methotrexate. Twenty-one bisbenzoxazole derivatives have been designed synthesized and evaluated to be an antiproliferative activity against four human tumor cell lines.

Synthesis and biological evaluation of new 3(2H)-pyridazinone derivatives as non-toxic anti-proliferative compounds against human colon carcinoma HCT116 cells.

Novel 3(2H)-pyridazinone derivatives were designed, synthesised in satisfactory yields and evaluated in different experimental assays to assess their preliminary toxicity in vivo and anti-proliferative effects against HCT116 cell lines in vitro. Artemia salina lethality test provided LC50 values >100 µg/mL for all compounds. Successive assays revealed that some compounds were endowed with a promising anti-proliferative effect against HCT116 cells, alone or stimulated by serotonin as a pro-inflammatory factor in order to mimick an inflamed model in vivo of cancer cell microenvironment. Moreover, the kinurenic acid level after treatment with these newly synthesised compounds was monitored as a marker of anti-proliferation in colon carcinoma models. The IC50 values obtained for the best-in-class compounds were comparable to that of daunorubicin as a reference drug. Conversely, these compounds were not able to counteract the spontaneous migration of human cancer HCT116 cell line in the wound healing paradigm.

Coumarin or benzoxazinone based novel carbonic anhydrase inhibitors: synthesis, molecular docking and anticonvulsant studies.

Among many others, coumarin derivatives are known to show human carbonic anhydrase (hCA) inhibitory activity. Since hCA inhibition is one of the underlying mechanisms that account for the activities of some antiepileptic drugs (AEDs), hCA inhibitors are expected to have anti-seizure properties. There are also several studies reporting compounds with an imidazole and/or benzimidazole moiety which exert these pharmacological properties. In this study, we prepared fifteen novel coumarin-bearing imidazolium and benzimidazolium chloride, nine novel benzoxazinone-bearing imidazolium and benzimidazolium chloride derivatives and evaluated their hCA inhibitory activities and along with fourteen previously synthesized derivatives we scanned their anticonvulsant effects. As all compounds inhibited purified hCA isoforms I and II, some of them also proved protective against Maximal electroshock seizure (MES) and ScMet induced seizures in mice. Molecular docking studies with selected coumarin derivatives have revealed that these compounds bind to the active pocket of the enzyme in a similar fashion to that previously described for coumarin derivatives.

Delayed versus primary sternal closure for left ventricular assist device implantation: Impact on mechanical circulatory support infections.

BACKGROUND: Delayed sternal closure may be required after left ventricular assist device (LVAD) implantation due to coagulopathy or hemodynamic instability. There is conflicting data regarding infection risk. METHODS: We performed a single-center, retrospective analysis of patients who received their first LVAD between May 2012 and January 2021. Patients were divided into delayed sternal closure (DSC) and primary sternal closure (PSC) groups. We used chi-squared or Fisher Exact tests, as appropriate, to compare the incidence of postoperative LVAD-related infections (mediastinal/sternal wound) and LVAD-specific infections (driveline and pump pocket) after definitive chest closure between these two groups. RESULTS: A total of 327 patients met eligibility criteria, including 127 (39%) patients that underwent DSC and 200 (61%) patients that had a PSC. Demographic and clinical characteristics were similar except for an overrepresentation of men (87% vs. 75%, p = .016), Interagency Registry of Mechanically Assisted Circulatory Support class I-II patients (89% vs 66%, p < .001), patients with a previous sternotomy (43% vs 13%, p < .001), and patients with chronic kidney disease (55% vs 43%, p = .030) in the DSC group. The median DSC time was 24 (IQR: 24-48) hours. The incidence of LVAD-related mediastinal/sternal wound infection was similar between the DSC and PSC groups (4.7% vs 3.0%, p = .419). There was no difference between DSC and PSC groups in the incidence of driveline infection (6.3% vs 9%, p = .411) and pump pocket infection (1.6% vs 1.5%, p =.901), respectively. CONCLUSIONS: DSC does not seem to increase the incidence of LVAD-related or LVAD-specific infection rates in heart failure patients undergoing device implantation surgery.

Synthesis, characterization, evaluation of metabolic enzyme inhibitors and in silico studies of thymol based 2-amino thiol and sulfonic acid compounds.

Eight new aminothiols (4a-g and 5) and three new sulfonic acid derivatives (6a-c) were synthesized, and their structures were characterized. Inhibitory effects of the obtained compounds on carbonic anhydrase I and II isoforms (hCA I and hCA II), butyrylcholinesterase (BChE) and acetylcholinesterase (AChE), enzymes were investigated. The newly synthesized compounds have inhibited hCA I with Kis ranging from 7.11 ± 1.46 nM (6a) to 670.52 ± 300.41 nM (4b) and, hCA II with Kis ranging from 16.83 ± 5.72 nM (6a) to 453.34 ± 208.56 nM (4c). Acetazolamide was employed as the positive control for both hCA isoforms (Ki for hCA I 198.81 ± 14.13 nM and Ki for hCA II 211.42 ± 13.10 nM), and among the new compounds obtained, it was observed that there were compounds that were active at much lower nM levels. All compounds were also evaluated for inhibition of AChE and BChE. They inhibited AChE and BChE enzymes in the range of Ki 5.24 ± 2.27 (6c) - 48.44 ± 21.82 (4g) for AChE and 4.86 ± 0.64 (6c) - 51.75 ± 12.56 (4a) for BChE, and the results were compared with the standard inhibitor Tacrine (Ki: 14.20 ± 8.83 nM toward AChE and Ki: 3.39 ± 1.91 nM for BChE). Cholinesterase (BChE and AChE) inhibitory abilities of all synthesized molecules were also performed in situ and molecular docking and molecular dynamics (MD) simulation studies. The molecular coupling scores of the compounds and the free binding energies calculated by MM/GBSA were found to be compatible. Examining the results obtained from this study shows that it may have the potential to develop new drugs to treat some global patients such as glaucoma and Alzheimer's disease (AD).

Histological assessment of liver and stomach damage caused by pyridazinone derivative antidepressant agents.

Depression is a serious psychological disorder that affects a significant population. We investigated the antidepressant activities of four pyridazinone derivatives that contain the hydrazide moiety using the forced swimming test (FST). The compounds tested exhibited good antidepressant activity compared to duloxetine. The most promising compound was compound 2, which reduced the duration of immobility during FST. The toxic effects of the four compounds on the histomorphology of the liver and stomach tissue also was evaluated.

Renewables as a pathway to environmental sustainability targets in the era of trade liberalization: empirical evidence from Turkey and the Caspian countries.

The quest for improved environmental quality through low-carbon emission has been explored in this study in the wake of the growing call for a transition to renewable energy use amidst widening trade relations between Turkey and the countries in the Caspian region including Azerbaijan, Iran, Kazakhstan, Russia, and Turkmenistan. This study draws strength from the United Nations Sustainable Development Goals (UN-SDGs) and their impact by 2030. These SDGs encompass pertinent targets on responsible energy consumption (SDG-12), access to clean and affordable energy (SDG-7), and climate change action (SDG-13). Empirical evidence from the dynamic ordinary least squares (DOLS) technique corroborated by the fully modified ordinary least squares (FMOLS) technique shows that a percent rise in renewable energy consumption level significantly abates carbon emission among these countries by about 0.26% while growing globalization vis-à-vis a percent increase in openness to trade significantly hampers environmental quality via inducement of carbon emission level by 0.32%. Extended findings from the Granger causality analysis corroborate the significance of the long-run coefficients with regard to the double-edged benefits of renewable energy consumption in enhancing both environmental quality and income levels through lower carbon emission and sustainable economic growth stimulations among the countries. The study confirmed the inverted U-shape relation between income growth and environmental deterioration, thus validating the EKC hypothesis for Turkey and the Caspian countries. This suggests that both blocs are still at the scale stage of their growth trajectory, where the emphasis is focused on increasing income level relative to environmental sustainability. As such, important policy measures were provided in the concluding section of this study.

Monoamine Oxidase-B (MAO-B) Inhibitors in the Treatment of Alzheimer's and Parkinson's Disease.

BACKGROUND: The MAO enzyme is presented in the brain and peripheral tissues and is a significant enzyme that is responsible for the deamination of biogenic amines and thus the regulation of neurotransmitter levels. The reaction of these neurotransmitters with the MAO enzyme produces aldehyde and free amine. MAO enzyme consists of two isoforms, MAO-A and MAO-B, which are characterized by amino acid sequence, three-dimensional structure, substrate preference, and inhibitor selectivity. Dopamine, tyramine, and tryptamine are substrates of both MAO isoforms and MAO inhibitors such as clorgiline and selegiline, which are used as medications in neurodegenerative and neurological diseases. In particular, MAO-A inhibitors are used in the treatment of depression, while MAO-B inhibitors are used in the treatment of Parkinson's disease. It is also investigated whether MAO-B inhibitors are effective in the treatment of Alzheimer's disease. Nowadays, life expectancy has increased, as a result, neurodegenerative diseases such as Parkinson's and Alzheimer's disease have started to occur more frequently. The elderly population is increasing day by day. As a result of these common diseases in elderly people, these people are unable to do their jobs and need care. Therefore, these diseases have become a significant health problem in society. METHODS: In this study, review, inclusion, and exclusion criteria were used. Peer-reviewed research articles were searched. The quality of the examined articles was evaluated with standard tools. The information obtained was analyzed conceptually by using qualitative content analysis methodology. RESULTS: One hundred and five papers were included in the review. The current MAO-B inhibitors and their usage areas are discussed together with the structures of the drugs; also, their possible effects in Alzheimer's and Parkinson's treatment are evaluated. In addition, different articles have been compiled in which structures such as arylalkylamines, chalcones, benzoquinone, benzoxazinone, and chromen are substituted with various functional groups and aromatic rings, along with thestructures of 44 different compounds that have recently been developed and their inhibitory effects on MAO-B enzyme. As a result, the structure required for MAO-B inhibition and SAR studies is discussed. CONCLUSION: Many studies demonstrate that MAO-B activity increases with age in brain tissue, cerebrospinal fluid (CSF), and platelets in Alzheimer's patients. This suggests that MAO-B inhibitor drugs, which may be effective in the treatment of Parkinson's disease, may also be effective in the treatment of Alzheimer's disease. This article was written to explain the multifaceted MAO-B inhibitor molecules.

An efficient synthesis of novel di-heterocyclic benzazole derivatives and evaluation of their antiproliferative activities.

A series of unsymmetrical nine di-heterocyclic compounds of benzazole derivatives were synthesized at one step via cyclization reaction. The compounds evaluated for in vitro cytotoxic activity against A549, A498, HeLa, and HepG2 cancer cell lines. The biological evaluation results show that 23, 26 and 29 exhibit better activity against HepG2 and HeLa cancer cell lines. Compound 23 also showed good activity against A549, and A498 cancer cell lines. The analogs were further performed molecular docking studies against human cytochrome P450 2C8 monooxygenase enzyme, calculated some theoretical quantum parameters, ADMET descriptor and molecular electrostatic potential analysis. The strategy applied in this research work may act as a perspective for the rational design of potential anticancer drugs. Communicated by Ramaswamy H. Sarma.

Synthesis, Cytotoxicity and Anti-Proliferative Activity Against AGS Cells of New 3(2H)-Pyridazinone Derivatives Endowed with a Piperazinyl Linker.

Novel twenty-three 3(2H)-pyridazinone derivatives were designed and synthesized based on the chemical requirements related to the anti-proliferative effects previously demonstrated within this scaffold. The introduction of a piperazinyl linker between the pyridazinone nucleus and the additional (un)substituted phenyl group led to some compounds endowed with a limited cytotoxicity against human gingival fibroblasts (HGFs) and good anti-proliferative effects against gastric adenocarcinoma cells (AGS) as evaluated by MTT and LDH assays, using doxorubicin as a positive control. Successive analyses revealed that the two most promising representative compounds (12 and 22) could exert their effects by inducing oxidative stress as demonstrated by the hydrogen peroxide release and the morphological changes (cell blebbing) revealed by light microscopy analysis after the haematoxylin-eosin staining. Moreover, to further assess the apoptotic process induced by compounds 12 and 22, Bax expression was measured by flow cytometry. These findings enlarged our knowledge of the structural requirements in this scaffold to display valuable biological effects against cancerous cell lines.

Synthesis, molecular modelling and biological activity of some pyridazinone derivatives as selective human monoamine oxidase-B inhibitors.

BACKGROUND: Since brain neurotransmitter levels are associated with the pathology of various neurodegenerative diseases like Parkinson and Alzheimer, monoamineoxidase (MAO) plays a critical role in balancing these neurotransmitters in the brain. MAO isoforms appear as promising drug targets for the development of central nervous system agents. Pyridazinones have a broad array of biological activities. Here, six pyridazinone derivatives were synthesized and their human monoamine oxidase inhibitory activities were evaluated by molecular docking studies, in silico ADME prediction and in vitro biological screening tests. METHODS: The compounds were synthesized by the reaction of different piperazine derivatives with 3 (2H)-pyridazinone ring and MAO-inhibitory effects were investigated. Docking studies were conducted with Maestro11.8 software. RESULTS: Most of the synthesized compounds inhibited hMAO-B selectively except compound 4f. Compounds 4a-4e inhibited hMAO-B selectively and reversibly in a competitive mode. Compound 4b was found as the most potent (ki = 0.022 ± 0.001 µM) and selective (SI (Ki hMAO-A/hMAO-B) = 206.82) hMAO-B inhibitor in this series. The results of docking studies were found to be consistent with the results of the in vivo activity studies. Compounds 4a-4e were found to be non-toxic to HepG2 cells at 25 µM concentration. In silico calculations of ADME properties indicated that the compounds have good pharmacokinetic profiles. CONCLUSION: It was concluded that 4b is possibly recommended as a promising nominee for the design and development of new pyridazinones which can be used in the treatment of neurological diseases.

The association between cardiac resynchronization therapy response and sexual activity in patients with heart failure.

BACKGROUND: Sexual activity is an important indicator of quality of life and is significantly impaired in patients with heart failure (HF). Cardiac resynchronization therapy (CRT) has positive effects on cardiac dysfunction and endothelial dysfunction that lead to erectile dysfunction (ED). We aimed to evaluate whether CRT may improve sexual activity in patients with HF. METHODS: In total, 136 patients (mean age 61.8 ± 12.8 years) were evaluated for the study. All patients filled the Sexual Health Inventory for Men (SHIM) questionnaire for evaluation of their erectile functions before CRT device implantation. One hundred eighty days after CRT device implantation, the patients were re-evaluated with SHIM questionnaire. RESULTS: In the whole study population, SHIM test scores were significantly increased after CRT (12.99 ± 3.22 vs. 18.03 ± 5.00; p<0.001). The patients were divided into two groups according to the CRT response. The increase in SHIM test scores was significantly more in the response (+) group than in the response (-) group [response (+) group: 6.94 ± 3.36; p<0.001 vs. response (-) group: 0.81 ± 1.77; p = 0.465]. A positive CRT response was found to be an independent predictor of SHIM score (p<0.001). CONCLUSION: Our study showed that CRT had positive effects on ED of patients with HF.

Nesfatin-1 levels in patients with slow coronary flow.

BACKGROUND: Nesfatin-1 is a novel anorectic neuropeptide with potent metabolic regulatory effects. AIM: We aimed to evaluate the relationship between nesfatin-1 levels and slow coronary flow (SCF). METHODS: A total of 60 consecutive patients with SCF and 60 consecutive patients with normal coronary flow (NCF) were enrolled into the study. Nesfatin-1 level was measured from blood serum samples using enzyme-linked immunosorbent assay test. RESULTS: Serum nesfatin-1 levels were significantly lower in the SCF group compared to the NCF group (p < 0.001). Low levels of nesfatin-1 were found to be significantly and independently associated with the SCF (odds ratio 0.982, 95% confidence interval 0.969-0.995, p = 0.005). CONCLUSIONS: The results of this study showed that serum nesfatin-1 level was lower in the SCF group than in the NCF group. Nesfatin-1 could play a role in the pathogenesis of SCF phenomenon with mechanisms such as inflammation and endothelial dysfunction. Further studies are needed to determine the relation between SCF and nesfatin-1.