18 research outputs found
Supplementary material for the article: Jevtić, I. I.; Došen-Mićović, L. I.; Ivanović, E. R.; Todorović, N. M.; Ivanović, M. D. Synthesis of Orthogonally Protected (±)-3-Amino-4-Anilidopiperidines and (±)-3- N -Carbomethoxyfentanyl. Synthesis (Germany) 2017, 49 (14), 3126–3136. https://doi.org/10.1055/s-0036-1588985
Supporting information for: [https://doi.org/10.1055/s-0036-1588985]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2492
Supplementary data for the article: Jevtić, I. I.; Savić Vujović, K.; Srebro, D.; Vučković, S.; Ivanović, M. D.; Kostić-Rajačić, S. V. Synthesis and Pharmacological Evaluation of Novel Cis and Trans 3-Substituted Anilidopiperidines. Pharmacol. Rep 2020, 72 (4), 1069–1075. https://doi.org/10.1007/s43440-020-00121-2
Supplementary material for: [ https://doi.org/10.1007/s43440-020-00121-2]Related to published version: [https://cherry.chem.bg.ac.rs/handle/123456789/4211
Supplementary data for the article: Jevtić, I. I.; Došen-Mićović, L.; Ivanović, E. R.; Ivanović, M. D. Hofmann Rearrangement of Carboxamides Mediated by N-Bromoacetamide. Synthesis (Germany) 2016, 48 (10), 1550–1560. https://doi.org/10.1055/s-0035-1561405
Supplementary material for: [https://doi.org/10.1055/s-0035-1561405]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1935
alpha-Glucosidase inhibitory activity and cytotoxic effects of some cyclic urea and carbamate derivatives
The inhibitory activities of selected cyclic urea and carbamate derivatives (1-13) toward alpha-glucosidase (alpha-Gls) in in vitro assay were examined in this study. All examined compounds showed higher inhibitory activity (IC50) against alpha-Gls compared to standard antidiabetic drug acarbose. The most potent was benzyl (3,4,5-trimethoxyphenyl) carbamate (12) with IC50 = 49.85 +/- 0.10 mu M. In vitro cytotoxicity of the investigated compounds was tested on three human cancer cell lines HeLa, A549 and MDA-MB-453 using MTT assay. The best antitumour activity was achieved with compound 2 (trans-5-phenethyl-1-phenylhexahydro-1H-imidazo[4,5-c] pyridin-2(3H)-one) against MDA-MB-453 human breast cancer cell line (IC50 = 83.41 +/- 1.60 mu M). Cyclic ureas and carbamates showed promising anti-alpha-glucosidase activity and should be further tested as potential antidiabetic drugs. The PLS model of preliminary QSAR study indicated that, in planing the future synthesis of more potent compounds, the newly designed should have the substituents capable of polar interactions with receptor sites in various positions, while avoiding the increase of their lipophilicity
μ-opioid/D2 dopamine receptor pharmacophore containing ligands: Synthesis and pharmacological evaluation
Herein, the synthesis and pharmacological evaluation of 13 novel compounds, designed as potential heterobivalent ligands for μ-opioid receptor (MOR) and dopamine D2 receptors (D2DAR), are reported. The compounds consisted of anilido piperidine and N-aryl piperazine moieties, joined by a variable-length methylene linker. The two moieties represent MOR and D2DAR pharmacophores, respectively. The synthesis encompassed four steps, securing the final products in 28–42 % overall yields. The approach has a considerable synthetic potential, providing access to various related structures. Pharmacological tests involved in vitro competitive assay for D2DAR using [3H] spiperon, as a standard radioligand, and in vivo antinociceptive tests for MOR. The measured dopamine affinities were modest to low, while antinociceptive activity was completely absent. Therefore, the compounds of the general structure prepared in this research are unlikely to be useful as opioid–dopamine receptor heterobivalent ligands
Supplementary material for the article: Jevtić, I. I.; Došen-Mićović, L. I.; Ivanović, E. R.; Todorović, N. M.; Ivanović, M. D. Synthesis of Orthogonally Protected (±)-3-Amino-4-Anilidopiperidines and (±)-3- N -Carbomethoxyfentanyl. Synthesis (Germany) 2017, 49 (14), 3126–3136. https://doi.org/10.1055/s-0036-1588985
Supporting information for: [https://doi.org/10.1055/s-0036-1588985]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2492
Design, synthesis and pharmacological evaluation of N-{4-[2-(4-aryl-piperazin-1-yl)-ethyl]-phenyl}-arylamides
5HT1A receptor targeting drugs have been used as the treatment for the many neuropsychiatric
disorders, such as schizophrenia and depression. As a part of ongoing research, we designed series of
new compounds that share arylpiperazine common structural motif with the 5HT1A receptor ligand
aripiprazole. Receptor-ligand interactions were determined by the molecular docking simulations,
revealing the positive impact of the phenyl substitution in the arylpiperazine part of the molecules. Nine
selected compounds were synthesized in four reaction steps in high overall yields (59-73%). In vitro
pharmacological evaluation of the synthesized compounds revealed three compounds (5b, 6b and 6c)
with high 5HT1A binding affinity, comparable with aripiprazole (Ki 12.0, 4.8, 12.8, 5.6 nM,
respectively). Compounds from b series, 5b and 6b, possess 2-methoxyphenyl substituents, while 6c
possess 2,3-dichlorophenyl substituent in the arylpiperazine part of the molecule. The pharmacological
results are therefore in accordance with the molecular docking simulations thus proving the rational
design. Compounds 5c, 6b and 6c can be considered as the candidates for further evaluation as new,
potential antidepressants
Synthesis, computational and pharmacological evaluation of novel N-{4-[2-(4-aryl-piperazin-1-yl)ethyl]phenyl}-arylamides
Serotonin, or 5-hydroxytryptamine (5-HT), is a biogenic amine most
noted as a neurotransmitter, an activator of the utmost subtype family of G-protein-
coupled receptors (GPCR). Drugs targeting 5-HT1A and other 5-HT receptors
treat central nervous system diseases such as schizophrenia and depression.
Recent advances in serotonin receptor structure research gave us several
crystal 5-HT1A receptor structures, most notably 5-HT1A bound to the antipsychotic
drug aripiprazole (Abilify®). This discovery prompted us to evaluate
a series of newly synthesized ligands for serotonergic activity since those arylpiperazine
derivatives share minimal general structure with aripiprazole. The
results of molecular docking analysis of unsubstituted starting substances
encouraged us to propound further modifications of the tail and head parts of
the parent molecules to maximize receptor binding affinity. Intrigued by the
results of molecular analysis, all foreseen derivatives were synthesized. The
pharmacological activity of all nine (5a and 6a are synthesized previously)
compounds was assessed by the in vitro tests and in silico pharmacokinetics
predictions for the most promising candidates. All tested ligands have improved
affinity compering to parent compounds (10a and 11a), 8b and 9b expressed
the best pharmacological profile with an improved binding affinity
toward serotonin 5-HT1A receptors (Ki 12.1 and 4.8 nM, respectively)
Development of fluorinated indanone-based derivatives for the imaging of monoamine oxidase B via positron emission tomography
Ziel/Aim The monoamine oxidase B (MAO B) isoenzyme is known to be
involved in the oxidative deamination of biogenic amines. While the use of
MAO B inhibitors is already well-established for the treatment of Parkinson’s
disease, recent reports suggest its involvement in certain types of brain
tumors.1 We herein aim at the synthesis and preclinical evaluation of fluorinated indanone-based derivatives targeting MAO B in the brain via positron
emission tomography (PET).
Methodik/Methods A small series of fluorinated indanone derivatives
was obtained via the O-alkylation or esterification starting with the
commercially available 6-hydroxy-2,3-dihydro-1H-inden-1-one in one or
two steps. Binding affinities towards the human MAO isoenzymes were
estimated in vitro by radioligand displacement. HL126 was selected for
radiofluorination via its corresponding boronic acid pinacol ester. In
vitro autoradiography of [18F]HL126 was performed in mice brain slices.
In vivo evaluation of [18F]HL126 in CD-1 mice was carried out and
metabolism studies were performed in plasma and brain samples via
radio-HPLC.
Ergebnisse/Results The fluorinated indanone derivatives were synthesized
in yields ranging from 65-89 %. The fluorophenyl ether derivative, HL126,
was further selected for radiofluorination based on its high binding affinity
towards MAO B (Ki = 6.9 ± 5.3 nM). [18F]HL126 was obtained by an alcohol-enhanced copper-mediated approach via the corresponding boronic
acid pinacol ester precursor with radiochemical yields of about 11 ± 3 %,
high radiochemical purities (≥99 %) and molar activities in the range of 20
GBq/mmol. In vitro autoradiography showed a specific blockade with
selective MAO-A/B inhibitors. PET/MRI analyses revealed that [18F]HL126
readily enters the brain. Some radiometabolites do cross the blood-brain
barrier.
Schlussfolgerungen/Conclusions Although metabolism studies with [18F]
HL126 revealed the presence of radiometabolites in the brain, the high binding affinity towards MAO B and the pronounced selectivity in in vitro autoradiography studies encourage further derivatization of indanone-based
scaffolds for targeting MAO B
Antidiabetics: Structural Diversity of Molecules with a Common Aim
BACKGROUND: Diabetes mellitus type 2 (DMT2) is an endocrine disease of global proportions which is currently affecting 1 in 12 adults in the world, with still increasing prevalence. World Health Organization (WHO) declared this worldwide health problem, as an epidemic disease, to be the only non-infectious disease with such categorization. People with DMT2 are at increased risk of various complications and have shorter life expectancy. The main classes of oral antidiabetic drugs accessible today for DMT2 vary in their chemical composition, modes of action, safety profiles and tolerability. Methods: A systematic search of peer-reviewed scientific literature and public databases has been conducted. We included the most recent relevant research papers and data in respect to the focus of the present review. The quality of retrieved papers was assessed using standard tools. Results: The review highlights the chemical structural diversity of the molecules that have the common target-DMT2. So-called traditional antidiabetics as well as the newest and the least explored drugs include polypeptides and amino acid derivatives (insulin, glucagon-like peptide 1, dipeptidyl peptidase-IV inhibitors, amylin), sulfonylurea derivatives, benzylthiazolidine-2,4-diones (peroxisome proliferator activated receptor-gamma agonists/glitazones), condensed guanido core (metformin) and sugar-like molecules (alpha-glucosidase and sodium/glucose co-transporter 2 inhibitors). Conclusion: As diabetes becomes a more common disease, interest in new pharmacological targets is on the rise