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Cholinesterase-like organocatalysis by imidazole and imidazole-bearing molecules.

ABSTRACT: Organocatalysis, which is mostly explored for its new potential industrial applications, also represents a chemical event involved in endogenous processes. In the present study, we provide the first evidence that imidazole and imidazole derivatives have cholinesterase-like properties since they can accelerate the hydrolysis of acetylthiocholine and propionylthiocholine in a concentration-dependent manner. The natural imidazole-containing molecules as L-histidine and histamine show a catalytic activity, comparable to that of imidazole itself, whereas synthetic molecules, as cimetidine and clonidine, were less active. In the experimental conditions used, the reaction progress curves were sigmoidal and the rational of such unexpected behavior as well as the mechanism of catalysis is discussed. Although indirectly, findings of the present study suggests that imidazolic compounds may interfere with the homeostasis of the cholinergic system in vivo.

SUBMITTER: Nieri P

PROVIDER: S-EPMC5377937 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Coumarin derivatives bearing benzoheterocycle moiety: synthesis, cholinesterase inhibitory, and docking simulation study.

Project description:OBJECTIVES:To investigate the efficiency of a novel series of coumarin derivatives bearing benzoheterocycle moiety as novel cholinesterase inhibitors. MATERIALS AND METHODS:Different 7-hydroxycoumarin derivatives were synthesized via Pechmann or Knoevenagel condensation and conjugated to different benzoheterocycle (8-hydroxyquinoline, 2-mercaptobenzoxazole or 2-mercaptobenzimidazole) using dibromoalkanes 3a-m: Final compounds were evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) by Ellman's method. Kinetic study of AChE inhibition and ligand-protein docking simulation were also carried out for the most potent compound 3b. RESULTS:Some of the compounds revealed potent and selective activity against AChE. Compound 3b containing the quinoline group showed the best activity with an IC50 value of 8.80 ?M against AChE. Kinetic study of AChE inhibition revealed the mixed-type inhibition of the enzyme by compound 3b. Ligand-protein docking simulation also showed that the flexibility of the hydrophobic five carbons linker allows the quinoline ring to form ?-? interaction with Trp279 in the PAS. CONCLUSION:We suggest these synthesized compounds could become potential leads for AChE inhibition and prevention of AD symptoms.

| S-EPMC5569448 | biostudies-literature

Parallel synthesis of an imidazole-4,5-dicarboxamide library bearing amino acid esters and alkanamines.

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| S-EPMC2651155 | biostudies-literature

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| S-EPMC5894062 | biostudies-literature

Synthesis, Single Crystal X-ray Analysis, and Antifungal Profiling of Certain New Oximino Ethers Bearing Imidazole Nuclei.

Project description:Fungal infections threaten human health, particularly in immune-compromised patients worldwide. Although there are a large number of antifungal agents available, the desired clinical attributes for the treatment of fungal infections have not yet been achieved. Azoles are the mainstay class of the clinically used antifungal agents. In the current study, the synthesis, spectroscopic characterization, and antifungal activity of certain new oximino ethers Va-n bearing imidazole nuclei are reported. The (E)-configuration of the imine double bond of the synthesized compounds Va-n has been confirmed via single crystal X-ray analysis of compound Vi as a representative example of this class of compounds. The molecular structure of compound Vi was crystallized in the monoclinic, P2?/c, a = 18.7879(14) Å, b = 5.8944(4) Å, c = 16.7621(12) Å, ? = 93.063(3)°, V = 1855.5(2) Å³, Z = 4. The in vitro antifungal activity of the synthesized compounds Va-n were evaluated using diameter of the inhibition zone (DIZ) and minimum inhibitory concentration (MIC) assays against different fungal strains. Compound Ve manifested anti-Candida albicans activity with an MIC value of 0.050 µmol/mL, being almost equipotent with the reference antifungal drug fluconazole (FLC),while compounds Vi and Vn are the most active congeners against Candida parapsilosis, being equipotent and about twenty-three times more potent than FLC with an MIC value of 0.002 µmol/mL. The results of the current report might support the development of new potent and safer antifungal azoles.

| S-EPMC6150221 | biostudies-literature

An Updated Review on the Synthesis and Antibacterial Activity of Molecular Hybrids and Conjugates Bearing Imidazole Moiety.

Project description:The rapid growth of serious infections caused by antibiotic resistant bacteria, especially the nosocomial ESKAPE pathogens, has been acknowledged by Governments and scientists and is one of the world's major health problems. Various strategies have been and are currently investigated and developed to reduce and/or delay the bacterial resistance. One of these strategies regards the design and development of antimicrobial hybrids and conjugates. This unprecedented critical review, in which our continuing interest in the synthesis and evaluation of the bioactivity of imidazole derivatives is testified, aims to summarise and comment on the results obtained from the end of the 1900s until February 2020 in studies conducted by numerous international research groups on the synthesis and evaluation of the antibacterial properties of imidazole-based molecular hybrids and conjugates in which the pharmacophoric constituents of these compounds are directly covalently linked or connected through a linker or spacer. In this review, significant attention was paid to summarise the strategies used to overcome the antibiotic resistance of pathogens whose infections are difficult to treat with conventional antibiotics. However, it does not include literature data on the synthesis and evaluation of the bioactivity of hybrids and conjugates in which an imidazole moiety is fused with a carbo- or heterocyclic subunit.

| S-EPMC7663458 | biostudies-literature

Parallel synthesis of a library of symmetrically- and dissymmetrically-disubstituted imidazole-4,5-dicarboxamides bearing amino acid esters.

Project description:The imidazole-4,5-dicarboxylic acid scaffold is readily derivatized with amino acid esters to afford symmetrically- and dissymmetrically-disubstituted imidazole-4,5-dicarboxamides with intramolecularly hydrogen bonded conformations that predispose the presentation of amino acid pharmacophores. In this work, a total of 45 imidazole-4,5-dicarboxamides bearing amino acid esters were prepared by parallel synthesis. The library members were purified by column chromatography on silica gel and the purified compounds characterized by LC-MS with LC detection at 214 nm. A selection of the final compounds was also analyzed by (1)H-NMR spectroscopy. The analytically pure final products have been submitted to the Molecular Library Small Molecule Repository (MLSMR) for screening in the Molecular Library Screening Center Network (MLSCN) as part of the NIH Roadmap.

| S-EPMC2635021 | biostudies-literature

Cross-trienamines in asymmetric organocatalysis.

Project description:Cross-conjugated trienamines are introduced as a new concept in asymmetric organocatalysis. These intermediates are applied in highly enantioselective Diels-Alder and addition reactions, providing functionalized bicyclo[2.2.2]octane compounds and γ'-addition products, respectively. The nature of the transformations and the intermediates involved are investigated by computational calculations and NMR analysis.

| S-EPMC3557926 | biostudies-literature

Caged Proline in Photoinitiated Organocatalysis.

Project description:Organocatalysis is an emerging field, in which small metal-free organic structures catalyze a diversity of reactions with a remarkable stereoselectivity. The ability to selectively switch on such pathways upon demand has proven to be a valuable tool in biological systems. Light as a trigger provides the ultimate spatial and temporal control of activation. However, there have been limited examples of phototriggered catalytic systems. Herein, we describe the synthesis and application of a caged proline system that can initiate organocatalysis upon irradiation. The caged proline was generated using the highly efficient 4-carboxy-5,7-dinitroindolinyl (CDNI) photocleavable protecting group in a four-step synthesis. Advantages of this system include water solubility, biocompatibility, high quantum yield for catalyst release, and responsiveness to two-photon excitation. We showed the light-triggered catalysis of a crossed aldol reaction, a Mannich reaction, and a self-aldol condensation reaction. We also demonstrated light-initiated catalysis, leading to the formation of a biocide in situ, which resulted in the growth inhibition of E. coli, with as little as 3 min of irradiation. This technique can be broadly applied to other systems, by which the formation of active forms of drugs can be catalytically assembled remotely via two-photon irradiation.

| S-EPMC6510250 | biostudies-literature

Synthesis, structure elucidation, and antifungal potential of certain new benzodioxole-imidazole molecular hybrids bearing ester functionalities.

Project description:Background:The incidence of fungal infections is a growing serious global health burden. There is an urgent medical demand to acquire new antifungal drug-like compounds having azole nuclei to get rid of the drawbacks of the currently available azole antifungal agents. Methods:The target compounds 5a-r were synthesized in a four-step reaction sequence using the appropriate acetophenone derivative as a starting material. The antifungal potential of the title compounds was assessed using DIZ and MIC assays according to the reported standard procedures. Results:The newly synthesized oximino esters 5a-r were identified with the aid of various spectroscopic approaches. Their assigned chemical structures were confirmed via single-crystal X-ray structure of compound 5o. The molecular structure of compound 5o was crystallized in the triclinic, P-1, a=9.898 (3) Å, b=10.433 (3) Å, c=11.677 (4) Å, α =86.886 (6)°, β =87.071 (7)°, γ =64.385 (6)°, V=1,085.2 (6) Å3, Z=2. The synthesized compounds 5a-r were in vitro evaluated for antifungal potential against four fungal strains. Compounds 5l and 5m bearing a trifluoromethylphenyl moiety showed the best anti-Candida albicans activity with minimum inhibitory concentration (MIC) value of 0.148 μmol/mL, while compound 5b displayed the best activity toward Candida tropicalis with MIC value of 0.289 μmol/mL. Compounds 5o and 5l were the most active congeners against Candida parapsilosis and Aspergillus niger, respectively. Conclusion:Single-crystal X-ray analysis of compound 5o confirmed without doubt the assigned chemical structures of the title compounds as well as confirmed the (E)-configuration of their oximino group. Compounds 5b, 5l, 5m, and 5o emerged as the most active compounds against the tested fungi and they could be considered as new antifungal lead candidates.

| S-EPMC6396673 | biostudies-other

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