- Reversible small molecule inhibitors of MAO A and MAO B with anilide motifs
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Background: Ligands consisting of two aryl moieties connected via a short spacer were shown to be potent inhibitors of monoamine oxidases (MAO) A and B, which are known as suitable targets in treatment of neurological diseases. Based on this general blueprint, we synthesized a series of 66 small aromatic amide derivatives as novel MAO A/B inhibitors. Methods: The compounds were synthesized, purified and structurally confirmed by spectroscopic methods. Fluorimetric enzymological assays were performed to determine MAO A/B inhibition properties. Mode and reversibility of inhibition was determined for the most potent MAO B inhibitor. Docking poses and pharmacophore models were generated to confirm the in vitro results. Results: N-(2,4-Dinitrophenyl)benzo[d][1,3]dioxole-5-carboxamide (55, ST-2043) was found to be a reversible competitive moderately selective MAO B inhibitor (IC50 = 56 nM, Ki = 6.3 nM), while N-(2,4-dinitrophenyl)benzamide (7, ST-2023) showed higher preference for MAO A (IC50 = 126 nM). Computational analysis confirmed in vitro binding properties, where the anilides examined possessed high surface complementarity to MAO A/B active sites. Conclusion: The small molecule anilides with different substitution patterns were identified as potent MAO A/B inhibitors, which were active in nanomolar concentrations ranges. These small and easily accessible molecules are promising motifs, especially for newly designed multitargeted ligands taking advantage of these fragments.
- Grau, Kathrin,Hagenow, Jens,Hagenow, Stefanie,Hefke, Lena,Khanfar, Mohammad,Proschak, Ewgenij,Stark, Holger
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p. 371 - 393
(2020/02/11)
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- Platelet ADP receptor inhibitors
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Novel compounds of formulae (I) to (VIII), which more particularly include sulfonylurea derivatives, sulfonylthiourea derivatives, sulfonylguanidine derivatives, sulfonylcyanoguanidine derivatives, thioacylsulfonamide derivatives, and acylsulfonamide derivatives which are effective platelet ADP receptor inhibitors. These derivatives may be used in various pharmaceutical compositions, and are particularly effective for the prevention and/or treatment of cardiovascular diseases, particularly those diseases related to thrombosis. The invention also relates to a method for preventing or treating thrombosis in a mammal comprising the step of administering a therapeutically effective amount of a compound of formulae (I) to (VIII), or a pharmaceutically acceptable salt thereof.
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- Platelet ADP receptor inhibitors
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Novel compounds of formulae (I) to (VIII), which more particularly include sulfonylurea derivatives, sulfonylthiourea derivatives, sulfonylguanidine derivatives, sulfonylcyanoguanidine derivatives, thioacylsulfonamide derivatives, and acylsulfonamide derivatives which are effective platelet ADP receptor inhibitors. These derivatives may be used in various pharmaceutical compositions, and are particularly effective for the prevention and/or treatment of cardiovascular diseases, particularly those diseases related to thrombosis. The invention also relates to a method for preventing or treating thrombosis in a mammal comprising the step of administering a therapeutically effective amount of a compound of formulae (I) to (VIII), or a pharmaceutically acceptable salt thereof.
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- Design, anticonvulsive and neurotoxic properties of retrobenzamides / N- (nitrophenyl)benzamides and N-(aminophenyl)benzamides
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Design, anticonvulsant properties in maximal electroshock-reduced seizures [MES] and seizures reduced by subcutaneous administration of pentetrazole (scPtz), and neurotoxicity of retrobenzamides (N- (nitrophenyl)benzamides and N-(aminophenyl) benzamides are reported. These data are further compared with those on carbamazepine, phenytoin, ameltolide and other reference compounds. Studies on retrobenzamides in mice dosed intraperitoneally point out a good anticonvulsant potential in the MES test for the amino derivatives (N-(aminophenyl)benzamides) and moderate activity for corresponding 'nitro' derivatives. In rats dosed orally, aminoretrobenzamides were, however, less active in the MES test than in mice dosed intraperitoneally. Differences between experimental animal species and administration routes lead to hypothesize rapid metabolization of compounds, reduced intestinal resorption and increased removal from body. The presence of a methyl substitution on the N-phenyl moiety of aminoretrobenzamides attenuated these discrepancies between mice and rats. Present results indicate that pharmacological values - including the dose offering anticonvulsant protection in 50 % of tested animals (ED50) and protective indices - obtained on some retrobenzamides may compete with phenytoin and carbamazepine values. By contrast with phenytoin, some retrobenzamides further exhibit activity in the scPtz test.
- Bourhim, Mustapha,Poupaert, Jacques H.,Stables, James P.,Vallee, Louis,Vamecq, Joseph
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- Quinone Imine Route to Benzimidazol-2-ylcarbamates. Part 1. Synthesis of Open-chain and Cyclic 5-Acylamino Derivatives.
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The synthesis of the N',N''-bismethoxycarbonyl-N-(4-acylaminophenyl)guanidines (4) and (7) is described.Oxidation of these with LTA has led to the benzimidazol-2-ylcarbamates. (8), (9) and (10) through a regiospecific cyclisation of quinone imine intermediates.If the acylamino group is part of a ring, the yield of benzimidazoles (15) increases with the size of the lactam ring.The direction of ring closure may be controlled by electronic and steric factors.
- Rajappa, Srinivasachari,Sreenivasan, Ramaswami,Khalwadekar, Asha
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p. 1657 - 1675
(2007/10/02)
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