- 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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- Copper-Catalyzed Direct Nitration on Aryl C-H Bonds by Concomitant Azidation-Oxidation with TMS Azide and TBHP under Aerobic Conditions
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An unprecedented copper-catalyzed in situ azidation-oxidation for the nitration of anilides and sulfonamides has been developed by direct CAr-H functionalization. This novel and efficient nitration protocol is achieved employing TMSN3 and TBHP without the exclusion of air or moisture. The synthetic applications of the 2-nitroanilides have been explored.
- Vinayak, Botla,Chandrasekharam, Malapaka
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p. 3528 - 3531
(2017/07/17)
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- Effective nitration of anilides and acrylamides by tert-butyl nitrite
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Nitro compounds are important intermediates in synthetic organic chemistry and the chemical industry. Herein, the efficient copper-catalyzed [10% Cu(NO3)2·3H2O] nitration of anilides was developed by using TBN (tert-butyl nitrite) as a nitrating reagent to give the corresponding nitro-substituted aromatic products in good to excellent yields. The use of TBN also led to the selective nitration of acrylamides at room temperature to afford only the (E) isomer of the nitration product. A series of anilides and acrylamides with a broad array of functional groups were well-tolerated by this procedure. This synthetic method has many advantages, which include inexpensive starting materials, mild reaction conditions, a fast reaction rate, and high yields. A mechanistic investigation indicates that a nitro radical, which is generated from the thermal homolysis of TBN, is involved in the two nitration processes. The efficient nitration of both anilides and acrylamides was achieved by using TBN (tert-butyl nitrite) as a metal-free nitrating reagent. This synthetic method has many advantages such as mild reaction conditions, a fast reaction rate, good to excellent yields, and a broad substrate scope. Our investigation indicates that a nitro radical is involved in the reaction mechanism.
- Ji, Yi-Fei,Yan, Hong,Jiang, Qi-Bai
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p. 2051 - 2060
(2015/03/18)
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- Copper-catalyzed mild nitration of protected anilines
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A practical copper-catalyzed direct nitration of protected anilines, by using one equivalent of nitric acid as the nitrating agent, has been developed. This procedure features mild reaction conditions, wide structural scope (with regard to both N-protecting group and arene substitution), and high functional-group tolerance. Dinitration with two equivalents of nitric acid is also feasible. Practical and reliable: A Cu-catalyzed selective nitration of para- and ortho-substituted aniline derivatives by using one equivalent of HNO3 has been developed that produces water as the only stoichiometric byproduct (see scheme; PG=protecting group). This method is compatible with strongly electron-deficient substrates, enabling dinitration (by using 2.0 equiv of HNO3). This method allows for a rapid access to relevant nitrogen-containing heterocyclic architectures.
- Hernando, Elier,Castillo, Rafael R.,Rodríguez, Nuria,G?mez Arrayás, Ram?n,Carretero, Juan C.
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supporting information
p. 13854 - 13859
(2016/02/18)
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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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- Cyclic and acyclic amidines and pharmaceutical compositions containing them for use as progesterone receptor binning agents
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Disclosed are cyclic and acyclic amidines, pharmaceutical compositions containing such amidines, and their use in treating or preventing progesterone receptor mediated diseases or conditions, such as osteopenia and osteoporosis.
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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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- Reaction of N-Aryl- and N-Alkyl-benzimidoyl Chlorides with Silver Nitrate
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N-Arylbenzimidoyl chlorides, in which the N-aryl group is unsubstituted at the ortho- and para-positions, react with AgNO3 to yield N-(nitroaryl)benzamides, in which the NO2 group resides in the ortho- or para-position.N-Arylbenzimidoyl chlorides, in which the N-aryl ring is 2,4,6-trisubstituted, react with AgNO3 to yield the corresponding N-aryl-N-nitrobenzamides.The formation of both types of product can be explained by the intermediacy of an O-nitro imidate.Spectroscopic and chemical evidence is presented for the formation of this intermediate in the reaction of N-(2,4,6-trisubstituted phenyl)benzimidoyl chlorides with AgNO3.Rearrangement of the O-nitro imidate is unimolecular and intramolecular.The rate of rearrangement is independent of the substituent in the C-aryl ring, but increases with the electon-withdrawing ability of the substituents in the N-aryl ring.A mechanism is proposed in which the imidoyl chloride reacts with AgNO3 to produce first a nitrilium ion which goes on to form an O-nitro imidate that subsequently rearranges via a homolytic cleavage of the O-NO2 bond.The ortho:para ratios of N-(nitroaryl)benzamides obtained in the present work indicate that O-nitro imidates are not responsible for the high 1/2ortho:para ratios sometimes observed in the nitration of anilides.N-Alkylbenzimidoyl chlorides react with AgNO3 to form the corresponding N-nitro- and N-nitrosobenzamides.The mechanism of formation of the N-alkyl-N-nitrobenzamide arises from a pathway analogous to that for N-aryl-N-nitrobenzamides, involving a nitrilium ion that gives rise to an O-nitro imidate.The evidence for the formation of the N-nitrosobenzamide points to an alternative reaction of the imidoyl chloride with AgNO3.One possible mechanism for this reaction is described.
- Iley, Jim,Carvalho, Emilia,Norberto, Fatima,Rosa, Eduarda
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p. 281 - 290
(2007/10/02)
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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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