- Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease
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The design, synthesis, and pharmacological evaluation of donepezil-indolyl based amines 7-10, amides 12-16, and carboxylic acid derivatives 5 and 11, as multipotent ASS234 analogs, able to inhibit simultaneously cholinesterase (ChE) and monoamine oxidase (MAO) enzymes for the potential treatment of Alzheimer's disease (AD), is reported. Theoretical studies using 3D-Quantitative Structure-Activity Relationship (3D-QSAR) was used to define 3D-pharmacophores for inhibition of MAO A/B, AChE, and BuChE enzymes. We found that, in general, and for the same substituent, amines are more potent ChE inhibitors (see compounds 12, 13versus7 and 8) or equipotent (see compounds 14, 15versus9 and 10) than the corresponding amides, showing a clear EeAChE inhibition selectivity. For the MAO inhibition, amides were not active, and among the amines, compound 14 was totally MAO A selective, while amines 15 and 16 were quite MAO A selective. Carboxylic acid derivatives 5 and 11 showed a multipotent moderate selective profile as EeACE and MAO A inhibitors. Propargylamine 15 [N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl) prop-2-yn-1-amine] resulted in the most potent hMAO A (IC50 = 5.5 ± 1.4 nM) and moderately potent hMAO B (IC50 = 150 ± 31 nM), EeAChE (IC50 = 190 ± 10 nM), and eqBuChE (IC 50 = 830 ± 160 nM) inhibitor. However, the analogous N-allyl and the N-morpholine derivatives 16 and 14 deserve also attention as they show an attractive multipotent profile. To sum up, donepezil-indolyl hybrid 15 is a promising drug for further development for the potential prevention and treatment of AD.
- Bautista-Aguilera, Oscar M.,Esteban, Gerard,Bolea, Irene,Nikolic, Katarina,Agbaba, Danica,Moraleda, Ignacio,Iriepa, Isabel,Samadi, Abdelouahid,Soriano, Elena,Unzeta, Mercedes,Marco-Contelles, José
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- From far west to east: Joining the molecular architecture of imidazole-like ligands in ho-1 complexes
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HO-1 overexpression has been reported in several cases/types of human malignancies. Unfortunately, poor clinical outcomes are reported in most of these cases, and the inhibition of HO-1 is considered a valuable and proven anticancer approach. To identify
- Fallica, Antonino Nicolò,Floresta, Giuseppe,Greish, Khaled,Patamia, Vincenzo,Pittalà, Valeria,Rescifina, Antonio,Sorrenti, Valeria
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- Benzo-fused heterocyclic compounds having a 5-membered ring processes for their preparation their use as medicaments their use as diagnostic agents and medicaments containing them
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Benzo-fused heterocyclic compounds having a 5-membered ring, processes for their preperation, their use as medicaments, their use as diagnostic agents and medicaments containing them. Benzo-fused heterocyclic compounds having a 5-membered ring, of the formula I STR1 where X is N or CR(6); Y is oxygen, S or NR(7); A and B together are a bond or are both hydrogen, if, at the same time, X is CR(6) and Y is NR(7), one of the substituents R(1) to R(6) is a --CO--N=C(NH2)2 group; the other respective substituents R(1) to R(6) are H, Hal or alkyl; up to two of the other substituents R(1) to R(6) are CN, NO2, N3, (C1 -C4)-alkoxy, CF3 ; up to one of the other substituents is R(8)--Cn H2n --Z-- or phenyl; R(7) is H, alk(en)yl or R(8)--Cn H2n --, and pharmaceutically tolerated salts there of, are described. A process f or the preparation of the compounds I which comprises reacting a compound of the formula II STR2 in which one of the substituents R(1)' to R(5)' is a --CO--L group and L is a leaving group which can easily be replaced nucleophilically, with guanidine, and, if appropriate, converting the product into the pharmacologically tolerated salt, furthermore is also described.
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- Novel indole-2-carboxamide and cycloalkeno[1,2-b]indole derivatives. Structure-activity relationships for high inhibition of human LDL peroxidation
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Series of indole-2-carboxamide and cycloalkeno[1,2-b]indole derivatives were synthesized and evaluated in order to determine the necessary structural requirements for a high inhibition of human LDL copper-induced peroxidation. Various modulations were sys
- Kuehm-Caubere, Catherine,Caubere, Paul,Jamart-Gregoire, Brigitte,Negre-Salvayre, Anne,Bonnefont-Rousselot, Dominique,Bizot-Espiard, Jean-Guy,Pfeiffer, Bruno,Caignard, Daniel-Henri,Guardiola-Lemaitre, Béatrice,Renard, Pierre
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p. 1201 - 1210
(2007/10/03)
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- Acetylenic and allenic derivatives of 2-(5-methoxyindolyl)methylamine: synthesis and evaluation as selective inhibitors of the monoamine oxidases A and B
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A series of acetylenic and allenic derivatives of 2-(5-methoxyindolyl)methylamine has been synthesized.The new compounds were studied as inhibitors of the A and B forms of the mitochondrial monoamine oxidase (MAO) from bovine brain, using (14)C-tyramine as the substrate and clorgyline and l-deprenyl as references.All the studied compounds were MAO inhibitors.However, these compounds either did not show selectivity (compounds 3a-3d, 4c, 4e, 4m and 4o) or they were selective for MAO-A (compounds 4a, 4b, 4d, 4f-4l, 4n and 4p).Some of the compounds showed a similar inhibitory potency for MAO-A and lower for MAO-B than clorgyline and the higher selectivity for MAO-A was about 2.5 times that of clorgyline.Selectivity was shown only by acetylenic and allenic potent inhibitors, but no simple relationship between inhibitory potency and selectivity was found.
- Cruces, M. A.,Elorriaga, C.,Fernandez-Alvarez, E.,Lopez, O. Nieto
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p. 257 - 265
(2007/10/02)
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