Discovery of a Potent and Selective Hetero‐Bivalent AChE Inhibitor via Bioisosteric Replacement

Nicolotti, Orazio; Pisani, Leonardo; Catto, Marco; Leonetti, Francesco; Giangreco, Ilenia; Stefanachi, Angela; Carotti, Angelo

doi:10.1002/minf.201000126

Cited by 8 publications

(9 citation statements)

References 19 publications

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“…[30][31][32] We are currently working along such a research line and the results will be presented in due course. The purity of all the intermediates, checked by 1 H NMR and HPLC, was always better than 90%.…”

Section: Discussionmentioning

confidence: 99%

Discovery of new 7-substituted-4-imidazolylmethyl coumarins and 4′-substituted-2-imidazolyl acetophenones open analogues as potent and selective inhibitors of steroid-11β-hydroxylase

Stefanachi

Hanke

Pisani

et al. 2015

European Journal of Medicinal Chemistry

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ABSTRACT:Diseases triggered by an abnormally high level of cortisol (hypercortisolism), such as the Cushing's and metabolic syndromes, could be successfully tackled by inhibitors of CYP11B1, a steroidal cytochrome P450 enzyme that catalyzes the last hydroxylation step of the cortisol biosynthesis. Structural optimization of 7-(benzyloxy)-4-(1H-imidazol-1-ylmethyl)-2H-chromen-2-one 2, a selective aromatase inhibitor, afforded the 4-(1H-imidazol-1-ylmethyl)-7-{[3-(trifluoromethoxy)benzyl]oxy}-2H-chromen-2-one 7, with improved inhibitory potency at human CYP11B1 (IC 50 = 5nM) and an enhanced selectivity over human CYP11B2 (SIB = 25) compared to lead compound 2 (IC 50 = 72nM, SIB=4.0) and metyrapone (IC 50 = 15 nM, SIB= 4.8), a non-selective drug used in the therapy of the Cushing's syndrome. Structure-activity relationship studies allowed the design and optimization of a novel series of potent and selective compounds, that can be regarded as open analogues of 2H-chromen-2-one derivatives.Compound 23, 2-(1H-imidazol-1-yl)-1-(4-{[3(trifluoromethoxy)benzyl]oxy}phenyl) ethanone, was the most interesting inhibitor of the series displaying a high potency at CYP11B1 (IC 50 = 15 nM), increased selectivities over CYP11B2 (SIB= 33), CYP19 (SIB= 390) and CYP17 ( 5% inhibition at 2.5µM concentration).

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Section: Discussionmentioning

confidence: 99%

Discovery of new 7-substituted-4-imidazolylmethyl coumarins and 4′-substituted-2-imidazolyl acetophenones open analogues as potent and selective inhibitors of steroid-11β-hydroxylase

Stefanachi

Hanke

Pisani

et al. 2015

European Journal of Medicinal Chemistry

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“…Meta-substituted derivatives 25-27 21 The final structural modifications of lead compound 21 were aimed at reducing molecular lipophilicity while maintaining good inhibitory activities on the target enzymes. One approach aimed at the modulation of the pK b of the basic head, through the elongation of an arm of the linker that allowed a higher distance between the two electron withdrawing phenyl rings from the basic nitrogen, resulting in lower pK b and logD.…”

Section: Sars and Ssrs Of Meta-and Para-nn-dialkylaminomethyl-7-benzmentioning

confidence: 99%

“…In addition, 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Table 3, was prepared through bioisosteric replacement of the 2H-chromen-2-one with the 2-quinolone as successfully done in the past for a dual binding site AChE inhibitor. 21 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 B, eeAChE and esBChE, respectively) and no activity on rMAO-A (0% inhibition at 10 µΜ). As for compounds 11 and 24, also 37 showed a mixed-type inhibition mode ( Figure 3C), with a K i equal to 0.10 ± 0.01 µΜ.…”

Section: Sars and Ssrs Of Meta-and Para-nn-dialkylaminomethyl-7-benzmentioning

confidence: 99%

“…15 The availability of X-ray crystallographic coordinates of many AChE−inhibitor complexes has allowed the identification of key interactions for high ligand binding affinity 16 and has enabled the target-based design of potent and selective AChE inhibitors (AChEIs). In this context, potent AChE inhibition by coumarin derivatives, 17,18 homo-and heterobis-quaternary ammonium salts, 19,20 2-quinolones, 21 and other heterocyclic compounds 22−24 have been reported by our group.…”

Section: ■ Introductionmentioning

confidence: 99%

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Structure-Based Design and Optimization of Multitarget-Directed 2H-Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases

et al. 2015

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The multifactorial nature of Alzheimer's disease calls for the development of multitarget agents addressing key pathogenic processes. To this end, by following a docking-assisted hybridization strategy, a number of aminocoumarins were designed, prepared, and tested as monoamine oxidases (MAOs) and acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitors. Highly flexible N-benzyl-N-alkyloxy coumarins 2-12 showed good inhibitory activities at MAO-B, AChE, and BChE but low selectivity. More rigid inhibitors, bearing meta- and para-xylyl linkers, displayed good inhibitory activities and high MAO-B selectivity. Compounds 21, 24, 37, and 39, the last two featuring an improved hydrophilic/lipophilic balance, exhibited excellent activity profiles with nanomolar inhibitory potency toward hMAO-B, high hMAO-B over hMAO-A selectivity and submicromolar potency at hAChE. Cell-based assays of BBB permeation, neurotoxicity, and neuroprotection supported the potential of compound 37 as a BBB-permeant neuroprotective agent against H2O2-induced oxidative stress with poor interaction as P-gp substrate and very low cytotoxicity.

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“…In previous reports, we identified an edrophonium–coumarin conjugate endowed with outstanding potency in the picomolar range and studied the isosteric replacement of its heterocyclic core . In this work, we aimed to improve the drug‐like properties by means of removing toxicophore alerts and metabolic reactive groups, namely the aniline and the phenolic groups present in the edrophonium fragment.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Potent Dual Binding Site Acetylcholinesterase Inhibitors via Homo‐ and Heterodimerization of Coumarin‐Based Moieties

et al. 2017

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Acetylcholinesterase (AChE) inhibitors still comprise the majority of the marketed drugs for Alzheimer's disease (AD). The structural arrangement of the enzyme, which features a narrow gorge that separates the catalytic and peripheral anionic subsites (CAS and PAS, respectively), inspired the development of bivalent ligands that are able to bind and block the catalytic activity of the CAS as well as the role of the PAS in beta amyloid (Aβ) fibrillogenesis. With the aim of discovering novel AChE dual binders with improved drug-likeness, homo- and heterodimers containing 2H-chromen-2-one building blocks were developed. By exploring diverse linkages of neutral and protonatable amino moieties through aliphatic spacers of different length, a nanomolar bivalent AChE inhibitor was identified (3-[2-(4-[(dimethylamino)methyl]-2-oxo-2H-chromen-7-yloxy)ethoxy]-6,7-dimethoxy-2H-chromen-2-one (6 d), IC50 =59 nm) from originally weakly active fragments. To assess the potential against AD, the disease-related biological properties of 6 d were investigated. It performed mixed-type AChE enzyme kinetics (inhibition constant Ki =68 nm) and inhibited Aβ self-aggregation. Moreover, it displayed an outstanding ability to protect SH-SY5Y cells from Aβ1-42 damage

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Discovery of a Potent and Selective Hetero‐Bivalent AChE Inhibitor via Bioisosteric Replacement

Cited by 8 publications

References 19 publications

Discovery of new 7-substituted-4-imidazolylmethyl coumarins and 4′-substituted-2-imidazolyl acetophenones open analogues as potent and selective inhibitors of steroid-11β-hydroxylase

Discovery of new 7-substituted-4-imidazolylmethyl coumarins and 4′-substituted-2-imidazolyl acetophenones open analogues as potent and selective inhibitors of steroid-11β-hydroxylase

Structure-Based Design and Optimization of Multitarget-Directed 2H-Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases

Discovery of Potent Dual Binding Site Acetylcholinesterase Inhibitors via Homo‐ and Heterodimerization of Coumarin‐Based Moieties

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