Loesche A

References (14)

Title : Synthesis and cholinesterase inhibiting potential of A-ring azepano- and 3-amino-3,4-seco-triterpenoids - Kazakova_2020_Bioorg.Chem_101_104001
Author(s) : Kazakova O , Smirnova I , Lopatina T , Giniyatullina G , Petrova A , Khusnutdinova E , Csuk R , Serbian I , Loesche A
Ref : Bioorg Chem , 101 :104001 , 2020
Abstract : In this study, a series of A-ring azepano- and 3-amino-3,4-seco-derivatives were synthesized from betulin, oleanolic, ursolic and glycyrrhetinic acids aiming to develop new cholinesterase inhibitors. Azepanobetulin, azepanoerythrodiol and azepanouvaol were modified to give amide and tosyl derivatives, while azepano-anhydrobetulines and azepano-glycyrrhetols were obtained for the first time. Oleanane and ursane type 3-amino-3,4-seco-4(23)-en triterpenic alcohols were synthesized by reducing the corresponding 2-cyano-derivatives accessible from Beckmann type 2 rearrangements. The compounds were screened in colorimetric Ellman's assays to determine their ability to act as inhibitors for the enzymes acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum). While most of these compounds were only moderate inhibitors for AChE, several of them were shown to be inhibitors for BChE acting as mixed-type inhibitors. Azepanobetulin 1, its C28-amide derivatives 7 and 8, azepano-11-deoxo-glycyrrhetol 12 and azepanouvaol 18 held inhibition constants K(i) ranging between 0.21 +/- 0.06 to 0.68 +/- 0.19 muM. Thus, they were approximately 4 to 10 times more active than standard galantamine hydrobromide. For all of the compounds reasonably high docking scores for BChE were obtained being in good agreement with the experimental results from the enzymatic studies. As a result, A-ring azepano-triterpenoids were found to be new scaffolds for the development of BChE inhibitors.
ESTHER : Kazakova_2020_Bioorg.Chem_101_104001
PubMedSearch : Kazakova_2020_Bioorg.Chem_101_104001
PubMedID: 32683137

Title : 4-Benzyloxylonchocarpin and Muracatanes A-C from Ranunculus muricatus L. and Their Biological Effects - Hussain_2020_Biomolecules_10_
Author(s) : Hussain H , Ali I , Wang D , Mamadalieva NZ , Hussain W , Csuk R , Loesche A , Fischer L , Staerk D , Anam S , AlZain MN , Mushtaq M , Ul-Haq Z , Ullah R , Noman OM , Abbas G , Green IR
Ref : Biomolecules , 10 : , 2020
Abstract : Ranunculus muricatus L. is a spiny fruit buttercup that is used in various traditional medicinal systems. In the current investigation of R. muricatus, the new chalcone 4-benzyloxylonchocarpin (1), the new anthraquinone muracatanes A (2), the new-to-nature anthraquinone muracatanes B (3), and the new naphthalene analog muracatanes C (4) were isolated, in addition to the three previously reported compounds, 4-methoxylonchocarpin (5), beta-sitosterol (6), and beta-sitosterol beta-D-glucopyranoside (7). Their structures were elucidated using 1D ((1)H and (13)C) and 2D (COSY, HSQC, and HMBC) NMR spectroscopy and HR-ESI-MS. Chalcone 1 showed potent acetylcholinesterase inhibitory effects with K(i) of 5.39 microM and K(i') of 3.54 microM, but none of the isolated compounds showed inhibitory activity towards butyrylcholinesterase. Anthraquinone 3 illustrated alpha-glucosidase inhibitory effects with IC(50)-values of 164.46 +/- 83.04 microM. Compound 5 displayed moderate cytotoxic activity towards ovarian carcinoma (A2780, IC(50) = 25.4 microM), colorectal adenocarcinoma (HT29, IC(50) = 20.2 microM), breast cancer (MCF7, IC(50) = 23.7 microM), and thyroid carcinoma (SW1736, IC(50) = 26.2 microM) while it was inactive towards pharynx carcinoma (FaDu: IC(50) > 30 microM).
ESTHER : Hussain_2020_Biomolecules_10_
PubMedSearch : Hussain_2020_Biomolecules_10_
PubMedID: 33212893

Title : Caffeic acid phenethyl ester (CAPE)-derivatives act as selective inhibitors of acetylcholinesterase - Giessel_2019_Eur.J.Med.Chem_177_259
Author(s) : Giessel JM , Loesche A , Csuk R
Ref : Eur Journal of Medicinal Chemistry , 177 :259 , 2019
Abstract : Unexpected inhibitory effects against eeAChE could be found for a newly synthesized class of caffeic acid phenethyl ester (CAPE) derivatives. Thus, phenethyl-(E)-3-(3,5-dimethoxy-4-phenethoxyphenyl)-acrylate (Ki=1.97+/-0.38muM, Ki =2.44+/-0.07muM) and 4-(2-(((E)-3-(3,4-bis(benzyloxy)phenyl)acryloyl)oxy)ethyl)-1,2-phenylene (2E,2'E)-bis(3-(3,4-bis(benzyloxy)phenyl)acrylate) (Ki=0.72+/-0.31muM, Ki =1.80+/-0.21muM) showed very good inhibition of eeAChE, while being non cytotoxic for malignant human cancer cells and non-malignant mouse fibroblasts. Also, they are weak inhibitors for BChE (from equine serum).
ESTHER : Giessel_2019_Eur.J.Med.Chem_177_259
PubMedSearch : Giessel_2019_Eur.J.Med.Chem_177_259
PubMedID: 31158743

Title : Novel 12-hydroxydehydroabietylamine derivatives act as potent and selective butyrylcholinesterase inhibitors - Loesche_2019_Bioorg.Chem_90_103092
Author(s) : Loesche A , Wiemann J , Rohmer M , Brandt W , Csuk R
Ref : Bioorg Chem , 90 :103092 , 2019
Abstract : The skeleton of the diterpene dehydroabietylamine was modified, and a set of 12-hydroxy-dehydroabietylamine derivatives was obtained. The compounds were screened in colorimetric Ellman's assays to determine their ability to act as inhibitors for the enzymes acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum). Additional investigations concerning the enzyme kinetics were performed and showed 12-hydroxy-N-(4-nitro-benzoyl)dehydroabietylamine (13) and 12-hydroxy-N-(isonicotinoyl)dehydroabietylamine (17) as selective BChE inhibitors holding good inhibition constants Ki=0.72+/-0.06muM and Ki=0.86+/-0.19muM, respectively.
ESTHER : Loesche_2019_Bioorg.Chem_90_103092
PubMedSearch : Loesche_2019_Bioorg.Chem_90_103092
PubMedID: 31280014

Title : Triterpene-Based Carboxamides Act as Good Inhibitors of Butyrylcholinesterase - Loesche_2019_Molecules_24_
Author(s) : Loesche A , Kahnt M , Serbian I , Brandt W , Csuk R
Ref : Molecules , 24 : , 2019
Abstract : A set of overall 40 carboxamides was prepared from five different natural occurring triterpenoids including oleanolic, ursolic, maslinic, betulinic, and platanic acid. All of which were derived from ethylene diamine holding an additional substituent connected to the ethylene diamine group. These derivatives were evaluated regarding their inhibitory activity of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) employing Ellman's assay. We further determined the type of inhibition and inhibition constants. Carboxamides derived from platanic acid have been shown to be potent and selective BChE inhibitors. Especially the mixed-type inhibitor (3beta)-N-(2-pyrrolidin-1-ylethyl)-3-acetyloxy-20-oxo-30-norlupan-28-amide (35) showed a remarkably low Ki of 0.07 +/- 0.01 microM (Ki' = 2.38 +/- 0.48 microM) for the inhibition of BChE.
ESTHER : Loesche_2019_Molecules_24_
PubMedSearch : Loesche_2019_Molecules_24_
PubMedID: 30866589

Title : Synthesis and Biological Evaluation of Structurally Varied 5'-\/6'-Isonucleosides and Theobromine-Containing N-Isonucleosidyl Derivatives - Xavier_2019_Pharmaceuticals.(Basel)_12_
Author(s) : Xavier NM , De Sousa EC , Pereira MP , Loesche A , Serbian I , Csuk R , Oliveira MC
Ref : Pharmaceuticals (Basel) , 12 : , 2019
Abstract : Isonucleosides are rather stable regioisomeric analogs of nucleosides with broad therapeutic potential. We have previously demonstrated the ability of 5' and 6'-isonucleosides to inhibit the activity of acetylcholinesterase, a major target for Alzheimer's disease therapy. Continuing with our research on this topic, we report herein on the synthesis and biological evaluation of a variety of novel terminal isonucleosides and theobromine isonucleotide analogs. Xylofuranose-based purine or uracil 5'-isonucleosides and xylofuranos-5'-yl or glucos-6'-yl theobromine derivatives were accessed via Mitsunobu coupling between partially protected xylofuranose or glucofuranose derivatives with a nucleobase using conventional or microwave-assisted heating conditions. Theobromine-containing N-isonucleosidyl sulfonamide and phosphoramidate derivatives were synthesized from isonucleosidyl acetate precursors. The most active compounds in the cholinesterase inhibition assays were a glucopyranose-based theobromine isonucleosidyl acetate, acting as a dual inhibitor of acetylcholinesterase (AChE, Ki = 3.1 microM) and butyrylcholinesterase (BChE, Ki = 5.4 microM), and a 2-O,4-O-bis-xylofuranos-5'-yl uracil derivative, which displayed moderate inhibition of AChE (Ki = 17.5 microM). Docking studies revealed that the active molecules are positioned at the gorge entrance and at the active site of AChE. None of the compounds revealed cytoxic activity to cancer cells as well as to non-malignant mouse fibroblasts.
ESTHER : Xavier_2019_Pharmaceuticals.(Basel)_12_
PubMedSearch : Xavier_2019_Pharmaceuticals.(Basel)_12_
PubMedID: 31269639

Title : Substituted cinnamic anhydrides act as selective inhibitors of acetylcholinesterase - Giessel_2019_Bioorg.Chem_90_103058
Author(s) : Giessel JM , Serbian I , Loesche A , Csuk R
Ref : Bioorg Chem , 90 :103058 , 2019
Abstract : Cinnamic anhydrides have been shown to be more than reactive reagents, but they also act as inhibitors of the enzyme acetylcholinesterease (AChE). Thus, out of a set of 33 synthesised derivatives, several of them were mixed type inhibitors for AChE (from electric eel). Thus, (E)-3-(2,4-dimethoxyphenyl)acrylic anhydride (2c) showed Ki=8.30+/-0.94microM and Ki'=9.54+/-0.38microM, and for (E)-3-(3-chlorophenyl)acrylic anhydride (2u) Ki=8.23+/-0.93microM and Ki'=13.07+/-0.46microM were measured. While being not cytotoxic to many human cell lines, these compounds showed an unprecedented and noteworthy inhibitory effect for AChE but not for butyrylcholinesterase (BChE).
ESTHER : Giessel_2019_Bioorg.Chem_90_103058
PubMedSearch : Giessel_2019_Bioorg.Chem_90_103058
PubMedID: 31212181

Title : Unexpected AChE inhibitory activity of (2E)alpha,beta-unsaturated fatty acids - Loesche_2018_Bioorg.Med.Chem.Lett_28_3315
Author(s) : Loesche A , Wiemann J , Al Halabi Z , Karasch J , Sippl W , Csuk R
Ref : Bioorganic & Medicinal Chemistry Lett , 28 :3315 , 2018
Abstract : A small library of (E) alpha,beta-unsaturated fatty acids was prepared, and 20 different saturated and mono-unsaturated fatty acids differing in chain length were subjected to Ellman's assays to determine their ability to act as inhibitors for AChE or BChE. While the compounds were only very weak inhibitors of BChE, seven molecules were inhibitors of AChE holding IC50=4.3-12.8muM with three of them as significant inhibitors of this enzyme. The results have shown trans 2-mono-unsaturated fatty acids are better inhibitors for AChE than their saturated analogs. Furthermore, the screening results indicate that the chain length is crucial for obtaining an inhibitory efficacy. The best results were obtained for (2E) eicosenoic acid (14) showing inhibition constants Ki=1.51+/-0.09muM and Ki'=7.15+/-0.55muM. All tested compounds were mixed-type inhibitors with a dominating competitive part. Molecular modelling calculations indicate a different binding mode of active/inactive compounds for the enzymes AChE and BChE.
ESTHER : Loesche_2018_Bioorg.Med.Chem.Lett_28_3315
PubMedSearch : Loesche_2018_Bioorg.Med.Chem.Lett_28_3315
PubMedID: 30220607

Title : Ursolic and oleanolic acid derivatives with cholinesterase inhibiting potential - Loesche_2018_Bioorg.Chem_85_23
Author(s) : Loesche A , Kowitsch A , Lucas SD , Al-Halabi Z , Sippl W , Al-Harrasi A , Csuk R
Ref : Bioorg Chem , 85 :23 , 2018
Abstract : Triterpenoids are in the focus of scientific interest, and they were evaluated for many pharmacological applications among them their ability to act as inhibitors of cholinesterases. These inhibitors are still of interest as drugs that improve the life quality of patients suffering from age-related dementia illnesses especially of Alzheimer's disease. Herein, we prepared several derivatives of ursolic and oleanolic acid and screened them in Ellman's assays for their ability to inhibit acetylcholinesterase and/or butyrylcholinesterase, and for each of the active compounds the type of inhibition was determined. As a result, several compounds were shown as good inhibitors for acetylcholinesterase and butyrylcholinesterase even in a micromolar range. An ursolic acid derived hydroxyl-propinyl derivative 10 was a competitive inhibitor for butyrylcholinesterase with an inhibition constant of Ki=4.29muM, and therefore being twice as active as gold standard galantamine hydrobromide. The best inhibitor for acetylcholinesterase, however, was 2-methyl-3-oxo-methyl-ursoloate (18), acting as a mixed-type inhibitor showing Ki=1.72microM and Ki'=1.28muM, respectively.
ESTHER : Loesche_2018_Bioorg.Chem_85_23
PubMedSearch : Loesche_2018_Bioorg.Chem_85_23
PubMedID: 30599410

Title : Piperlongumine B and analogs are promising and selective inhibitors for acetylcholinesterase - Wiemann_2017_Eur.J.Med.Chem_139_222
Author(s) : Wiemann J , Karasch J , Loesche A , Heller L , Brandt W , Csuk R
Ref : Eur Journal of Medicinal Chemistry , 139 :222 , 2017
Abstract : Piperlongumine B (19), an alkaloid previously isolated from long pepper (Piper longum) has been synthesized for the first time in a short sequence and in good yield together with 19 analogs. Screening of these compounds in Ellman's assays showed several of them to be good inhibitors of acetylcholinesterase while being less active for butyrylcholinesterase. Activity of the compounds increased with the ring size of the heterocycle, and a maximum of activity was observed for an analog holding 12 methylene groups in the aliphatic side chain. These compounds may be regarded as promising candidates for the development of efficient inhibitors of acetylcholinesterase being useful for the treatment of Alzheimer's disease.
ESTHER : Wiemann_2017_Eur.J.Med.Chem_139_222
PubMedSearch : Wiemann_2017_Eur.J.Med.Chem_139_222
PubMedID: 28802122

Title : Novel dehydroabietylamine derivatives as potent inhibitors of acetylcholinesterase - Wiemann_2017_Bioorg.Chem_74_145
Author(s) : Wiemann J , Loesche A , Csuk R
Ref : Bioorg Chem , 74 :145 , 2017
Abstract : Nowadays, the inhibition of acetylcholinesterase is one of the main pharmacological strategies for the treatment of Alzheimer's disease. Therefore, a set of thirty-four derivatives of the diterpenoid dehydroabietylamine has been synthesized and screened in colorimetric Ellman's assays to determine their ability to inhibit the enzymes acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum). A systematic variation of the substitution of dehydroabietylamides enabled an approach to analogs showing a remarkable inhibition potency for AChE. Particularly N-benzoyldehydroabietylamines 11, 12 and 13 were excellent inhibitors for AChE, showing inhibition rates comparable to standard galantamine hydrobromide.
ESTHER : Wiemann_2017_Bioorg.Chem_74_145
PubMedSearch : Wiemann_2017_Bioorg.Chem_74_145
PubMedID: 28797788

Title : Amino derivatives of platanic acid act as selective and potent inhibitors of butyrylcholinesterase - Heller_2016_Eur.J.Med.Chem_126_652
Author(s) : Heller L , Kahnt M , Loesche A , Grabandt P , Schwarz S , Brandt W , Csuk R
Ref : Eur Journal of Medicinal Chemistry , 126 :652 , 2016
Abstract : A set of thirtyfive 30-norlupan derivatives (2-36) was prepared from the natural triterpenoid platanic acid (PA), and the hydroxyl group at C-3, the carboxyl group at C-17 and the carbonyl group at C-20 were modified. These derivatives were tested for their inhibitory activity for the enzymes acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum) using Ellman's assay. Extra enzyme kinetic studies were performed. The most active compound was (3beta, 20R)-3-acetyloxy-20-amino-30-norlupan-28-oate (32) showing a Ki value of 0.01 +/- 0.003 muM for BChE. This compound proved to be a selective (FB = 851), mixed-type inhibitor for BChE.
ESTHER : Heller_2016_Eur.J.Med.Chem_126_652
PubMedSearch : Heller_2016_Eur.J.Med.Chem_126_652
PubMedID: 27936444

Title : Repurposing N,N'-bis-(arylamidino)-1,4-piperazinedicarboxamidines: An unexpected class of potent inhibitors of cholinesterases - Loesche_2016_Eur.J.Med.Chem_125_430
Author(s) : Loesche A , Wiese J , Sommerwerk S , Simon V , Brandt W , Csuk R
Ref : Eur Journal of Medicinal Chemistry , 125 :430 , 2016
Abstract : Drug repurposing (=drug repositioning) is an effective way to cut costs for the development of new therapeutics and to reduce the time-to-market time-span. Following this concept a small library of compounds was screened for their ability to act as inhibitors of acetyl- and butyrylcholinesterase. Picloxydine, an established antiseptic, was shown to be an inhibitor for both enzymes. Systematic variation of the aryl substituents led to analogs possessing almost the same good properties as gold standard galantamine hydrobromide.
ESTHER : Loesche_2016_Eur.J.Med.Chem_125_430
PubMedSearch : Loesche_2016_Eur.J.Med.Chem_125_430
PubMedID: 27689726

Title : Converting maslinic acid into an effective inhibitor of acylcholinesterases - Schwarz_2015_Eur.J.Med.Chem_103_438
Author(s) : Schwarz S , Loesche A , Lucas SD , Sommerwerk S , Serbian I , Siewert B , Pianowski E , Csuk R
Ref : Eur Journal of Medicinal Chemistry , 103 :438 , 2015
Abstract : During the last decade, maslinic acid has been evaluated for many biological properties, e.g. as an anti-tumor or an anti-viral agent but also as a nutraceutical. The potential of maslinic acid and related derivatives to act as inhibitors of acetyl- or butyryl-cholinesterase was examined in this communication in more detail. Cholinesterases do still represent an interesting group of target enzymes with respect to the investigation and treatment of the Alzheimer's disease and other dementia illnesses as well. Although other triterpenoic acids have successfully been tested for their ability to act as inhibitors of cholinesterases, up to now maslinic acid has not been part of such studies. For this reason, three series of maslinic acid derivatives possessing modifications at different centers were synthesized and subjected to Ellman's assay to determine their inhibitory strength and type of inhibitory action. While parent compound maslinic acid was no inhibitor in these assays, some of the compounds exhibited an inhibition of acetylcholinesterase in the single-digit micro-molar range. Two compounds were identified as inhibitors of butyrylcholinesterase showing inhibition constants comparable to those of galantamine, a drug often used in the treatment of Alzheimer's disease. Furthermore, additional selectivity as well as cytotoxicity studies were performed underlining the potential of several derivatives and qualifying them for further investigations. Docking studies revealed that the different kinetic behavior within the same compound series may be explained by the ability of the compounds to enter the active site gorge of AChE.
ESTHER : Schwarz_2015_Eur.J.Med.Chem_103_438
PubMedSearch : Schwarz_2015_Eur.J.Med.Chem_103_438
PubMedID: 26383128