Synthesis and evaluation of potential cholinesterases inhibitors

Charles University, Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Author: Neto-Honorius Houngbedji Supervisor: PharmDr. Mgr. Martin Krátký, Ph.D. Title of diploma thesis: Synthesis and evaluation of potential inhibitors of cholinesterases During the last years, the number of patients affected by Alzheimer's disease has been constantly increasing. This disease, which burdens the patients as well as their milieu, requires a costly treatment, based on the use of acetylcholinesterase inhibitors currently. The theoretical part summarizes the contemporary knowledge about the pathology, epidemiology and therapy of Alzheimer's disease. This part also presents the results of previous research of salicylanilide-based cholinesterase inhibitors. The use of acetylcholinesterase inhibitors in the treatment of Alzheimer's disease led to the design of eight novel compounds (esters of salicylanilides and phosphorus acids) with inhibitory activity against cholinesterases. Thus, the experimental part of this diploma thesis consists in the synthesis, characterization and biological evaluation of the novel inhibitors. Finally, three new compounds were synthesized and evaluated successfully. Their inhibitory activities (IC50) were within the range of 48.13-66.13 µM against..

Synthesis and evaluation of potential cholinesterases inhibitors

Univerzita Karlova, Farmaceutická fakulta v Hradci Králové Katedra organické a bioorganické chemie Řešitel práce: Neto-Honorius Houngbedji Vedoucí práce: PharmDr. Mgr. Martin Krátký, Ph.D. Název diplomové práce: Syntéza a hodnocení potenciálních inhibitorů cholinesteráz Počet pacientů trpících Alzheimerovou chorobou v posledních letech neustále narůstá. Tato choroba, zatěžující jak pacienta, tak jeho okolí, vyžaduje nákladnou léčbu, která t.č. spočívá především v používání inhibitorů acetylcholinesterázy. Teoretická část práce shrnuje aktuální poznatky o patologii, epidemiologii a terapii Alzheimerovy choroby. Prezentuje také výsledky předešlého výzkumu v oblasti salicylanilidových inhibitorů cholinesteráz. Používání inhibitorů acetylcholinesterázy v terapii Alzheimerovy choroby vedlo k navržení osmi nových látek na bázi esterů kyselin fosforu a salicylanilidů s inhibiční aktivitou vůči cholinesterázám. Náplň praktické části diplomové práce tak spočívá v syntéze, charakterizaci a biologickém hodnocení nových inhibitorů cholinesteráz. Ve výsledku se podařilo syntetizovat a vyhodnotit tři nové sloučeniny, jejichž inhibiční aktivita (IC50) se pohybovala v rozmezí 48,13-66,13 µM vůči acetylcholinesteráze a 2,37-170,10 µM vůči butyrylcholinesteráze. U nejaktivnějšího inhibitoru...Charles University, Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Author: Neto-Honorius Houngbedji Supervisor: PharmDr. Mgr. Martin Krátký, Ph.D. Title of diploma thesis: Synthesis and evaluation of potential inhibitors of cholinesterases During the last years, the number of patients affected by Alzheimer's disease has been constantly increasing. This disease, which burdens the patients as well as their milieu, requires a costly treatment, based on the use of acetylcholinesterase inhibitors currently. The theoretical part summarizes the contemporary knowledge about the pathology, epidemiology and therapy of Alzheimer's disease. This part also presents the results of previous research of salicylanilide-based cholinesterase inhibitors. The use of acetylcholinesterase inhibitors in the treatment of Alzheimer's disease led to the design of eight novel compounds (esters of salicylanilides and phosphorus acids) with inhibitory activity against cholinesterases. Thus, the experimental part of this diploma thesis consists in the synthesis, characterization and biological evaluation of the novel inhibitors. Finally, three new compounds were synthesized and evaluated successfully. Their inhibitory activities (IC50) were within the range of 48.13-66.13 µM against...Katedra organické a bioorganické chemieDepartment of Organic And Bioorganic ChemistryFarmaceutická fakulta v Hradci KrálovéFaculty of Pharmacy in Hradec Králov

Synthesis and evaluation of potential cholinesterases inhibitors

Charles University, Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Author: Neto-Honorius Houngbedji Supervisor: PharmDr. Mgr. Martin Krátký, Ph.D. Title of diploma thesis: Synthesis and evaluation of potential inhibitors of cholinesterases During the last years, the number of patients affected by Alzheimer's disease has been constantly increasing. This disease, which burdens the patients as well as their milieu, requires a costly treatment, based on the use of acetylcholinesterase inhibitors currently. The theoretical part summarizes the contemporary knowledge about the pathology, epidemiology and therapy of Alzheimer's disease. This part also presents the results of previous research of salicylanilide-based cholinesterase inhibitors. The use of acetylcholinesterase inhibitors in the treatment of Alzheimer's disease led to the design of eight novel compounds (esters of salicylanilides and phosphorus acids) with inhibitory activity against cholinesterases. Thus, the experimental part of this diploma thesis consists in the synthesis, characterization and biological evaluation of the novel inhibitors. Finally, three new compounds were synthesized and evaluated successfully. Their inhibitory activities (IC50) were within the range of 48.13-66.13 µM against..

2-Hydroxy-N-fenylbenzamidy a jejich estery inhibují acetylcholinesterázu a butyrylcholinesterázu

The development of novel inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) represents a viable approach to alleviate Alzheimer's disease. Thirty-six halogenated 2-hydroxy-N-phenylbenzamides (salicylanilides) with various substitution patterns and their esters with phosphorus-based acids were synthesized in yields of 72% to 92% and characterized. They were evaluated for in vitro inhibition of AChE from electric eel and BuChE from equine serum using modified Ellman's spectrophotometric method. The benzamides exhibited a moderate inhibition of AChE with IC50 values in a narrow concentration range from 33.1 to 85.8 mu M. IC50 values for BuChE were higher (53.5-228.4 mu M). The majority of derivatives inhibit AChE more efficiently than BuChE and are comparable or superior to rivastigmine-an established cholinesterases inhibitor used in the treatment of Alzheimer's disease. Phosphorus-based esters especially improved the activity against BuChE with 5-chloro-2-{[4-(trifluoromethyl)phenyl]carbamoyl}phenyl diethyl phosphite 5c superiority (IC50 = 2.4 mu M). This derivative was also the most selective inhibitor of BuChE. It caused a mixed inhibition of both cholinesterases and acted as a pseudo-irreversible inhibitor. Several structure-activity relationships were identified, e.g., favouring esters and benzamides obtained from 5-halogenosalicylic acids and polyhalogenated anilines. Both 2-hydroxy-N-phenylbenzamides and esters share convenient physicochemical properties for blood-brain-barrier penetration and thus central nervous system delivery.ých inhibitorů acetylcholinesterázy (AChE) a butyrylcholinesterázy (BuChE) představuje životaschopný přístup ke zmírnění Alzheimerovy choroby. Třicet šest halogenovaných 2-hydroxy-N-fenylbenzamidů (salicylanilidů) s různými substitučními vzory a jejich estery s kyselinami na bázi fosforu bylo syntetizováno ve výtěžcích 72% až 92% a charakterizováno. Byly hodnoceny in vitro inhibice AChE z elektrického úhoře a BuChE z koňského séra pomocí modifikované Ellmanovy spektrofotometrické metody. Benzamidy vykazovaly mírnou inhibici AChE s hodnotami IC50 v úzkém koncentračním rozmezí od 33,1 do 85,8 mu M. Hodnoty IC50 pro BuChE byly vyšší (53,5 až 228,4 uM). Většina derivátů inhibuje AChE účinněji než BuChE a je srovnatelná nebo lepší než rivastigmin-zavedený inhibitor cholinesteráz používaný při léčbě Alzheimerovy choroby. Estery na bázi fosforu zvláště zlepšily aktivitu proti BuChE s 5-chlor-2 - {[4- (trifluormethyl) fenyl] karbamoyl} fenyl diethylfosfitem 5c (IC50 = 2,4 um M). Tento derivát byl také nejelektivnějším inhibitorem BuChE. Způsobil smíšenou inhibici obou cholinesteráz a působil jako pseudo-ireverzibilní inhibitor. Bylo identifikováno několik vztahů mezi strukturou a aktivitou, např. Zvýhodněné estery a benzamidy získané z 5-halogenenosalicylových kyselin a polyhalogenovaných anilinů. Jak 2-hydroxy-N-fenylbenzamidy, tak estery sdílejí vhodné fyzikálně-chemické vlastnosti pro pronikání hematoencefalickou bariérou, a tím dodávku centrálního nervového systému

Novel Inhibitors of Acetyl- and Butyrylcholinesterase Derived from Benzohydrazides: Synthesis, Evaluation and Docking Study

On the basis of previous reports, novel 2-benzoylhydrazine-1-carboxamides were designed as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Inhibitors of these enzymes have many clinical applications. 2-(Substituted benzoyl)hydrazine-1-carboxamides decorated with N-methyl or tridecyl were prepared with three methods from commercially available or self-prepared hydrazides and isocyanates. For methyl derivatives, N-succinimidyl N-methylcarbamate was used or methyl isocyanate was prepared via Curtius rearrangement. Tridecyl isocyanate was synthesized again via Curtius rearrangement or from triphosgene and tridecylamine. The compounds were evaluated for the inhibition of AChE and BChE using Ellman’s spectrophotometric method. Most of the derivatives showed the dual inhibition of both enzymes with IC50 values of 44–100 µM for AChE and from 22 µM for BChE. In general, the carboxamides inhibited AChE more strongly. A large number of the compounds showed better or quite comparable inhibition of cholinesterases in vitro than that of the drug rivastigmine. Molecular docking was performed to investigate the possible conformation of the compounds and their interactions with target enzymes. In both AChE and BChE, the compounds occupied the enzyme active cavity, and, especially in the case of BChE, the compounds were placed in close proximity to the catalytic triad