2-Hydroxy-<i>N</i>-phenylbenzamides and Their Esters Inhibit Acetylcholinesterase and Butyrylcholinesterase
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-<i>N</i>-phenylbenzamides (salicylanilides) with various substitution patterns an...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2019-11-01
|
| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/9/11/698 |
| _version_ | 1811290715344338944 |
|---|---|
| author | Martin Krátký Šárka Štěpánková Neto-Honorius Houngbedji Rudolf Vosátka Katarína Vorčáková Jarmila Vinšová |
| author_facet | Martin Krátký Šárka Štěpánková Neto-Honorius Houngbedji Rudolf Vosátka Katarína Vorčáková Jarmila Vinšová |
| author_sort | Martin Krátký |
| collection | DOAJ |
| description | 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-<i>N</i>-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 IC<sub>50</sub> values in a narrow concentration range from 33.1 to 85.8 µM. IC<sub>50</sub> values for BuChE were higher (53.5−228.4 µM). 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 <b>5c</b> superiority (IC<sub>50</sub> = 2.4 µM). 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-<i>N</i>-phenylbenzamides and esters share convenient physicochemical properties for blood-brain-barrier penetration and thus central nervous system delivery. |
| first_indexed | 2024-04-13T04:17:37Z |
| format | Article |
| id | doaj.art-827e22d74bb147fc85350ec30870a88a |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-04-13T04:17:37Z |
| publishDate | 2019-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-827e22d74bb147fc85350ec30870a88a2022-12-22T03:02:56ZengMDPI AGBiomolecules2218-273X2019-11-0191169810.3390/biom9110698biom91106982-Hydroxy-<i>N</i>-phenylbenzamides and Their Esters Inhibit Acetylcholinesterase and ButyrylcholinesteraseMartin Krátký0Šárka Štěpánková1Neto-Honorius Houngbedji2Rudolf Vosátka3Katarína Vorčáková4Jarmila Vinšová5Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech RepublicDepartment of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech RepublicDepartment of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech RepublicDepartment of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech RepublicDepartment of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech RepublicDepartment of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech RepublicThe development of novel inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) represents a viable approach to alleviate Alzheimer’s disease. Thirty-six halogenated 2-hydroxy-<i>N</i>-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 IC<sub>50</sub> values in a narrow concentration range from 33.1 to 85.8 µM. IC<sub>50</sub> values for BuChE were higher (53.5−228.4 µM). 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 <b>5c</b> superiority (IC<sub>50</sub> = 2.4 µM). 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-<i>N</i>-phenylbenzamides and esters share convenient physicochemical properties for blood-brain-barrier penetration and thus central nervous system delivery.https://www.mdpi.com/2218-273X/9/11/698acetylcholinesterasebenzamidesbutyrylcholinesteraseenzyme inhibitionestersin vitro inhibitionphosphorus derivativessalicylanilides |
| spellingShingle | Martin Krátký Šárka Štěpánková Neto-Honorius Houngbedji Rudolf Vosátka Katarína Vorčáková Jarmila Vinšová 2-Hydroxy-<i>N</i>-phenylbenzamides and Their Esters Inhibit Acetylcholinesterase and Butyrylcholinesterase Biomolecules acetylcholinesterase benzamides butyrylcholinesterase enzyme inhibition esters in vitro inhibition phosphorus derivatives salicylanilides |
| title | 2-Hydroxy-<i>N</i>-phenylbenzamides and Their Esters Inhibit Acetylcholinesterase and Butyrylcholinesterase |
| title_full | 2-Hydroxy-<i>N</i>-phenylbenzamides and Their Esters Inhibit Acetylcholinesterase and Butyrylcholinesterase |
| title_fullStr | 2-Hydroxy-<i>N</i>-phenylbenzamides and Their Esters Inhibit Acetylcholinesterase and Butyrylcholinesterase |
| title_full_unstemmed | 2-Hydroxy-<i>N</i>-phenylbenzamides and Their Esters Inhibit Acetylcholinesterase and Butyrylcholinesterase |
| title_short | 2-Hydroxy-<i>N</i>-phenylbenzamides and Their Esters Inhibit Acetylcholinesterase and Butyrylcholinesterase |
| title_sort | 2 hydroxy i n i phenylbenzamides and their esters inhibit acetylcholinesterase and butyrylcholinesterase |
| topic | acetylcholinesterase benzamides butyrylcholinesterase enzyme inhibition esters in vitro inhibition phosphorus derivatives salicylanilides |
| url | https://www.mdpi.com/2218-273X/9/11/698 |
| work_keys_str_mv | AT martinkratky 2hydroxyiniphenylbenzamidesandtheirestersinhibitacetylcholinesteraseandbutyrylcholinesterase AT sarkastepankova 2hydroxyiniphenylbenzamidesandtheirestersinhibitacetylcholinesteraseandbutyrylcholinesterase AT netohonoriushoungbedji 2hydroxyiniphenylbenzamidesandtheirestersinhibitacetylcholinesteraseandbutyrylcholinesterase AT rudolfvosatka 2hydroxyiniphenylbenzamidesandtheirestersinhibitacetylcholinesteraseandbutyrylcholinesterase AT katarinavorcakova 2hydroxyiniphenylbenzamidesandtheirestersinhibitacetylcholinesteraseandbutyrylcholinesterase AT jarmilavinsova 2hydroxyiniphenylbenzamidesandtheirestersinhibitacetylcholinesteraseandbutyrylcholinesterase |