New N,N-dimethylcarbamate inhibitors of acetylcholinesterase: design synthesis and biological evaluation.
A series of N,N-dimethylcarbamates containing a N,N-dibenzylamino moiety was synthesized and tested to evaluate their ability to inhibit Acetylcholinesterase (AChE). The most active compounds 4 and 8, showed 85 and 69% of inhibition at 50 μM, respectively. Furthermore, some basic SAR rules were outlined: an alkyl linker of six methylene units is the best spacer between the carbamoyl and dibenzylamino moieties; electron-withdrawal substituents on aromatics rings of the dibenzylamino group reduce the inhibitory power. Compound 4 produces a slow onset inhibition of AChE and this is not due to the carbamoylation of the enzyme, as demonstrated by the time-dependent inhibition assay of AChE with compound 4 and by MALDI-TOF MS analysis of trypsinized AChE inhibited by compound 4. Instead, compound 4 could act as a slow-binding inhibitor of AChE, probably because of its high conformational freedom due to the linear alkyl chain.
a Department Chimica e Tecnologie del Farmaco , Sapienza University of Rome , Rome , Italy.
Daniela
D
De Vita
a Department Chimica e Tecnologie del Farmaco , Sapienza University of Rome , Rome , Italy.
Fabiana
F
Pandolfi
b Department Scienze di Base e Applicate per l'Ingegneria , Sapienza University of Rome , Rome , Italy , and.
Luigi
L
Ornano
b Department Scienze di Base e Applicate per l'Ingegneria , Sapienza University of Rome , Rome , Italy , and.
Marta
M
Feroci
b Department Scienze di Base e Applicate per l'Ingegneria , Sapienza University of Rome , Rome , Italy , and.
Isabella
I
Chiarotto
b Department Scienze di Base e Applicate per l'Ingegneria , Sapienza University of Rome , Rome , Italy , and.
Ilaria
I
Sileno
a Department Chimica e Tecnologie del Farmaco , Sapienza University of Rome , Rome , Italy.
Federico
F
Pepi
a Department Chimica e Tecnologie del Farmaco , Sapienza University of Rome , Rome , Italy.|c Istituto Pasteur-Fondazione Cenci Bolognetti, Department Chimica e Tecnologie del Farmaco, Sapienza University of Rome , Rome , Italy.
Roberta
R
Costi
a Department Chimica e Tecnologie del Farmaco , Sapienza University of Rome , Rome , Italy.|c Istituto Pasteur-Fondazione Cenci Bolognetti, Department Chimica e Tecnologie del Farmaco, Sapienza University of Rome , Rome , Italy.
Roberto
R
Di Santo
a Department Chimica e Tecnologie del Farmaco , Sapienza University of Rome , Rome , Italy.
Luigi
L
Scipione
D000110:Acetylcholinesterase / Q000378:metabolism*; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D013058:Mass Spectrometry; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D002219:Carbamates; D002800:Cholinesterase Inhibitors; C000614257:N,N-dimethylcarbamate; D000110:Acetylcholinesterase
Acetylcholinesterase inhibitors; MALDI-TOF-MS; carbamate