Novel Carbamates as Orally Active Acetylcholinesterase Inhibitors Found to Improve Scopolamine-Induced Cognition Impairment: Pharmacophore-Based Virtual Screening, Synthesis, and Pharmacology

Abstract

A systematic virtual screening (VS) experiment, consisting of the development of 3D-pharmacophore, screening of virtual library, synthesis, and pharmacology, is reported. The predictive pharmacophore model (correlation = 0.955) with one H-bond donor and three hydrophobic features was developed using HypoGen on a training set of 24 carbamates as AChE inhibitors. The model was validated on a test set of 40 carbamates (correlation = 0.844). The pharmacophore-based VS of virtual library led to the identification of novel carbamates as potent AChE inhibitors. The synthesis and pharmacological evaluation of nine carbamates against three diverse assay systems, namely (i) in vitro Ellman method, (ii) in vivo passive avoidance test, and (iii) aldicarb-sensitivity assay, led to the discovery of orally active novel AChE inhibitors which improved scopolamine-induce cognition impairment in Swiss male mice. Finally, two novel lead compounds 85 and 86 are selected as candidate molecules for further optimization.

Cyclic acyl guanidines bearing carbamate moieties allow potent and dirigible cholinesterase inhibition of either acetyl- or butyrylcholinesterase

“…SARs of carbamates have been investigated before 41,42 and could be to some degree confirmed on quinazoline compounds. 17,41,42 Heptyl carbamates lead to BChE selectivity and 4-isopropylphenyl carbamates can increase selectivity in the opposite direction.…”

“…17,41,42 Heptyl carbamates lead to BChE selectivity and 4-isopropylphenyl carbamates can increase selectivity in the opposite direction. 17,41,42 Interestingly, the two isomeric sets of carbamates (14-17 and 29-33) (Scheme 1A and B) show different biological profiles.…”

“…17,41,42 Heptyl carbamates lead to BChE selectivity and 4-isopropylphenyl carbamates can increase selectivity in the opposite direction. 17,41,42 Interestingly, the two isomeric sets of carbamates (14-17 and 29-33) (Scheme 1A and B) show different biological profiles. N-1 Methyl substituted compounds (14)(15)(16)(17) show moderate inhibitory activities at both enzymes ranging from one to two digit micromolar activities without significant selectivity.…”

“…This increase in both activity at BChE and selectivity over AChE, is common for the heptyl carbamate and has been previously described for several related heterocycles. 17,41,42 To increase the basicity of the heterocyclic template, reduced analogs of compounds 14, 15 (butyl and heptyl carbamates of N-1 methylated tricycle) were synthesized via carbonyl reduction to yield compounds 36 and 37 (Scheme 2 and Table 1). N-Unsubstituted 4-isopropylphenyl carbamate 39 loses the potency at both enzymes with only 34% inhibitory activity of AChE at 50 lM and 19% inhibitory activity of BChE at 50 lM.…”

Rearrangement Reactions for the Synthesis of Some Oxa- and Aza-tricyclic Rings Heterocyclic Compounds

“…Physostigmine (eserine) and its phenylcarbamoyl derivative have been used medically to improve memory and relief in Alzheimer's disease [24][25][26].…”