Design of novel carbamate acetylcholinesterase inhibitors based on the multiple binding sites of acetylcholinesterase

Abstract

This work describes the design, synthesis, AChE inhibitory activity, and structure-activity relationship of compounds related to a recently discovered series of AChE inhibitors: phthalimide alkyloxyphenyl N-methylcarbamates. The influence of structural variations on inhibitory potency was carefully investigated by modifying different alkyloxy chain lengths and positions between phthalimide and phenyl N-methylcarbamate. The biological properties of the series were investigated in some detail by considering their activity on isolated enzymes. All of the newly synthesized derivatives, when tested on isolated AChE from the brain of the housefly (Musca domestica), were more active than phenyl N-methylcarbamate. In particular, compound I1 displayed the best AChE inhibition (352-fold higher than phenyl N-methylcarbamate, and 29-fold higher than metolcarb), which suggested that the phthalimide group of I1 bound strongly to the residues lining the gorge, and phenyl N-methylcarbamate bound at the catalytic sites.

Reactivity of Hydroxy and Amino Derivatives of 2-Phenyl-1H-imidazoline and 2-Phenyl-1H-imidazole toward Isocyanates: Synthesis of Appropriate Carbamates and Ureas

“…White crystals, yield 0.25 g (56%), mp 205–207°C; 1 H‐NMR (360 MHz, DMSO‐ d 6 ): δ 1.14–1.37 (m, 6H, Cy), 1.63 (d, 1H, Cy), 1.76 (d, 2H, Cy), 1.88 (d, 2H, Cy), 6.95 (s, 1H, H‐9), 7.01 (t, 1H, H‐2), 7.19 (s, 1H, H‐6 ), 7.27 (t, 1H, H‐3), 7.36 (s, 1H, H‐6 ), 7.83 (d, 1H, H‐4), 8.41 (d, 1H, H‐1), 11.47 (s, 1H, H‐5), 12.67 (s, 1H, H‐8); IR (potassium bromide): ν 3306, 3199 (NH), ν 1663 (CO), δ 1547 (NH in CONH), γ 745 (CH arom.) cm −1 .…”

“…Nowadays, new compounds are developed in which imidazole or imidazoline derivatives acts as a chiral ligands for enantioselective catalysis . In addition, carbamates are fundamental fragments of many polymers, pesticides, and drugs, and are tested as acetylcholinesterase inhibitors . Derivatives based on ureas as the next derivatives of carbonic acid are usually used as agrochemicals, pharmaceuticals, or in petrochemical industry.…”

Identifying and characterizing promiscuous targets: Implications for virtual screening

“…Furthermore, several examples of crystal structures of multisite binders have also been reported [12][13][14][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36]. For example, to date, five ALR2 ligand scaffold families have been characterized by X-ray crystallography, represented by sorbinil, tolrestat, IDD 594 and two members of the naphtho [1,2-d] isothiazole acetic acid series [22].…”

“…Crystal structures of some microsomal drug-metabolizing P450 cytochromes show a large substrate-binding pocket that can accommodate more than one ligand simultaneously [31]. ACHE inhibitors can bind to the active site 'gorge,' the peripheral site, and at several other sites on ACHE [20]. Thrombin binds to fibrin at two non-substrate sites, one of high affinity and the other of low affinity [26,27].…”

“…Several recent studies have described proteins which bind different ligands in different ways. For example, crystallographic structures for multisite binders and multi-conformer binders have been reported for CDK2 [11], LXRb [12], the integrins a1b1 and a2b1 [13], VEGFR2 [14], FXA [15,16], factor H [17], LRP6 [18], ACHE [19,20], ALR2 [21,22], P38 [23], b-secretase [24,25], thrombin [26,27], PPAR-g [28][29][30], cytochromes P450 [31], LAIR-1 and LAIR-2 [32], LTBP-2 [33], PXR [34,35] and NS2B-NS3 [36]. Furthermore, computational docking studies and site-directed mutagenesis for g-secretase [37], oncoprotein c-Myc [38], CCR5 [39][40][41][42] and CXCR4 [43][44][45][46][47] also show strong evidence for multiple-ligand-binding sites.…”