title: Design, synthesis and evaluation of 2,4-disubstituted pyrimidines as cholinesterase inhibitors.
abstract: A group of 2,4-disubstituted pyrimidine derivatives (7a-e, 8a-e and 9a-d) that possess a variety of C-2 aliphatic five- and six-membered heterocycloalkyl ring in conjunction with a C-4 arylalkylamino substituent were designed, synthesized and evaluated as cholinesterase (ChE) inhibitors. The steric and electronic properties at C-2 and C-4 positions of the pyrimidine ring were varied to investigate their effect on ChE inhibitory potency and selectivity. The structure-activity relationship (SAR) studies identified N-benzyl-2-thiomorpholinopyrimidin-4-amine (7c) as the most potent cholinesterase inhibitor (ChEI) with an IC(50)=0.33 microM (acetylcholinesterase, AChE) and 2.30muM (butyrylcholinesterase, BuChE). The molecular modeling studies indicate that within the AChE active site, the C-2 thiomorpholine substituent was oriented toward the cationic active site region (Trp84 and Phe330) whereas within the BuChE active site, it was oriented toward a hydrophobic region closer to the active site gorge entrance (Ala277). Accordingly, steric and electronic properties at the C-2 position of the pyrimidine ring play a critical role in ChE inhibition.
authors.affiliation: School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Tarek
authors.initials: T
authors.lastname: Mohamed
authors.forename: Praveen P N
authors.initials: PP
authors.lastname: Rao
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D015195:Drug Design; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D011743:Pyrimidines