Synthesis and quantitative structure-activity relationships of phosphoramidates and phosphorodiamidates incorporating amino acid esters

Two series of O-aryl and N-aryl O-ethyl phosphoramidates and phosphorodiami dates respectively containing alpha -amino acid ester moieties have been sy nthesized and characterized by H-1 NMR, IR and mass spectroscopy. Stepwise multiple regression analysis showed that the anticholinesterase activity wa s strongly correlated with the chemical structures represented by the stere o-electronic and hydrophobic parameters with correlation coefficient of 0.9 99. These results revealed that the inhibition activity of both series was inversely correlated with the steric bulk of the p-aryl substituents and di rectly with the bulk of the alkyl groups of the amino acid moieties, wherea s m-aryl substituents have no steric effect on the inhibition process. The inhibition was enhanced by strong pi -electron acceptor aryl substituents a nd reduced by electron donating alkyl groups of the amino acids. This suppo rted the proposed inhibition mechanism of nucleophilic attack of a hydroxyl group at the enzyme active site on the partially positive phosphorus atom in organophosphorus compounds. The inhibition was also increased by more hy drophilic substituents. These results showed the importance of both the rea ctivity of these compounds and their steric interaction with the AChE activ e site in controlling enzyme inhibition, in addition to the ease of more hy drophobic compounds to reach the enzyme active site.