Síntese, caracterização, modelagem molecular e estudo da atividade biológica de novos bisfosforamidatos e bisfosforoditioatos

Abstract

A series of new compounds, N, N'-bis(dialkylphosphoryl)diamines and S, S'- bis(dialkylphosphoryl)l,3-propanedithiols were prepared by a Todd-Atherton reaction of dialkylphosphites with symmetrical diamines or 1,3-propanedithiols in a biphasic system. They were characterized by IR, 1H-NMR, 13C-NMR, 31p-NMR and mass spectrometry. Compounds with butoxy, isobutoxy and isopropoxy groups on the phosphorus atom showed the lowest LD 50 values when tested against Artemia salina, Musca domestica and Stomoxys calcitrans. All the other compounds which showed high LD 50 values were considered non toxic. The pharmacological and toxicological evaluation of N,N'-bis(diisobutylphosphoril)- 1,3-propylenediamine and S,S'-bis(diisobutylphosforil)-1,3-propanedithio| showed them be inactive against mice in a concentration of 200 mg/Kg The effect on the germination and on the growth of lettuce seeds were observed in an assay with bisphosphoroamidates. The results of a molecular modeling study suggest that the biological activity of the compounds may be related to AChE inhibition. Contrary to classical organophophorus AChE inhibitors, the compounds synthetized in this study do not possess a good leaving group, which suggests that they may act only as reversible inhibitors