Expanding the Scope of Higher Phosphoramidates by Designing Oligomers with a P-N Backbone

Abstract

Polydiphosphorodiamidates are an unknown class of inorganic polymers with P(V) atoms alternating with N(III) atoms in the backbone. Due to the very well-known properties of phosphoramidates, these promising polymers are postulated to be hydrolytically degradable, fire retardant, biocompatible and have immense biological applications in drug delivery, gene therapy, and disease control. For example, phosphoramidate derivatives of existing commercial drugs have been found to have better efficacy and therapeutic potential. The aim of this project was to synthesise, purify and characterise a library of oligomeric compounds containing P-N linkages, expanding the scope of higher phosphoramidates. To tackle this, salt elimination (using Et3N base) and lithiation (using LDA in situ) methods were used to give a library of four N-P-Ns (OMe derivatives), six symmetric and three asymmetric P-N-Ps and three higher oligomers (containing OPh and OEt moieties on P atoms) which were characterised mainly by multinuclear NMR spectroscopy and ESI mass spectrometry. Preliminary GPC analysis of the oligomer containing OPh substituents on P and a n-butyl substituent on N, revealed a mol. wt of 1809 Da (with monomeric mol wt. as 211.2008 g/mol), thus confirming 8-9 P-N units in the backbone. Further, a selection of each class of oligomers (4x P-N, 2x N-P-N, 4x P-N-P and 1x P-N-P-NP compounds) were evaluated for their antimicrobial activity at varying concentrations against E.coli, S.aureus, C.albicans and A.fumigatus by broth microdilution method using Amoxicillin and Amphotericin B as positive controls. The MIC value for all the tested compounds was found to be >128 μM which is likely due to the absence of functional groups that renders activity on our oligomers. Lastly, initial hydrolytic stability studies at various pH values was attempted. Taken together, this research has made some key contributions in the rapidly growing field of phosphoramidates but additional studies need to be undertaken for a better understanding of controlled synthesis and functionalisation of P-N in order to have desired properties for applications out in the world.