Design and Synthesis of Phosphonamidates (ProTides) and Phosphonodiamidates prodrugs of novel Acyclic Nucleoside Phosphonates as potential antibacterial, anthelmintic and antiviral compounds

In the last 50 years, Nucleoside Analogues (NA's) and Acyclic Nucleoside Phosphonates (ANP's) have played a role of pivotal importance as antiviral agents. As of april 2016, acyclic nucleoside have been approved as antiviral drugs for the treatment of 9 human infectious diseases (HIV, HBV, HCV, HCMV, HSV, HPV, RSV, VZV, and influenza virus). In the drug group of acyclic nucleoside phosphonate (ANP) analogues, there are 10 FDA-approved (combination) drugs. Moreover, many class of ANP's and NA's might be considered as potential candidates for further exploration of their anticancer, antifungal and antibiotic activity. ANP's are compounds containing a phosphonic acid group completely ionized at physiological pH and then, they are molecules impermeable to mucosal and cellular membranes. It is also important to consider that carrier-mediated transport often requires very close structural resemblance to natural products. Prodrugs role is to enhance oral bioavailability and to overtake physicochemical, pharmaceutical, pharmacokinetic and pharmacodynamic barriers. Thus, the limited bioavailability of ANP's can be bypassed masking phosphonate group with lipophilic prodrug capable of altering cell and tissue distribution/elimination patterns of the parent drug. In particular, aryloxy phosphonamidate (ProTide) and phosphonodiamidate prodrugs showed a great ability to facilitate passive diffusion through the cell membranes and an enhanced bioavailability if compared to their parent compounds. The purpose of this project was to synthesize a novel class of ANP's and its aryloxy phosphonamidate and phosphonodiamidate prodrugs. The achievement of the aim brought the synthesis of 4 prodrugs and the successful application of ProTide Approach on a new class of ANP's. These compounds will be tested as potential antibacterial, anthelmintic and antiviral compounds. This project was developed in School of Pharmacy at Cardiff University, within an Erasmus+ project.