Phosphonates and Phosphonate Prodrugs in Medicinal Chemistry: Past Successes and Future Prospects

Abstract

Compounds with a phosphonate group, i.e., –P(O)(OH)2 group attached directly to the molecule via a P-C bond serve as suitable non-hydrolyzable phosphate mimics in various biomedical applications. In principle, they often inhibit enzymes utilizing various phosphates as substrates. In this review we focus mainly on biologically active phosphonates that originated from our institute (Institute of Organic Chemistry and Biochemistry in Prague); i.e., acyclic nucleoside phosphonates (ANPs, e.g., adefovir, tenofovir, and cidofovir) and derivatives of non-nucleoside phosphonates such as 2-(phosphonomethyl) pentanedioic acid (2-PMPA). Principal strategies of their syntheses and modifications to prodrugs is reported. Besides clinically used ANP antivirals, a special attention is paid to new biologically active molecules with respect to emerging infections and arising resistance of many pathogens against standard treatments. These new structures include 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidines or so-called “open-ring” derivatives, acyclic nucleoside phosphonates with 5-azacytosine as a base moiety, side-chain fluorinated ANPs, aza/deazapurine ANPs. When transformed into an appropriate prodrug by derivatizing their charged functionalities, all these compounds show promising potential to become drug candidates for the treatment of viral infections. ANP prodrugs with suitable pharmacokinetics include amino acid phosphoramidates, pivaloyloxymethyl (POM) and isopropoxycarbonyloxymethyl (POC) esters, alkyl and alkoxyalkyl esters, salicylic esters, (methyl-2-oxo-1,3-dioxol-4-yl) methyl (ODOL) esters and peptidomimetic prodrugs. We also focus on the story of cytostatics related to 9-[2-(phosphonomethoxy)ethyl]guanine and its prodrugs which eventually led to development of the veterinary drug rabacfosadine. Various new ANP structures are also currently investigated as antiparasitics, especially antimalarial agents e.g., guanine and hypoxanthine derivatives with 2-(phosphonoethoxy)ethyl moiety, their thia-analogues and N-branched derivatives. In addition to ANPs and their analogs, we also describe prodrugs of 2-(phosphonomethyl)pentanedioic acid (2-PMPA), a potent inhibitor of the enzyme glutamate carboxypeptidase II (GCPII), also known as prostate-specific membrane antigen (PSMA). Glutamate carboxypeptidase II inhibitors, including 2-PMPA have been found efficacious in various preclinical models of neurological disorders which are caused by glutamatergic excitotoxicity. Unfortunately its highly polar character and hence low bioavailability severely limits its potential for clinical use. To overcome this problem, various prodrug strategies have been used to mask carboxylates and/or phosphonate functionalities with pivaloyloxymethyl, POC, ODOL and alkyl esters. Chemistry and biological characterization led to identification of prodrugs with 44–80 fold greater oral bioavailability (tetra-ODOL-2-PMPA).

An exploratory investigation of the CSF metabolic profile of HIV in a South African paediatric cohort using GCxGC-TOF/MS

“…The elevated methylphosphonic acid detected in the HIV + cohort may serve as an indicator of ART exposure in this group and needs further investigation. Compounds with phosphonate groups – characterized by a direct P–C bond, are typically used as anti-retroviral phosphate analogues that inhibit enzymes that rely on different phosphate substrates, thereby suppressing viral replication by competitively inhibiting the viral DNA polymerase (Krecmerova et al, 2022 ).…”

Phosphonate and Thiasugar Analogues of Glucosamine-6-phosphate: Activation of the glmS Riboswitch and Antibiotic Activity

“…Removal or inversion of the stereochemistry of the 4-hydroxy group leads to a total loss of activation. ,, However, a position that can be potentially varied is the phosphate group at OH-6. Phosphate mimics have found widespread application in drug design − and offer access to phosphatase-resistant GlcN6P mimetics. Indeed, this approach has been pursued previously.…”

Development of a General Organophosphorus Radical Trap: Deoxyphosphonylation of Alcohols

“…These phosphonates are often found within antiviral therapeutics, particularly those that target polymerase-mediated viral replication . Their hydrolytic stability and increased membrane permeability can improve pharmacokinetic profiles − and may lower dosing requirements. , The potential of this method to directly interconvert the natural site of phosphorylation in sugars and nucleosides to the phosphonate derivative further motivated us to enable alcohols as the radical precursor (Figure ). − …”