DESIGN AND SYNTHESIS OF ORGANOPHOSPHORUS COMPOUNDS WITH ANTIVIRAL AND OTHER BIOACTIVITIES

Investigations of phosphonates and related biophosphate analogues as inhibitors of viral nucleic acid polymerases are summarized. General syntheses of a-halo phosphonoacetic acid (PAA) and methanediphosphonic acid (MDP) derivatives have been extended to preparation of seven a-halo phenyl(phosphonomethyl)phosphinates (PhMpP). Two phosphonates containing potentially reactive a-keto groups, oxophosphonoacetate (phosphonoglyoxalate, COPAA) and oxome-thanediphosphonate (carbonyldiphosphonate, COMDP) are discussed. A convenient, two-step synthesis of trisodium thiophosphonoformate (TPFA) from trimethyl phosphonoformate (Me3PFA) [via Me3TPFA] is presented. TPFA selectively inhibits HIV-1 reverse transcriptase (RT) relative to both human DNA polymerase a (pol a) and four herpesvirus DNA polymerases. The significance of membrane Na+/Pi cotransport inhibition by phosphonates is briefly addressed. © 1990, Taylor & Francis Group, LLC. All rights reserved.