Inorganic pyrophosphate (PP i ) is the product of the polymerization reaction catalyzed by DNA and RNA polymerases. A number of novel non hydrolsable PP i analogues was synthesized; some of them inhibited the polymerization reaction catalyzed by hepatitis C virus RNA dependent RNA polymerase (NS5B). A new pharmacophore based on a non hydrolysable methylenediphosphonate backbone has been developed. The structure activity relationship analysis of 12 bisphosphonates is presented and the structural features crucial for NS5B polymerase activity inhibition are stated.
Inorganic pyrophosphate (PPi) mimetics designed on a basis of methylenediphosphonic acid backbone are promising inhibitors of two key HIV replication enzymes, IN [1] and RT [2]. Herein, we present chemical synthesis of eleven methylenebisphosphonates (BPs) with their NMR and HRMS analysis synthesized via five different ways. Also, we present data on inhibition of HIV RT catalyzed phosphorolysis and polymerization by synthesized BPs using two methods based on denaturing urea PAGE. Tests were also performed for thymidine analogue mutations reverse transcriptase (TAM RT), which was expressed and purified for that. Structure–activity relationships and inhibitory activity data of synthesized BPs are presented in “Methylene bisphosphonates as the inhibitors of HIV RT phosphorolytic activity” [2].
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