Non-hydrolysable analogues of inorganic pyrophosphate as inhibitors of hepatitis C virus RNA-dependent RNA-polymerase

Abstract

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.

Investigation of the effect of medium in the preparation of alendronate: till now the best synthesis in the presence of an ionic liquid additive

“…Many publications deal with the preparation of alendronate . We have also studied its synthesis starting from γ‐aminobutyric acid (GABA) ( 1 ) in methanesulfonic acid (MSA) as the solvent (Table ; Scheme ).…”

“…No data were provided on the purities . The synthesis of alendronate was described in a series of other solvents, eg, acetonitrile, n ‐octane, phenol and its derivatives, anisole, benzenesulfonic acid, diphenyl ether, etc. The yields were highly dependent on these solvents, and in most cases, the purity of the product was not reported.…”

Synthetic Procedures Leading towards Aminobisphosphonates

“…They are based on modification of the first procedure elaborated by Plöger et al with formamide as a substrate [35]. yields and are of good purity [16,[23][24][25][26]. Because of its technological importance, this reaction is still quite intensively studied and optimized; however, most of the studies are done in industrial laboratories, and their results are mostly disseminated as patents.…”

“…Presumably, the addition of phosphites to ketophosphonates was the first procedure for preparation of dialkyl 1-hydroxy-1,1-bisphosphonates [16,19,57]. Starting ketophosphonates are obtained by the Arbuzov reaction of acyl chlorides with trialkyl phosphites and used as substrates in the next step, namely, the addition of dialkyl phosphite to carbonyl double bonds (a representative example for preparation of tetramethyl pamidronate 22 is shown in Scheme 13).…”

“…They are standardly prepared by a large-scale, one-step reaction of carboxylic acids with phosphorus trichloride and phosphorous or phosphoric acids, followed by hydrolysis with water; the procedure was optimized by Kieczykowski et al [14]. The reaction is carried out in selected solvents (phenylsulphonic acid, various phenols, chlorobenzene, diphenyl ether or ionic liquids) with sulfone and methanesulphonic acid being preferred choices [11,[15][16][17][18][19][20]. Despite many theories [19,[21][22][23], the exact mechanism of this reaction is not fully understood; however, the formation of acid chloride as a first intermediate has been undoubtedly demonstrated (Scheme 1).…”