Enantioselective Synthesis of γ-Phenyl-γ-amino Vinyl Phosphonates and Sulfones and Their Application to the Synthesis of Novel Highly Potent Antimalarials

Abstract

Racemic and enantioselective syntheses of γ-phenyl-γ-amino vinyl phosphonates and sulfones have been achieved using Horner–Wadsworth–Emmons olefination of trityl protected α-phenyl-α-amino aldehydes with tetraethyl methylenediphosphonate and diethyl ((phenylsulfonyl)­methyl)­phosphonate, respectively, without any racemization. The present strategy has also been successfully applied to the synthesis of peptidyl vinyl phosphonate and peptidyl vinyl sulfone derivatives as potential cysteine protease inhibitors of Chagas disease, K11002, with 100% de. The developed synthetic protocol was further utilized to synthesize hybrid molecules consisting of artemisinin as an inhibitor of major cysteine protease falcipain-2 present in the food vacuole of the malarial parasite. The synthesized artemisinin–dipeptidyl vinyl sulfone hybrid compounds showed effective in vitro inhibition of falcipain-2 and potent parasiticidal efficacies against Plasmodium falciparum in nanomolar ranges. Overall, the developed synthetic protocol could be effectively utilized to design cysteine protease inhibitors not only as novel antimalarial compounds but also to be involved in other life-threatening diseases.

The antimalarial activity of 1,2,4‐trioxolane/trioxane hybrids and dimers: A review

“…The ART‐sulfone hybrid 23 (IC 50 : 17.1 nM; EC 50 : 3.0 nM) showed potent inhibitory activity against falcipain‐2 and CQS 3D7 strain of P. falciparum and the antiplasmodial activity was 9 times superior to that of ART (IC 50 : 27 nM). [ 42 ] Hence, hybrids 22 and 23 could act as promising candidates for further evaluations.…”