Synthesis, Stereochemistry and Antiparasitic Activity of Derivatives of (4R)-4,6-Dihydroxy-N-methyl-1,2,3,4-tetrahydroisoquinoline

Abstract

Condensation of phenylephrine with different aldehydes, under Pictet-Spengler cyclisation conditions, afforded a series of tetrahydroisoquinoline derivatives as mixtures of cis/trans isomers. Single crystal X-ray analysis of the dibenzoate derivative of one of the 4-nitrophenyl isomers confirmed it to be the trans isomer. The conformation of the cis isomer was determined through computational experiments and comparison of the predicted and observed 1H NMR spectra, particularly the magnitude of the coupling constants. Fourteen tetrahydroisoquinoline derivatives were then evaluated for their activity towards T. b. rhodesiense, two strains of P. falciparum, and mammalian cells. The most promising derivative, the undecyl derivative, showed good activity towards T. b. rhodesiense with an IC50 value in the sub-micromolar range and good selectivity over mammalian cells. The same derivative also showed activity against both strains of P. falciparum with IC50 values in the low micromolar range.