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.

Preise des Royal Australian Chemical Institute 2018

“…Mocerino interessiert sich für supramolekulare Chemie (insbesondere für chirale Calixarene) und für Chemiedidaktik. In einem ChemistrySelect ‐Beitrag beschrieb er die Synthese von Tetrahydroisochinolin‐Derivaten und ihre Wirkung gegen Parasiten …”

Royal Australian Chemical Institute Awards 2018

“…Mocerino is interested in supramolecular chemistry (in particular chiral calixarenes) and chemistry education. He has reported in ChemistrySelect on the synthesis and antiparasitic activity of tetrahydroisoquinoline derivatives …”

“…In einem ChemistrySelect-Beitrag beschrieb er die Synthese von Te trahydroisochinolin-Derivaten und ihre Wirkung gegen Parasiten. [8] Leo [10]…”

Aminoquinoline-Pyrimidine-Modified Anilines: Synthesis, In Vitro Antiplasmodial Activity, Cytotoxicity, Mechanistic Studies and ADME Predictions

“…To combat drug‐resistant malaria, several strategies have been employed for the generation of novel antimalarial agents, including identification of inhibitors of novel antimalarial targets, discovery/derivatization of natural antimalarials, and synthetic modulation of known drugs/pharmacophores . The ‘molecular hybridization’ approach is a relatively new methodology wherein two antimalarial pharmacophores are covalently linked together (hybridized) to produce a hybrid scaffold, having the ability to concomitantly act on the two parent targets.…”