Synthesis and antitrypanosomal evaluation of derivatives of N-benzyl-1,2-dihydroquinolin-6-ols: Effect of core substitutions and salt formation.

Abstract

Analogs of the trypanocidal lead compound 1-benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate were prepared to extend the structure-activity relationship in this series of molecules, improve the in vivo antitrypanosomal activity of the lead, and determine whether ester prodrugs are needed to overcome the instability of the dihydroquinolin-6-ols. Two of the most active compounds identified in this study were 1-benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride and 1-(2-methoxy)benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride. These stable solids possessed low nanomolar IC(50) values against Trypanosoma brucei rhodesiense STIB900 in vitro and provided cures in an early treatment acute mouse model of African trypanosomiasis when given ip at 50mg/kg/day for four consecutive days.

DOI: 10.1016/j.bmc.2010.11.003

Cite this paper

@article{Reid2011SynthesisAA, title={Synthesis and antitrypanosomal evaluation of derivatives of N-benzyl-1,2-dihydroquinolin-6-ols: Effect of core substitutions and salt formation.}, author={Carolyn S Reid and Donald A Patrick and Shanshan He and Jean Fotie and Kokku Premalatha and Richard R. Tidwell and Michael Zhuo Wang and Qiang Liu and Pavel Gershkovich and Kishor M. Wasan and Tanja Wenzler and Reto Brun and Karl A. Werbovetz}, journal={Bioorganic & medicinal chemistry}, year={2011}, volume={19 1}, pages={513-23} }