SYNTHESIS AND ANTIPLASMODIAL EVALUATION OF A NEW TRIOXAQUINE

Hannah N. Wamakima, Peter G. Kirira, Margaret M. Nganga, Winnie R. Gimode, Brendon Naicker, Matshawendile Tukulula and Francis W. Muregi*

ABSTRACT

The ultimate objective of this work was to develop a novel antimalarial hybrid drug based on quinoline and trioxane pharmacophoric scaffold that is effective against drug-resistant malaria, especially in the face of emerging resistance against artemisinin based combination therapy (ACT). The synthetic design involved introduction of a linker to 4,7-dichloroquinoline and subsequent coupling with artesunate to form the dual drug. The structure’s molecular formula C30H38N3ClO7 was confirmed by electron spray ionization mass spectrum that showed a molecular ion peaks at m/z 588.24 and 590.24 amu with a relative abundance of 100% and 38.8% respectively against an exact value of 587.24 amu. Through biological studies, it was established that the drug’s antiplasmodial activity (IC50) against chloroquine (CQ)-sensitive (CQS, D6) and CQ-resistant (CQR, W2) isolates (CQS, 6.89 ng mL-1; CQR, 3.62 ng mL-1) was comparable (p>0.05) to that of artesunate (CQR, 6.67 ng mL-1; CQR, 4.04 ng mL-1), currently the most potent antimalarial in the artemisinin family. The drug had a good safety profile, with low percentage inhibition of human HeLa cell proliferation (29%), and IC50 values >10 000 ng mL-1. The findings validate the concept of ‘‘covalent bitherapy’’ as a feasible strategy in antimalarial drug development.

Keywords: Malaria, Drug resistance, Hybrid drug, Covalent biotherapy.