Publication: SYNTHESIS AND ANTIPLASMODIAL EVALUATION OF A NEW TRIOXAQUINE
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2019-01-11
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EUROPEAN JOURNAL OF PHARMACEUTICAL AND MEDICAL RESEARCH
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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.
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Keywords
laria, Drug resistance, Hybrid drug, Covalent biotherapy