Title:The Case for Development of 11-Aza-artemisinins for Malaria
VOLUME: 22 ISSUE: 31
Author(s):Rozanne Harmse, Ho Ning Wong, Frans Smit, Richard K. Haynes and David D. N'Da
Affiliation:Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa.
Keywords:Artemisinin, azaartemisinin, dihydroartemisinin, malaria, metabolism, resistance, stability.
Abstract:The current treatment regimens for uncomplicated malaria comprise
an artemisinin in combination with another drug (ACT). However, the recent
emergence of resistance to ACTs in South East Asia dramatically emphasizes
the need for new artemisinins. The current artemisinins have been in use since
the late 1970s and have relatively poor thermal, chemical and metabolic stabilities - all are metabolized or hydrolyzed
in vivo to dihydroartemisinin (DHA) that itself undergoes facile decomposition in vivo. The current
artemisinins possess neurotoxicity as demonstrated in animal models, an issue that mandates increased vigilance
in view of trends to use of protracted treatment regimens involving sequential administration of different
ACTs against the resistant disease. As artemisinins induce the most rapid reduction in parasitaemia of any
drug, common sense dictates that any new artemisinin derivative, selected on the bases of more robust chemical
and thermal stability, metabolic stability with respect to the generation of DHA in vivo, and relatively benign
neurotoxicity should be used in any new ACT whose components are rationally chosen in order to
counter resistant malaria and inhibit transmission. 11-Azaartemisinin and its N-substituted derivatives attract
because of overall ease of preparation from artemisinin. Some derivatives also possess notable thermal stabilities
and although metabolic pathways of the derivatives are as yet unknown, none can provide DHA. The
azaartemisinins synthesized over the past 20 years are critically discussed on the basis of their synthetic
accessibility and biological activities with the view to assessing suitability to serve as new artemisinin
derivatives for treatment of malaria.
