Novel antimalarial drug candidate RKA 182

Click on structure and buttons to explore

Artemether and Artesunate, first-generation analogues used in artemisinin-based combination therapy (ACT), are expensive and have limited availability. This led to the development of RKA 182. Compared to the 1,2,4-trioxane ring in Artemisinin, RKA 182 has a tetraoxane ring and an adamantane core for stability in vivo. The main focus for optimisation was a stable, polar side chain (green) to counterbalance the lipophilicity of the adamantane group.
After extensive testing on hit series 1 (pink), a template was chosen and lead optimisation led to synthesis of RKA 182 (IC₅₀ = 0.87 nM). In rats, RKA 182 delivered the compound as a ditosylate salt with improved bioavailability (38%). In the preclinical stage, RKA 182 demonstrated superiority over current drugs for ACT (IC₅₀ < 5nM) and has outstanding antimalarial activity. However, it is incompatible with the single dose cure approaches so further, second generation tetraoxane molecules, E209 and N205, were developed by the medicinal chemistry group.

P. M. O’Neill, R. K. Amewu, G. L. Nixon, F. Bousejra ElGarah, M. Mungthin, J. Chadwick, A. E. Shone, L. Vivas, H. Lander, V. Barton, S. Muangnoicharoen, P. G. Bray, J. Davies, B. K. Park, S. Wittlin, R. Brun, M. Preschel, K. Zhang and S. A. Ward, Angew Chem Int Ed Engl, 2010, 49, 5693-5697