Structure–Activity Relationship Studies of a Novel Class of Transmission Blocking Antimalarials Targeting Male Gametes

Malaria is still
a leading cause of mortality among children in
the developing world, and despite the immense progress made in reducing
the global burden, further efforts are needed if eradication is to
be achieved. In this context, targeting transmission is widely recognized
as a necessary intervention toward that goal. After carrying out a
screen to discover new transmission-blocking agents, herein we report
our medicinal chemistry efforts to study the potential of the most
robust hit, DDD01035881, as a male-gamete targeted compound. We reveal
key structural features for the activity of this series and identify
analogues with greater potency and improved metabolic stability. We
believe this study lays the groundwork for further development of
this series as a transmission blocking agent.