M-13: Synthesis of Tetrahydrobenzonaphthyridines as a Novel Series of Antimalarial Compounds
Rutgers University United States
Synthesis of a novel series of antimalarial compounds to combat the recent, concerning parasite resistance to Artemisinin-based combination therapy in the Greater Mekong subregion.
ORAL PRESENTATION: 12:45PM
Compound development was done at Rutgers University under the guidance of Dr. Spencer Knapp. Using targeted analog synthesis, a series of active antimalarial compounds was created improving upon a scaffold found by a St. Jude Hospital High-throughput phenotypic screening.
After a high throughput phenotypic screening of a library of compounds done by St Jude Children’s Research hospital, a series of tetrahydrobenzonaphthyridines was identified to be active and structurally dissimilar to current therapies. However, this class of compounds shows poor water solubility. Therefore, new analogs were synthesized aiming to improve this physicochemical property while maintaining activity against multiple malaria strains. This poster presents recently created antimalarial compounds that have been synthesized by the Knapp Group as well as their EC50s evaluated by our collaborators at the University of Kentucky. The values reported are the activities against both wild type and resistant strains of Plasmodium falciparum.
A recent World Health Organization (WHO) report revealed 216 million cases of malaria in 2016, most of which occurred in Sub-Saharan Africa and resulted in 445,000 deaths. The disease is particularly lethal to children under 5, who accounts for 70% of all deaths. Even though malaria cases and deaths have dropped significantly in the past 20 years due to the use of Artemisinin-based combination therapy (ACT), a concerning parasite resistance to artemisinin has been detected in 5 countries of the Greater Mekong subregion; Studies have confirmed that artemisinin resistance has emerged independently in many areas of this subregion. The new synthesized compounds aim to improve upon the physicochemical properties and activity of the original class of hit compounds. Current analogs show tenfold increase in the activity. The goal is to find a lead compound eligible to be a clinical candidate.