Validation of New Antimalarial Leads

2015 Objectives: The major focus is on understanding SAR and mechanism of the dihydropyridines (DHP). We will also continue to examine pharmacological synergy between the DHIQ’s and other antimalarial drugns. Finally, we will also focus hit-to-lead for multiple possible new series. Objective 1 – DHP Lead Optimization We will continue to focus on generation of drug-resistant mutants for the DHP’s and on the use of biochemical approaches to isolation of the target of the DHP’s. These studies are intended to enable selection of novel chemotypes acting on the DHP targeted pathway. We will also support routine testing of potency of the DHP analogs produced by the Mantetsch laboratory to enable publication of the SAR studies. Objective 2 – DHIQ combinations We will continue to examine the combination of the DHIQ PfATP4 inhibiotrs with other classes of inhibitors in vitro. The objective is to select an optimal combination partner that enhances the depth of kill of the DHIQ’s while maintaining their rapid mode of action. Objective 2 – Nominate novel series from screening campaigns. We have develpoed preliminary SAR and SPR for 20 novel series of antimalarials. This has allowed us to winnow from 20+ series to 2-3 of potential interest for further development. The current objective is to publish the non-developable series to qualify them as validated hits. We also plan to more further develop SAR on the higher priority series to be able to progress to hit-to-lead.