The synthesis of aminoquinoline-based antimalarials and botulinum neurotoxin A inhibitors

The goal is to replace chloroquine (CQ) against which the growing number of MDR P. falciparum strains emerge; to develop new tetraoxane-based antimalarials since recently the appearance of reduced clinical efficacy of drugs containing artemisinin was reported (NatRevMicrobiol 2010, 8, 272); translate lead nontoxic potent BoNT/A LC SMNPIs into bioavailable, low nM inhibitors that will serve as drug candidates. Develop the drugs that treat Botulism resulting from BoNT poisoning. To that end, this project will encompass the development of antimalarials and botulinum neurotoxin dual inhibitors. Diazachrysenes, cholic acid- and adamantane-based SMNPIs have been shown to inhibit CQR P.f. strains with IC50<10nM, and cure P.berghei mice at 50-80mg/kg/day without detected toxic effect upon necropsy and in vitro. Another ACQ-based steroidal antimalarial is potent BoNT inhibitor as well: BoNT/A LC IC50=2.20µM; Ki=3.20µM. The project will include the synthesis of new chemotypes and optimization of current leads; potential in vivo candidates will be assayed in human, mouse and/or rat liver microsomes for metabolic stability. Modern computational chemistry methods, dynamic simulations of interacting molecules and calculations of electrostatic potentials of compounds on different pH levels, using advanced computational methods. Collaboration with WRAIR (malaria), USAMRIID (BoNT inhibition), and SAIC-NCI (computer modeling), (collaboration through CRADAs and/or joint research projects).