Discovery of amodiachins, a novel class of 4-aminoquinoline antimalarials active against multi-drug resistant Plasmodium falciparum.

A structure activity relationship study was undertaken centered on the 4-aminoquinoline antimalarial, amodiaquine. The research described herein focuses on the optimization for metabolic stability and in vivo activity of amodiachin analogs as potential antimalarials. A series of compounds was synthesized, and antiplasmodial activity assessed against cultured P. falciparum (Pf) infected erythrocytes and cytotoxicity was determined in HepG2 cells. Selected compounds were advanced for P. yoelli (Py) parasite suppression and additional in vivo experiments in a murine malaria model. The results of this work indicate that the addition of a piperidine heterocycle improves antiparasitic activity and varying the length and branching of a terminal N-alkyl enhances metabolic stability and in vivo efficacy. The research described here highlights the outstanding antimalarial candidate 43 (ADC-028) which exhibits low nanomolar IC50 values against drug-sensitive and multidrug-resistant Pf in an in vitro assay and demonstrates low cytotoxicity. After evaluation for metabolic stability in murine microsomes (t1/2 = 48.2 min), 43 was examined for in vivo Py suppression and in vivo efficacy, which demonstrated a non-recrudescence dose (NRD) of 16 mg/kg/d. A pharmacokinetic study in mice showed that 43 has excellent metabolic stability in vivo with a T1/2 = 84 hr in the bloodstream and respectable bioavailability (F = 76%). This study identifies 43 as a potential candidate for further evaluation and highlights the importance of discovering novel compounds to overcome drug resistance for treatment of malaria.