February
24,
2017
Dr. R. Kiplin Guy, Dean
College of Pharmacy
University of Kentucky
To address the dearth of chemotypes that can be used to drive drug development for malaria, we utilized a phenotypic whole cell screen of erythrocytic co-cultures of malaria to identify novel chemical compounds that suppressed growth of malaria. Careful hit validation for the results of this campaign led prioritization of the dihydroisoquinolones (DHIQs), a novel anti-malarial chemotype, for development.
A short, facile route was developed, allowing synthesis of a wide range of DHIQ analogs to explore structure-activity relationships (SAR) and structure-property relationships (SPR). These SAR and SPR studies identified DHIQs possessing strong potency in vitro against multiple drug-resistant strains of P. falciparum (EC50 values < 25 nM), minimal cytotoxicity against multiple strains of human cells (EC50 values > 25 µM), good aqueous solubility, and good permeability. The DHIQs are cidal, act with reasonable speed, and are efficacious against all intra-erythrocytic stages. The DHIQs do modestly inhibit gametocytogensis and exflagellation.
Studying the DHIQs in vivo established that they are well-tolerated in multiple species (MTDs > 200 mg/kg), orally bioavailable in multiple species (%F > 30%), and potently suppress parasitemia in both a P. berghei model (ED50 values < 50 mg/kg) and a humanized mouse model of P. falciparum (ED50 values < 5 mg/kg). They have now moved into clinical trials.
Several DHIQs were used to generate drug-resistant progeny strains of P. falciparum, giving multiple clonal progeny with EC50 shifts greater than 2-fold. Deep sequencing of these strains revealed each possessed a single non-synonymous mutation the codon for one amino acid in PfATP4, a putative proton/ion channel. Subsequent mechanistic work indicates that the compounds potently affect sodium and proton flux between the erythrocyte cytosol and the parasite cytosol.
Overall these results strongly support the continued development of this series as a potential new therapy for malaria.
Host: Prof. Jennifer E. Golden
