Exploring the transmission-blocking activity of antiplasmodial 3, 6-diarylated imidazopyridazines. Issue 3 (2nd September 2021)

• Record Type: Journal Article
• Authors: Coertzen, Dina; Reader, Janette; van der Watt, Mariëtte E.; Leshabane, Meta M.; Langeveld, Henrico; Cheuka, Peter M.; Dziwornu, Godwin A.; Chibale, Kelly; Birkholtz, Lyn-Marie
• Is Part Of: Transactions of the Royal Society of South Africa. Volume 76:Issue 3(2021)
• Page Start: 225
• Page End: 233
• Publication Date: 2021-09-02
• Subjects: malaria -- kinase inhibitors -- imidazopyridazines -- antiplasmodial -- antimalarial -- transmission-blocking; Science -- Periodicals; Natural history -- South Africa -- Periodicals; 508.68
• DOI: 10.1080/0035919X.2021.1982792
• Languages: English
• ISSNs: 0035-919X

Abstract

Abstract : The effectiveness of current antimalarial therapies that cure patients of the pathogenic asexual blood stages is rapidly declining due to the spread of antimalarial drug resistance. This requires the development of novel chemotypes curative for asexual blood stages but additionally, such chemotypes should also target the sexually differentiated gametocytes and thereby block disease transmission. Kinase inhibitors, specifically imidazopyridazines, were previously described as highly effective, dual-active compounds in vitro . However, amongst other shortcomings, poor solubility and cardiotoxicity risks prevented these compounds from being further developed. In a recent study, novel 3, 6-diarylated imidazopyridazine derivatives showed improved solubility and a decrease in inhibition of the human ether-a-go-go- related gene (hERG), suggesting reduced cardiotoxicity risks, with potent sub-micromolar antiplasmodial activities. Here, we report the in vitro activity of these 3, 6-diarylated imidazopyridazine derivates against both asexual blood and gametocyte stages of the human malaria parasite, Plasmodium falciparum, in vitro . We highlight several potentially dual-active compounds with nanomolar activities (IC50 's 0.7–104 nM) against both drug sensitive and resistant strains of P. falciparum with these compounds also displaying activity against transmissible gametocytes (IC50 's 1180.3–1787.5 nM). Taken together, the new generation 3, 6-diarylated imidazopyridazines have potent activity against P. falciparum parasites in vitro with improved physicochemical and toxicity profiles.