Potent Plasmodium falciparum gametocytocidal compounds identified by exploring the kinase inhibitor chemical space for dual active antimalarials

06 Feb 2018

Mariëtte E van der Watt,  Janette Reader,  Alisje Churchyard,  Sindisiwe H Nondaba, Sonja B Lauterbach,  Jandeli Niemand,  Sijuade Abayomi,  Riëtte A van Biljon, Jessica I Connacher,  Roelof D J van Wyk,  Claire Le Manach,  Tanya Paquet, Diego González Cabrera,  Christel Brunschwig,  Anjo Theron,  Sonia Lozano-Arias, Janneth F I Rodrigues,  Esperanza Herreros,  Didier Leroy,  James Duffy,  Leslie J Street, Kelly Chibale,  Dalu Mancama,  Theresa L Coetzer,  Lyn-Marie Birkholtz

Journal of Antimicrobial Chemotherapy




Novel chemical tools to eliminate malaria should ideally target both the asexual parasites and transmissible gametocytes. Several imidazopyridazines (IMPs) and 2-aminopyridines (2-APs) have been described as potent antimalarial candidates targeting lipid kinases. However, these have not been extensively explored for stage-specific inhibition of gametocytes in Plasmodium falciparumparasites. Here we provide an in-depth evaluation of the gametocytocidal activity of compounds from these chemotypes and identify novel starting points for dual-acting antimalarials.


We evaluated compounds against P. falciparum gametocytes using several assay platforms for cross-validation and stringently identified hits that were further profiled for stage specificity, speed of action and ex vivo efficacy. Physicochemical feature extraction and chemogenomic fingerprinting were applied to explore the kinase inhibition susceptibility profile.


We identified 34 compounds with submicromolar activity against late stage gametocytes, validated across several assay platforms. Of these, 12 were potent at <100 nM (8 were IMPs and 4 were 2-APs) and were also active against early stage gametocytes and asexual parasites, with >1000-fold selectivity towards the parasite over mammalian cells. Front-runner compounds targeted mature gametocytes within 48 h and blocked transmission to mosquitoes. The resultant chemogenomic fingerprint of parasites treated with the lead compounds revealed the importance of targeting kinases in asexual parasites and gametocytes.


This study encompasses an in-depth evaluation of the kinase inhibitor space for gametocytocidal activity. Potent lead compounds have enticing dual activities and highlight the importance of targeting the kinase superfamily in malaria elimination strategies.

Read the full article on Oxford Academic's website.