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- Title
Potent Plasmodium falciparum gametocytocidal compounds identified by exploring the kinase inhibitor chemical space for dual active antimalarials.
- Authors
van der Watt, Mariëtte E.; Reader, Janette; Churchyard, Alisje; Nondaba, Sindisiwe H.; Lauterbach, Sonja B.; Niemand, Jandeli; Abayomi, Sijuade; van Biljon, Riëtte A.; Connacher, Jessica I.; van Wyk, Roelof D. J.; Le Manach, Claire; Paquet, Tanya; González Cabrera, Diego; Brunschwig, Christel; Theron, Anjo; Lozano-Arias, Sonia; Rodrigues, Janneth F. I.; Herreros, Esperanza; Leroy, Didier; Duffy, James
- Abstract
<bold>Objectives: </bold>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 falciparum parasites. 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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
MALARIA treatment; PLASMODIUM falciparum; PATHOGENIC microorganisms; ARTEMISININ; ANTIMALARIALS; PROTOZOA; RESEARCH; PARASITOLOGY; PROTEIN kinase inhibitors; PHOSPHOTRANSFERASES; RESEARCH methodology; CELL physiology; EVALUATION research; MEDICAL cooperation; COMPARATIVE studies; AMINOPYRIDINES; MICROBIOLOGICAL techniques; PHARMACODYNAMICS; CHEMICAL inhibitors
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2018, Vol 73, Issue 5, p1279
- ISSN
0305-7453
- Publication type
journal article
- DOI
10.1093/jac/dky008