Medicinal Chemistry Optimization of Antiplasmodial Imidazopyridazine Hits from High Throughput Screening of a SoftFocus Kinase Library: Part 1 Claire Le Manach, †,⊥ Diego Gonza ̀ lez Cabrera, † Frederic Douelle, † Aloysius T. Nchinda, † Yassir Younis, † Dale Taylor, ∞ Lubbe Wiesner, ∞ Karen L. White, § Eileen Ryan, § Corinne March, § Sandra Duffy, ø Vicky M. Avery, ø David Waterson, ‡ Michael J. Witty, ‡ Sergio Wittlin, ◊,∫ Susan A. Charman, § Leslie J. Street, † and Kelly Chibale* ,†,#,⊥ † Department of Chemistry, University of Cape Town, Rondebosch, 7701 Cape Town, South Africa ∞ Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, 7925 Cape Town, South Africa ø Discovery Biology, Eskitis Institute, Griffith University (Nathan Campus), Don Young Road, Brisbane Qld 4111, Australia § Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), 381 Royal Parade, Parkville VIC 3052, Australia ‡ Medicines for Malaria Venture, ICC, Route de Pre ́ -Bois 20, PO Box 1826, 1215 Geneva, Switzerland ◊ Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland ∫ University of Basel, Socinstrasse 57, 4002 Basel, Switzerland # Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701 Cape Town, South Africa ⊥ South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch, 7701 Cape Town, South Africa * S Supporting Information ABSTRACT: A novel class of imidazopyridazines identified from whole cell screening of a SoftFocus kinase library was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant strain) and NF54 (sensitive strain). Structure-activity relationship studies led to the identification of highly potent compounds against both strains. Compound 35 was highly active (IC 50 : K1 = 6.3 nM, NF54 = 7.3 nM) and comparable in potency to artesunate, and 35 exhibited 98% activity in the in vivo P. berghei mouse model (4-day test by Peters) at 4 × 50 mg/ kg po. Compound 35 was also assessed against P. falciparum in the in vivo SCID mouse model where the efficacy was found to be more consistent with the in vitro activity. Furthermore, 35 displayed high (78%) rat oral bioavailability with good oral exposure and plasma half-life. Mice exposure at the same dose was 10-fold lower than in rat, suggesting lower oral absorption and/or higher metabolic clearance in mice. M alaria remains a major concern for public health, especially in tropical and subtropical areas and affects 207 million people worldwide. 1 The disease is transmitted by female mosquitoes and is caused by five different species of the protozoan Plasmodium parasite, namely, falciparum, vivax, malariae, ovale, and knowlesi that infect and destroy red blood cells leading to high fever, anemia, cerebral malaria, and possibly death. 1 Of these, falciparum is the most prevalent species in sub Saharan Africa and the most lethal, being responsible for over 627 000 deaths a year, 1 especially among young children and pregnant women. Malaria may be cured if diagnosed in time and treated with proper medicines. However, the rapid development of drug resistance has compromised the use of previously effective drugs such as chloroquine, sulfadoxine/pyrimethamine, and signs of artemisinin resistance have started to emerge in southeast Asia. 2,3 To overcome this, various types of drug combinations with independent modes of action have been gradually introduced; however, these present only a temporary solution. 4 The development of new antimalarial agents is thus urgently needed to counter the ever-increasing spread of drug- resistant malaria. In this regard, phenotypic whole cell high throughput screening (HTS) has been a powerful tool for identifying novel antimalarial chemotypes. 5 Using an image-based assay, 6 HTS of a BioFocus DPI SoftFocus kinase library 7 identified a number of chemotypes Received: January 17, 2014 Published: February 25, 2014 Article pubs.acs.org/jmc © 2014 American Chemical Society 2789 dx.doi.org/10.1021/jm500098s | J. Med. Chem. 2014, 57, 2789-2798