In vitro evaluation of imidazo[4,5-c]quinolin-2-ones as gametocytocidal antimalarial agents

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Abstract

Novel imidazo[4,5-c]quinolin-2-ones were synthesized and evaluated in asexual blood stage and late stage gametocyte assays of Plasmodium falciparum, a major causative agent of malaria. The design of these compounds is based on a recently identified lead compound from a high throughput screen. A concise synthesis was developed that allowed for generation of analogues with substitution around both the quinoline and imidazolidinone rings. Through structure–activity relationship studies, a number of potent compounds were identified that possessed excellent antimalarial activity against both the asexual and sexual stages with minimal cytotoxicity in mammalian cells. This is the first Letter describing SAR and gametocytocidal activity of imidazo[4,5-c]quinolin-2-ones, a new lead series for malaria treatment and prevention.

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Acknowledgments

The authors would like to thank Paul Shinn, Danielle VanLeer, and Jennifer Bennison for assistance with compound management. This work was supported by the Intramural Research Programs of the National Center for Advancing Translational Sciences and Public Health Service Grant AI101396 from the National Institute of Allergy and Infectious Diseases. T.Q.T. is a JSPS Research Fellow in Biomedical and Behavioral Research at the NIH.

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These authors contributed equally to this work.

Current address: US Food & Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993, United States.

§

Current address: National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555, Japan.

Current address: aTyr Pharma Inc., 3545 John Hopkins Court, Suite #250, San Diego, CA 92121, United States.

Current address: Microbiology and Immunology Department, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, United States.

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