Acridone derivatives, which have
been shown to have in
vitro and in vivo activity against Plasmodium spp, inhibit Toxoplasma gondii proliferation at picomolar concentrations. Using enzymatic assays,
we show that acridones inhibit both T. gondii cytochrome bc
1 and dihydroorotate dehydrogenase
and identify acridones that bind preferentially to the Qi site of cytochrome bc
1. We identify
acridones that have efficacy in a murine model of systemic toxoplasmosis.
Acridones have potent activity against T. gondii and represent a promising new class of preclinical compounds.
Herein, we describe 39 novel quinolone compounds bearing a hydrophilic amine chain and varied substituted benzyloxy units. These compounds demonstrate broad-spectrum activities against acid-fast bacterium, Gram-positive and -negative bacteria, fungi, and leishmania parasite. Compound 30 maintained antitubercular activity against moxifloxacin-, isoniazid-, and rifampicin-resistant Mycobacterium tuberculosis, while 37 exhibited low micromolar activities (<1 μg/mL) against World Health Organization (WHO) critical pathogens: Cryptococcus neoformans, Acinetobacter baumannii, and Pseudomonas aeruginosa.Compounds in this study are metabolically robust, demonstrating % remnant of >98% after 30 min in the presence of human, rat, and mouse liver microsomes. Several compounds thus reported here are promising leads for the treatment of diseases caused by infectious agents.
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