Quinolone carboxylic acids as a novel monoketo acid class of human immunodeficiency virus type 1 integrase inhibitors

Article abstract of DOI:10.1021/jm900460z

Human immunodeficiency virus type 1 (HIV-1) integrase is a crucial target for antiretroviral drugs, and several keto - enol acid class (often referred to as diketo acid class) inhibitors have clinically exhibited-marked antiretroviral activity. Here, we show the synthesis and the detailed structure - activity relationship of the quinolone carboxylic acids as a novel monoketo acid class of integrase inhibitors. 6-(3-Chloro-2-fluorobenzyl)-1-((2S)-1-hydroxy-3,3- dimethylbutan-2-yl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 51, which showed an IC₅₀ of 5.8 nMin the strand transfer assay and an ED₅₀ of 0.6 nMin the antiviral assay, and 6-(3-chloro-2-fluorobenzyl) -1-((2S)-1-hydroxy-3-methylbutan-2-yl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3- carboxylic acid 49, which had an IC₅₀ of 7.2 nMand an ED₅₀ of 0.9 nM, were the most potent compounds in this class. The monoketo acid 49 was much more potent at inhibiting integrasecatalyzed strand transfer processes than 3′-processing reactions, as is the case with the keto - enol acids. Elvitegravir 49 was chosen as a candidate for further studies and is currently in phase 3 clinical trials.