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Abstract
A series of novel 6-(pyrazolylmethyl)-4-oxo-4H-quinoline-3-carboxylic acid derivatives bearing different substituents on the N-position of quinoline ring were designed and synthesized as potential HIV-1 integrase (IN) inhibitors, based on the structurally related GS-9137 scaffold. The structures of all new compounds were confirmed by 1H-NMR, 13C-NMR and ESI (or HRMS) spectra. Detailed synthetic protocols and the anti-IN activity studies are also presented.
Highlights
Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes reverse transcriptase, protease, and integrase which have been identified as key targets to arrest the HIV life cycle
We considered that the phenyl ring at C-6 could be replaced by a bioisosteric pyrazole ring; halogen atoms were introduced at C-4′ on the pyrazole ring with two hydrophobic methyl groups at the C-3′ and C-5′ positions; (2) Variable substituent groups were introduced at
After hydrolysis of 5–10 in 10% aq NaOH or HCl, the corresponding 4-oxo-4H-quinoline-3-carboxylic acid derivatives 11a–c–16a–c were obtained in yields ranging from 42% to 81%
Summary
Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes reverse transcriptase, protease, and integrase which have been identified as key targets to arrest the HIV life cycle. Most of the currently used oral drugs for the treatment of HIV infection inhibit the first two of these enzymes. The infection has been difficult to cure because of drug resistance and immune response [1]. The viral enzyme integrase (IN), which is essential for interrupting the viral replication cycle and has no counterpart in mammalian cells, is a crucial target for the development of new HIV-1 inhibitors with high selectivity and low toxicity [2,3]. As a kind of HIV-1 inhibitors, quinolone derivatives have great attractive to researcher because of their small extremely versatile molecules, Molecules 2012, 17 synthesized at low cost on a large scale and endowed with well-known biochemical properties [4,5].
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