Design, synthesis and biological evaluation of 3-hydroxyquinazoline-2, 4(1H, 3H)-diones as dual inhibitors of HIV-1 reverse transcriptase-associated RNase H and integrase. Issue 17 (1st September 2019)

• Record Type: Journal Article
• Authors: Gao, Ping; Cheng, Xiqiang; Sun, Lin; Song, Shu; Álvarez, Mar; Luczkowiak, Joanna; Pannecouque, Christophe; De Clercq, Erik; Menéndez-Arias, Luis; Zhan, Peng; Liu, Xinyong
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 17(2019)
• Page Start: 3836
• Page End: 3845
• Publication Date: 2019-09-01
• Subjects: HIV-1 -- RNase H -- Integrase -- Dual inhibitors; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.07.011
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: A novel series of 3-hydroxyquinazoline-2, 4(1 H, 3 H )-diones derivatives has been designed and synthesized. Their biochemical characterization revealed that most of the compounds were effective inhibitors of HIV-1 RNase H activity at sub to low micromolar concentrations. Among them, II-4 was the most potent in enzymatic assays, showing an IC50 value of 0.41 ± 0.13 μM, almost five times lower than the IC50 obtained with β-thujaplicinol. In addition, II-4 was also effective in inhibiting HIV-1 IN strand transfer activity (IC50 = 0.85 ± 0.18 μM) but less potent than raltegravir (IC50 = 71 ± 14 nM). Despite its relatively low cytotoxicity, the efficiency of II-4 in cell culture was limited by its poor membrane permeability. Nevertheless, structure-activity relationships and molecular modeling studies confirmed the importance of tested 3-hydroxyquinazoline-2, 4(1 H, 3 H )-diones as useful leads for further optimization.