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

Ping Gao; Xiqiang Cheng; Lin Sun; Shu Song; Mar Álvarez; Joanna Luczkowiak; Christophe Pannecouque; Erik De Clercq; Luis Menéndez-Arias; Peng Zhan; Xinyong Liu

doi:10.1016/j.bmc.2019.07.011

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

Bioorg Med Chem. 2019 Sep 1;27(17):3836-3845. doi: 10.1016/j.bmc.2019.07.011. Epub 2019 Jul 6.

Authors

Affiliations

¹ Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan 250012, China.
² Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid), Madrid, Spain.
³ Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
⁴ Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid), Madrid, Spain. Electronic address: [email protected].
⁵ Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan 250012, China. Electronic address: [email protected].
⁶ Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan 250012, China. Electronic address: [email protected].

PMID: 31324562
DOI: 10.1016/j.bmc.2019.07.011

Abstract

A novel series of 3-hydroxyquinazoline-2,4(1H,3H)-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(1H,3H)-diones as useful leads for further optimization.

Keywords: Dual inhibitors; HIV-1; Integrase; RNase H.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-HIV Agents / chemical synthesis
Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology*
Caco-2 Cells
Cell Line
Cell Membrane Permeability / drug effects
Dose-Response Relationship, Drug
Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
HIV Integrase / metabolism*
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV Reverse Transcriptase / metabolism
HIV-1 / drug effects
HIV-2 / drug effects
Humans
Models, Molecular
Molecular Structure
Quinazolinones / chemical synthesis
Quinazolinones / chemistry
Quinazolinones / pharmacology*
Ribonuclease H, Human Immunodeficiency Virus / antagonists & inhibitors*
Ribonuclease H, Human Immunodeficiency Virus / metabolism
Structure-Activity Relationship

Substances

Anti-HIV Agents
Enzyme Inhibitors
Quinazolinones
HIV Integrase
reverse transcriptase, Human immunodeficiency virus 1
HIV Reverse Transcriptase
Ribonuclease H, Human Immunodeficiency Virus