title: Design and discovery of 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide inhibitors of HIV-1 integrase.
abstract: Raltegravir (RAL) is a first clinically approved integrase (IN) inhibitor for the treatment of HIV but rapid mutation of the virus has led to chemo-resistant strains. Therefore, there is a medical need to develop new IN inhibitors to overcome drug resistance. At present, several IN inhibitors are in different phases of clinical trials and few have been discontinued due to toxicity and lack of efficacy. The development of potent second-generation IN inhibitors with improved safety profiles is key for selecting new clinical candidates. In this article, we report the design and synthesis of potent 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide analogues as second-generation IN inhibitors. These compounds satisfy two structural requirements known for potent inhibition of HIV-1 IN catalysis: a metal chelating moiety and a hydrophobic functionality necessary for selectivity against the strand transfer reaction. Most of the new compounds described herein are potent and selective for the strand transfer reaction and show antiviral activity in cell-based assays. Furthermore, this class of compounds are drug-like and suitable for further optimization and preclinical studies.
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shangdong 250012, China.
authors.forename: Daoguang
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Bikash
authors.initials: B
authors.lastname: Debnath
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shangdong 250012, China.
authors.forename: Shenghui
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Tino Wilson
authors.initials: TW
authors.lastname: Sanchez
authors.affiliation: Laboratory for Molecular Virology and Gene Therapy, Division of Molecular Medicine, KU Leuven (KULeuven), Kapucijnenvoer 33, B-3000 Leuven, Flanders, Belgium.
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shangdong 250012, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Laboratory for Molecular Virology and Gene Therapy, Division of Molecular Medicine, KU Leuven (KULeuven), Kapucijnenvoer 33, B-3000 Leuven, Flanders, Belgium.
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: neamati@med.umich.edu.
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shangdong 250012, China. Electronic address: guisenzhao@sdu.edu.cn.
authors.forename: Guisen
authors.initials: G
authors.lastname: Zhao
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006678:HIV / Q000187:drug effects*; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000596446:5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide; D019428:HIV Integrase Inhibitors; D011743:Pyrimidines; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1
keywords: 5-Hydroxy-6-oxo-1,6-dihydropyrimidine analogues; HIV-1 integrase inhibitors; INSTIs