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.
Subject(s)
Drug Discovery , HIV Integrase Inhibitors/pharmacology , HIV Integrase/metabolism , HIV/drug effects , Pyrimidines/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/chemistry , Humans , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity RelationshipABSTRACT
A series of novel pyrimidone analogues have been designed and synthesized as HIV-1 integrase (IN) inhibitors. This study demonstrated that introducing a substituent in the N1-position of the pyrimidone scaffold does not significantly influence IN inhibitory activity. Molecular docking studies showed these compounds could occupy the IN active site and form pi-pi interactions with viral DNA nucleotides DC16 and DA17 to displace reactive viral DNA 3'OH and block intasome activity.
Subject(s)
HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , HIV-1/enzymology , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Catalytic Domain , DNA, Viral/chemistry , DNA, Viral/metabolism , HIV Integrase Inhibitors/chemical synthesis , HIV-1/chemistry , HIV-1/drug effects , Humans , Models, Molecular , Molecular Docking Simulation , Pyrimidinones/chemical synthesisABSTRACT
Human lens epithelium-derived growth factor (LEDGF)/p75 plays an important role in the HIV life cycle by stimulating integrase (IN)-led viral DNA integration into cellular chromosomes. Mechanistic studies show the majority of IN inhibitors chelate magnesium ions in the catalytic active site, a region topologically distant from the LEDGF/p75 binding site. Compounds disrupting the formation of LEDGF/p75 and IN complexes serve as a novel mechanistic approach different from current antiretroviral therapies. We previously built pharmacophore models mimicking LEDGF/p75 residues and identified four classes of LEDGF/p75-IN inhibitors. Substructure and similarity searches yielded additional LEDGF/p75-IN inhibitors containing an acylhydrazone moiety. The most potent of the acylhydrazones inhibited LEDGF/p75-IN interaction with an IC(50) value of 400nM. We explored structure-activity relationships (SAR) and identified new acylhydrazones, hydrazines, and diazenes as lead molecules for further optimization. Two lead LEDGF/p75-IN inhibitors showed antiviral activity.
Subject(s)
HIV Integrase Inhibitors/chemistry , Intercellular Signaling Peptides and Proteins/chemistry , Peptides/chemistry , Amino Acid Sequence , Binding Sites , Cell Line , Cell Proliferation/drug effects , Drug Evaluation, Preclinical , HIV Integrase/chemistry , HIV Integrase/genetics , HIV Integrase/metabolism , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/pharmacology , Humans , Hydrazines/chemistry , Hydrazones/chemistry , Imides/chemistry , Molecular Docking Simulation , Peptides/chemical synthesis , Peptides/pharmacology , Protein Interaction Maps/drug effects , Protein Structure, Tertiary , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Structure-Activity RelationshipABSTRACT
HIV-1 integrase (IN), one of the essential enzymes in HIV infection, has been validated as a target for HIV treatment. While more than 20 drugs have been approved by the FDA to treat HIV/AIDS, only one drug, Raltegravir (1), was approved as an IN inhibitor. The rapid mutation of the virus, which leads to multidrug resistant HIV strains, presents an urgent need to find potent compounds that can serve as second-generation IN inhibitors. The pyrazolone scaffold, predicted by a computational modeling study using GS-9137(2) as a pharmacophoric model, has shown to inhibit the IN catalytic activities in low micromolar range. We have synthesized various analogs based on the pyrazolone scaffold and performed SAR studies. This paper will showcase the up-to-date result of this scaffold as a promising HIV-1 IN inhibitor.
