6-Benzylamino 4-oxo-1,4-dihydro-1,8-naphthyridines and 4-oxo-1,4-dihydroquinolines as HIV integrase inhibitors

doi:10.1016/j.bmcl.2010.11.108

Bioorganic & Medicinal Chemistry Letters

Volume 21, Issue 2, 15 January 2011, Pages 760-763

https://doi.org/10.1016/j.bmcl.2010.11.108 Get rights and content

Abstract

SAR studies on the quinolone carboxylic acid class of HIV-1 integrase inhibitors focused on improving the metabolic stability and led to the discovery of 27 and 38.

Graphical abstract

SAR studies on the quinoline carboxylic acid class of HIV-1 integrase inhibitors focused on improving the metabolic stability and led to the discovery of 27 and 38.

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Discovery of 4-oxoquinolines, a new chemical class of anti-HIV-1 compounds
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Citation Excerpt :
The molecular mechanism of gyrase inactivation occurs through the chelation of Mg2+ ions at the catalytic centers of bacterial gyrases. This mechanistic idea of enzymatic inactivation by chelating a divalent cation has been applied to the development of HIV-1 INSTIs (Nagasawa et al., 2011; Pasquini et al., 2008; Sato et al., 2006). EVG is an example of a successful modification of quinolone-3-carboxylic acids (Kobayashi et al., 2011; Sato et al., 2009).
Antiretroviral therapy (ART) against HIV-1 infection offers the promise of controlling disease progression and prolonging the survival of HIV-1-infected patients. However, even the most potent ART regimens available today cannot cure HIV-1. Because patients will be exposed to ART for many years, physicians and researchers must anticipate the emergence of drug-resistant HIV-1, potential adverse effects of the current drugs, and need for future drug development. In this study, we screened a small-molecule compound library using cell-based anti-HIV-1 assays and discovered a series of novel anti-HIV-1 compounds, 4-oxoquinolines. These compounds exhibited potent anti-HIV-1 activity (EC₅₀ < 0.1 μM) with high selectivity indexes (CC₅₀/EC₅₀ > 2500) and favorable pharmacokinetic profiles in mice. Surprisingly, our novel compounds have a chemical backbone similar to the clinically used integrase (IN) strand transfer inhibitor (INSTI) elvitegravir, although they lack the crucial 3-carboxylate moiety needed for the common INSTI diketo motif. Indeed, the new 4-oxoquinoline derivatives have no detectable INSTI activity. In addition, various drug-resistant HIV-1 strains did not display cross resistance to these compounds. Interestingly, time-of-addition experiments indicated that the 4-oxoquinoline derivative remains its anti-HIV-1 activity even after the viral integration stage. Furthermore, the compounds significantly suppressed p24 antigen production in HIV-1 latently infected cells exposed with tumor necrosis factor alpha. These findings suggest that our 4-oxoquinoline derivatives with no 3-carboxylate moiety may become novel lead compounds in the development of anti-HIV-1 drugs.
One-pot regio- and stereoselective synthesis of tertiary phosphine chalcogenides with (E)-N-ethenyl-1,2-dihydroquinoline functionalities
2016, Tetrahedron Letters
Viral enzymes containing magnesium: Metal binding as a successful strategy in drug design
2012, Coordination Chemistry Reviews
Citation Excerpt :
GS-9137 (19, Elvitegravir) bears two coordinating groups, a β-ketone and a carboxylic acid. Modification of the fused rings of Elvitegravir has been recently performed [97] leading to naphthyridinone-containing inhibitors with good performances and further developments are expected. The milestone of the “metal chelation strategy” against HIV IN is represented by compound 20 (Raltegravir, Isentress®, Fig. 9), that belongs to a series of 4,5-dihydroxypyrimidine-4-carboxamides [98,99].
Metal-activated enzymes are important targets in drug discovery in general and for antivirals in particular. Such proteins contain one or more metal ion cofactors, prevalently located in the active site, which are essential to perform biological functions. Understanding enzyme structure and mechanism at a molecular level is important for the design of specific inhibitors that can be used for pharmacological purposes. Because of their peculiar physicochemical characteristics, magnesium ions participate in many catalytic processes involved in nucleic acid biochemistry, thus playing a pivotal role in the replication of many different viruses. In this context, chelation of the magnesium ions cofactors represents an attractive and validated strategy for the development of novel antiviral agents. In many cases, the starting point of the design of efficient drugs was identified in the β-diketoacid prototypes, which evolved in novel chemotypes bearing various chelating motifs able to bind these divalent metal ions. The application of this strategy has allowed significant results to be achieved in recent years in the development of antiviral agents, culminating in the approval of the first HIV integrase inhibitor in 2007.
This review focuses on the magnesium metal cofactors and on their catalytic and biological properties, as well as on the structural features of the most relevant metal chelating compounds developed as antiviral agents against some of the most important viral targets: human immundeficiency virus integrase, reverse transcriptase RNase H, influenza virus endonuclease, and hepatitis C virus polymerase.
Synthesis and biological evaluation of HQCAs with aryl or benzyl substituents on N-1 position as potential HIV-1 integrase inhibitors
2011, Bioorganic and Medicinal Chemistry
A series of new 5-hydroxylquinolone-3-carboxylic acids (HQCAs) with various aryl or benzyl substituents on N-1 position were synthesized and evaluated for their anti-HIV activity in C8166 cell culture. Most of the target compounds displayed activity against wide-type HIV-1 in the low micromolar range in infected C8166 cells. The most active compound 5g exhibited activity against wild-type HIV-1 and HIV-1 mutant virus A17 with an EC₅₀ value of 3.17 and 17.88 μM, respectively. The biological results and the docking study revealed that the substitution pattern on N-1 position of the quinolone core might contribute to physicochemical properties of HQCAs and resulted in great influence on their antiviral potency.
Structural modifications of quinolone-3-carboxylic acids with anti-HIV activity
2011, Bioorganic and Medicinal Chemistry
Citation Excerpt :
The synthesized compounds 2a–k were evaluated by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay3 for cytotoxicity and antiviral activity in C8166 cells infected with the wild-type HIV-1 (LAI strain IIIB). Elviltegravir, currently being in phase III trials,4 was included as reference compound. The cytotoxicity and antiviral activities of these compounds are listed in Table 1.
A series of new quinolone-3-carboxylic acids featuring a hydroxyl group at C-5 position were synthesized and evaluated for their in vitro activity against HIV in C8166 cell culture. All the compounds showed anti-HIV-1 activity with low micromolar to submicromolar EC₅₀ values. The most active compound 2k exhibited activity against wild-type HIV-1 with an EC₅₀ value of 0.13 μΜ. Preliminary structure–activity relationship of the newly synthesized quinolone analogues was also investigated. Further docking study revealed that the anti-HIV activity of these compounds might involve a two-metal chelating mechanism.
N-(7-Methyl-1,8-naphthyridin-2-yl)acetamide-acetic acid (1/1)
2013, Acta Crystallographica Section E: Structure Reports Online

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6-Benzylamino 4-oxo-1,4-dihydro-1,8-naphthyridines and 4-oxo-1,4-dihydroquinolines as HIV integrase inhibitors

Abstract

Graphical abstract

J. Biol. Chem.

Cell

Nat. Rev. Drug Disc.

Retrovirology

Nat. Rev. Drug Disc.

J. Med. Chem.