From dihydroxypyrimidine carboxylic acids to carboxamide HIV-1 integrase inhibitors: SAR around the amide moiety

doi:10.1016/j.bmcl.2006.10.054

Bioorganic & Medicinal Chemistry Letters

Volume 17, Issue 2, 15 January 2007, Pages 350-353

https://doi.org/10.1016/j.bmcl.2006.10.054 Get rights and content

Abstract

4,5-Dihyroxypyrimidine carboxamides, which evolved from a related series of HCV NS5b polymerase inhibitors, have been optimized to provide selective HIV integrase strand transfer inhibitors. Extensive SAR around the benzylamide moiety led to the identification of the p-fluorobenzylamide as optimal in the enzymatic assay.

Graphical abstract

Section snippets

Acknowledgments

We thank Odalys Paz Gonzalez and Ralph Laufer for PK studies; William B. Schleif and Peter J. Felock for biological testing; Steven Harper and Michael Rowley for their helpful support and suggestions. This work was supported in part by a grant from the MIUR.

References and notes (12)

P. Pace et al.
Bioorg. Med. Chem. Lett.
(2004)
I. Stansfield et al.
Bioorg. Med. Chem. Lett.
(2004)
Y. Pommier et al.
Nat. Rev.
(2005)
M.R. Fesen et al.
Proc. Natl. Acad. Sci. U.S.A.
(1993)
Y. Pommier et al.
Curr. Top. Med. Chem.
(2004)
L. Zhuang et al.
J. Med. Chem.
(2003)

There are more references available in the full text version of this article.

Cited by (50)

Fluorine in anti-HIV drugs approved by FDA from 1981 to 2023
2023, European Journal of Medicinal Chemistry
Human immunodeficiency virus (HIV) is the etiological agent of acquired immunodeficiency syndrome (AIDS). Nowadays, FDA has approved over thirty antiretroviral drugs grouped in six categories. Interestingly, one-third of these drugs contain different number of fluorine atoms. The introduction of fluorine to obtain drug-like compounds is a well-accepted strategy in medicinal chemistry. In this review, we summarized 11 fluorine-containing anti-HIV drugs, focusing on their efficacy, resistance, safety, and specific roles of fluorine in the development of each drug. These examples may be of help for the discovery of new drug candidates bearing fluorine in their structures.
A QSAR study of integrase strand transfer inhibitors based on a large set of pyrimidine, pyrimidone, and pyridopyrazine carboxamide derivatives
2017, Journal of Molecular Structure
Citation Excerpt :
The study was conducted using the variable selection methodology of Ordered Predictors Selection (OPS) [26], and the model was built using Partial Least Squares (PLS). Selected from literature, the 199 compound dataset was described as INSTI against HIV-1 integrase (IN); it was formed by: (i) 134 pyrimidone-derived compounds synthesized and tested by Ferrara et al. [15], Muraglia et al. [16], Gardelli et al. [17], Di Francesco et al. [18], Nizi et al. [19], Petrocchi et al. [20], and Donghi et al. [21]; (ii) 56 pyrimidine derivatives by Pace et al. [22], Summa et al. [23], and Petrocchi et al. [24]; and (iii) 9 pyridopyrazine derivatives by Wai et al. [25]. Although the chemical structure of the dataset compounds may vary, all of them present the DKA substructure (Fig. 2), therefore they inhibit the HIV-IN by the chelation of the Mg2+ cofactor.
In the present study, 199 compounds derived from pyrimidine, pyrimidone and pyridopyrazine carboxamides with inhibitory activity against HIV-1 integrase were modeled. Subsequently, a multivariate QSAR study was conducted with 54 molecules employed by Ordered Predictors Selection (OPS) and Partial Least Squares (PLS) for the selection of variables and model construction, respectively. Topological, electrotopological, geometric, and molecular descriptors were used. The selected real model was robust and free from chance correlation; in addition, it demonstrated favorable internal and external statistical quality. Once statistically validated, the training model was used to predict the activity of a second data set (n = 145). The root mean square deviation (RMSD) between observed and predicted values was 0.698. Although it is a value outside of the standards, only 15 (10.34%) of the samples exhibited higher residual values than 1 log unit, a result considered acceptable. Results of Williams and Euclidean applicability domains relative to the prediction showed that the predictions did not occur by extrapolation and that the model is representative of the chemical space of test compounds.
Design and synthesis of N-methylpyrimidone derivatives as HIV-1 integrase inhibitors
2015, Bioorganic and Medicinal Chemistry
Citation Excerpt :
In the past two decades, IN-targeted antiviral research has led to the identification of various inhibitor types, of which the most prominent scaffolds feature is a diketo acid (DKA) structure or its heterocyclic bioisosteres.5–9 The dihydroxypyrimidine carboxamide derived from the evolution of DKA is a potent, reversible, and selective HIV-1 integrase strand transfer inhibitor.10 Extensive research on these chemotypes culminated with raltegravir11,12 (Fig. 1), it is the first drug approved for clinical use target to HIV integrase.
A series of novel β-diketo derivatives which combined the virtues of dihydroxypyrimidine carboxamide derived from the evolution of DKA and polyhydroxylated aromatics moieties, were designed and synthesized as potential HIV-1 integrase (IN) inhibitors and evaluated their inhibition to the strand transfer process of HIV-1 integrase and anti-HIV-1 activity. The result indicates that 3,4,5-trihydroxylated aromatic derivatives exhibit good inhibition to HIV-1 integrase, but dihydroxylated aromatic derivatives appear little inhibition to HIV-1 integrase. In addition, the preliminary structure–activity relationship (SAR) of these new derivatives was rationalized by docking studies.
Sketching the historical development of pyrimidones as the inhibitors of the HIV integrase
2015, European Journal of Medicinal Chemistry
Citation Excerpt :
The last two analogues were the most potent among the all tested to suppress IN enzyme. Furthermore, compounds 2aii, 2aiii, 2aiv, 2avii and 2biii–2bv furnished 20 nM, 30 nM, 40 nM, 20 nM, 10 nM, 50 nM and 20 nM of IC50s, respectively, suggesting the class of compounds as promising inhibitors of HIV integrase enzyme targeting at strand transfer in addition to the indentification of p-fluorobenzylamide as optimal entity for the potency [34]. Simultaneously, some 4,5-dihydroxypyrimidine carboxamides (3a and 3b) and N-alkyl-5-hydroxypyrimidinone carboxamides (3c) were developed and checked for their in vitro inhibitory potency in the cellular HIV spread assay against HIV integrase strand transfer function [35].
Heterocyclic substances perform a very unique role in drug design and discovery. This article provides the primary objectives of the analysis within pyrimidine centered new heterocyclic elements chronologically from their finding focusing on one of the essential enzyme of HIV virus particle that is integrase upon suppressing its strand transfer function. The class of compounds reviewed here includes bicyclic pyrimidines, dihydroxypyrimidines, pyrimidine-2,4-dinones, N-methylpyrimidones, pyranopyrimidine, pyridine–quinoline conjugates, pyrimidine-2-carboxamides, N-3 hydroxylated pyrimidine-2,4-diones as well as their various substituted analogues. Such initiatives released an effective drug Raltegravir as a first FDA approved anti-HIV integrase inhibitor as well as several of its derivatives along with other pyrimidones is under clinical or preclinical growth. Some of the provided scaffolds indicated dual anti-HIV efficacies against HIV reverse transcriptase and integrase enzymes at both cites as 3′-processing and strand transfer, while several scaffolds exhibited potency against Raltegravir resistant HIV mutant strains determining themselves a potent class of compounds having appealing upcoming implementations. Connections of the new compounds' molecular structure and HIV viral target has been overviewed to be able to accomplish further growth of promising anti-HIV agents in future drug discovery process.
Development of a receptor model for efficient in silico screening of HIV-1 integrase inhibitors
2014, Journal of Molecular Graphics and Modelling
Integrase (IN) is a key viral enzyme for the replication of the type-1 human immunodeficiency virus (HIV-1), and as such constitutes a relevant therapeutic target for the development of anti-HIV agents. However, the lack of crystallographic data of HIV IN complexed with the corresponding viral DNA has historically hindered the application of modern structure-based drug design techniques to the discovery of new potent IN inhibitors (INIs). Consequently, the development and validation of reliable HIV IN structural models that may be useful for the screening of large databases of chemical compounds is of particular interest. In this study, four HIV-1 IN homology models were evaluated respect to their capability to predict the inhibition potency of a training set comprising 36 previously reported INIs with IC₅₀ values in the low nanomolar to the high micromolar range. Also, 9 inactive structurally related compounds were included in this training set. In addition, a crystallographic structure of the IN-DNA complex corresponding to the prototype foamy virus (PFV) was also evaluated as structural model for the screening of inhibitors. The applicability of high throughput screening techniques, such as blind and ligand-guided exhaustive rigid docking was assessed. The receptor models were also refined by molecular dynamics and clustering techniques to assess protein sidechain flexibility and solvent effect on inhibitor binding. Among the studied models, we conclude that the one derived from the X-ray structure of the PFV integrase exhibited the best performance to rank the potencies of the compounds in the training set, with the predictive power being further improved by explicitly modeling five water molecules within the catalytic side of IN. Also, accounting for protein sidechain flexibility enhanced the prediction of inhibition potencies among the studied compounds. Finally, an interaction fingerprint pattern was established for the fast identification of potent IN inhibitors. In conclusion, we report an exhaustively validated receptor model if IN that is useful for the efficient screening of large chemical compounds databases in the search of potent HIV-1 IN inhibitors.
A novel synthesis of 1,2,4-oxadiazoles and isoxazoles
2014, Tetrahedron
A novel synthesis of 1,2,4-oxadiazoles and isoxazoles is described by utilizing the reactions between amidoximes and α,β-alkynic aldehydes and/or ketones. Conjugate addition products, obtained from amidoximes and α,β-alkynic aldehydes and/or ketones, afford 1,2,4-oxadiazoles and isoxazoles when treated with bases and acids, respectively. 1,2,4-Oxadiazoles can also be synthesized directly from amidoximes and α,β-alkynic aldehydes in a one-pot manner under basic conditions. The reactions are general for a variety of starting compounds and tolerate the presence of aryl, heteroaryl and alkyl groups.

View all citing articles on Scopus

^†: Present address: Almirall SA, Calle Treball 2-4, Sant Just Desvern, Barcelona 08960, Spain.

View full text

From dihydroxypyrimidine carboxylic acids to carboxamide HIV-1 integrase inhibitors: SAR around the amide moiety

Abstract

Graphical abstract

Section snippets

Acknowledgments

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Nat. Rev.

Proc. Natl. Acad. Sci. U.S.A.

Curr. Top. Med. Chem.

J. Med. Chem.