6,7-Dihydroxy-1-oxoisoindoline-4-sulfonamide-containing HIV-1 integrase inhibitors

doi:10.1016/j.bmcl.2012.10.088

Bioorganic & Medicinal Chemistry Letters

Volume 22, Issue 24, 15 December 2012, Pages 7309-7313

https://doi.org/10.1016/j.bmcl.2012.10.088 Get rights and content

Abstract

Although an extensive body of scientific and patent literature exists describing the development of HIV-1 integrase (IN) inhibitors, Merck’s raltegravir and Gilead’s elvitegravir remain the only IN inhibitors FDA-approved for the treatment of AIDS. The emergence of raltegravir-resistant strains of HIV-1 containing mutated forms of IN underlies the need for continued efforts to enhance the efficacy of IN inhibitors against resistant mutants. We have previously described bicyclic 6,7-dihydroxyoxoisoindolin-1-ones that show good IN inhibitory potency. This report describes the effects of introducing substituents into the 4- and 5-positions of the parent 6,7-dihydroxyoxoisoindolin-1-one platform. We have developed several sulfonamide-containing analogs that enhance potency in cell-based HIV assays by more than two orders-of-magnitude and we describe several compounds that are more potent than raltegravir against the clinically relevant Y143R IN mutant.

Graphical abstract

Section snippets

Acknowledgments

This work was supported in part by the Intramural Research Program of the NIH, Center for Cancer Research, Frederick National Laboratory for Cancer Research and the National Cancer Institute, National Institutes of Health and the Joint Science and Technology Office of the Department of Defense. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations

References and notes (29)

M.K. Lewinski et al.
X.Z. Zhao et al.
Bioorg. Med. Chem. Lett.
(2009)
X.Z. Zhao et al.
Bioorg. Med. Chem.
(2009)
H. Jin et al.
Bioorg. Med. Chem. Lett.
(2008)
B.A. Johns et al.
Bioorg. Med. Chem. Lett.
(2009)
X. Fan et al.
Bioorg. Med. Chem.
(2011)
S. Hare et al.
Nature
(2010)
A. Engelman et al.
Nat. Rev. Microbiol.
(2012)
C. Marchand et al.
Curr. Top. Med. Chem.
(2009)
C. Liao et al.
Future Med. Chem.
(2010)

V. Summa et al.

J. Med. Chem.

(2008)

Y. Pommier et al.

Nat. Rev. Drug Disc.

(2012)

C. Charpentier et al.

HIV Med.

(2008)

P.K. Quashie et al.

BMC Med.

(2012)

Cited by (22)

Synthesis of heterocycles by utilizing phthalaldehydic acid: An overview
2022, Tetrahedron
Citation Excerpt :
Along the same lines, compounds containing oxoisoindoline 1 core represent precious and interesting pharmacological and biological activities and these compounds are significantly paid immense attention by researchers. This scaffold is noticed due to its aggrecanase inhibition [15] (useful in osteoarthritis treatment), HIV-1 integrase inhibition [16], PARP inhibition [17] (useful in cancer treatment), Covalent Prolyl Oligopeptidase Inhibition [18], β1, β2-adrenergic antagonism [19] and Voltage-Gated Sodium Channel NaV1.7 blocking [20] effects. The intended scaffold is expected to exhibit novel activities (Fig. 2).
In this review, the construction of polycyclic compounds by taking advantage of phthaldehydic acid as a starting material has been explained. The in-depth description about recent several reactions applied with phthaldehydic acid and their mechanism to synthesize these various heterocycles have been mentioned and compared thoroughly as well. The major goal of this review is to introduce the latest advances about using phthaldehydic acid in various reactions to construct a plethora of novel polycyclic structures expected to be bioactive compounds.
Asymmetric Cascade Aza-Henry/Lactamization Reaction in the Highly Enantioselective Organocatalytic Synthesis of 3-(Nitromethyl)isoindolin-1-ones from α-Amido Sulfones
2022, Journal of Organic Chemistry
The asymmetric synthesis of novel 3-substituted isoindolinones is herein reported. A new cascade reaction was developed that consisted of the asymmetric nitro-Mannich reaction of suitable α-amido sulfones designed from 2-formyl benzoates, followed by the in situ cyclization of the adducts. Very high enantioselectivities, up to 98% ee, and very good yields were obtained in the presence of the readily available neutral bifunctional organocatalyst derived from trans-1,2-diaminocyclohexane, which is known as Takemoto’s catalyst. The investigation of the reactivity of the obtained products allowed either the selective Boc-deprotection or reduction of the nitro group, leading to further functionalized 3-substituted isoindolinones without affecting the enantiomeric purity.
The First Highly Enantioselective Synthesis of 3-Sulfinyl-Substituted Isoindolinones Having Adjacent Carbon and Sulfur Stereocenters
2021, Journal of Organic Chemistry
A highly stereoselective access to 3-sulfinyl-substituted isoindolinones has been achieved by a tandem organocatalytic addition/cyclization reaction of 2-carbobenzyloxy-N-tosylbenzylidenimine with thiols and succeeding diastereoselective oxidation with MCPBA. First, enantioenriched isoindolinone N,S-acetals have been obtained through a dynamic kinetic asymmetric transformation induced by a bifunctional chiral thiourea organocatalyst. In turn, the newly created carbon stereocenter enabled a high diastereocontrol in the subsequent sulfoxidation. Based on DFT calculations, a theoretical rationale for the stereoselectivity of the oxidation reaction is also provided.
1-Isoindolinone scaffold-based natural products with a promising diverse bioactivity
2020, Fitoterapia
Citation Excerpt :
1-isoindolinone is one such promising scaffolds found in a wide variety of naturally occurring and synthetically prepared bioactive compounds. 1-isoindolinone based compounds that influence diverse biological activities/molecules due to their role(s) as anxiolytic/anticonvulsant, TNFα-inhibitory, antiangiogenic, 5-HT antagonistic/antidepressant [1–5], PARP-1-inhibitory [6], histone deacetylase inhibitory [7–8], antihyperglycemic [9–13], dopamine receptor affinity [14–16], MDM2-p53 inhibitory activity [17–22], α1-Adrenoceptor antagonist [23–25], HIV-1 integrase (IN) inhibitor [26], and many more have been used in diverse pharmaceutical applications [27–42]. Existing literature provides excellent resources for total synthesis including certain biosynthetic pathways, and mechanisms of action [43–45].
Isoindolin-1-one or 1-isoindolinone framework is referred to phthalimidines or benzo fused γ-lactams of the corresponding γ-amino carboxylic acids and has been of prime interest for scientists for last several decades. 1-Isoindolinone framework is found in a wide range of naturally occurring compounds with diverse biological activities and therapeutic potential for various chronic diseases. Recent developments in synthetic methods for their procurement have opened a new era of 1-isoindolinone chemistry. This review aims to provide an alphabetical quick reference guide to only 1-isoindolinone based natural products and its variable fused, oxidized and reduced state skeleton with information for advanced chemotaxonomic analyses, cellular targets/pathways and diverse biological activities and future use for medicinal chemistry.
Combined ligand and structure-based approaches on HIV-1 integrase strand transfer inhibitors
2014, Chemico-Biological Interactions
Citation Excerpt :
We performed the QPLD and MD studies on PFV intasome methodically to investigate and rigorously analyze the importance of active compounds in the HIV-1 IN inhibition. For this study, data set consisting of 128 HIV-1 IN STIs was collected from the literature [29–32]. All the 128 dihydroxy isoindole derivatives were reported by the same research group.
HIV-1 integrase (IN) is an essential enzyme in the viral replication cycle and represents a promising target for anti-HIV drug design. In the present study, pharmacophore modeling and atom-based 3D-QSAR studies were carried out on a series of compounds belonging to dihydroxy isoindole derivatives as HIV-1 IN strand transfer inhibitors. The best pharmacophore model generated consists of six features AADHRR: two hydrogen bond acceptors (A), a hydrogen bond donor (D), a hydrophobic group (H) and two aromatic rings (R). Based on the best pharmacophore model, a statistically valid atom-based 3D-QSAR model was developed. The obtained atom-based 3D-QSAR model has an excellent correlation coefficient value (R² = 0.87) and also exhibited good predictive power (Q² = 0.72). The best pharmacophore model was further validated through enrichment calculations and it shows strong predictive power with a high performance in identifying active ligands from the total hits (actives + decoys). QM-polarized ligand docking and molecular dynamics simulations of selected active compounds in the active site of prototype foamy virus intasome gave important insights into the chemical and structural basis involved in the molecular recognition process. The O,O,O donor atom triad of compounds show metal chelation with divalent Mg²⁺ ions bound to the three catalytic amino acids in the enzyme’s active site and π-stacking interaction with the viral DNA residue DA17. The results might have implications for rational design of specific HIV-1 integrase strand transfer inhibitors with improved affinity and selectivity.
Antiviral activity of isoindole derivatives
2020, Journal of Medicinal and Chemical Sciences

View all citing articles on Scopus

View full text

Published by Elsevier Ltd.

6,7-Dihydroxy-1-oxoisoindoline-4-sulfonamide-containing HIV-1 integrase inhibitors

Abstract

Graphical abstract

Section snippets

Acknowledgments

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem.

Nature

Nat. Rev. Microbiol.

Curr. Top. Med. Chem.

Future Med. Chem.

J. Med. Chem.

Nat. Rev. Drug Disc.

HIV Med.

BMC Med.