Synthesis of derivatives of the keto-pyrrolyl-difluorophenol scaffold: Some structural aspects for aldose reductase inhibitory activity and selectivity

doi:10.1016/j.bmc.2012.12.015

Bioorganic & Medicinal Chemistry

Volume 21, Issue 4, 15 February 2013, Pages 869-873

https://doi.org/10.1016/j.bmc.2012.12.015 Get rights and content

Abstract

Seven novel ARIs (3a–c, 4a–c and 5) were synthesized with the implementation of an optimized and, partially, selective synthetic procedure, via a Friedel–Crafts acylation reaction. The synthesized ARIs have values of IC₅₀^ALR2 ranging from 0.19 μM (in case of compound 3b) to 2.3 μM (in case of compound 4a), while the values of selectivity index towards ALR1 range from 1 (in case of compound 3b) to 238 (in case of compound 3a). Finally, we found out that the presence of an additional (secondary) aromatic area is not a prerequisite feature for ARI activity.

Graphical abstract

Introduction

Diabetes mellitus is a complex metabolic disorder that is characterized by abnormal metabolism of carbohydrates, proteins and lipids, as a result of lack of insulin production or insulin resistance.¹ During the 20th century diabetes has acquired an epidemic prevalence and from the beginning of the 21st century it is developing to a pandemic phenomenon. In 2011, 366 million people were affected from the disease, while by 2030 the number is estimated to reach 522 million patients, with frequency of prevalence 7.7%.² In addition, diabetes is not exclusively a disease of the developed world, since it appears in very high rates in some developing countries of Asia and Latin America.³ Diabetes is closely associated with high morbidity and mortality due to its chronic complications that develop over the years because of insufficient glycemic control.⁴ Among these chronic complications are angiopathy and cardiovascular diseases, neuropathy, nephropathy, retinopathy and cataract.⁵

The enzyme that is considered responsible for diabetes’ chronic complications is aldose reductase (ALR2, AR, AKR1B1, EC 1.1.1.21), a cytosolic enzyme, member of the aldo-ketoreductase superfamily, which under normal conditions is responsible for a series of physiologic functions.⁶ ALR2 is the first enzyme of the polyol pathway, which converts glucose into sorbitol using NADPH as a co-factor. Sorbitol is slowly converted into fructose by the second enzyme of the pathway, sorbitol dehydrogenase (SDH), which uses NAD⁺ as a co-factor.⁷

ALR2 has a low affinity to glucose and the polyol pathway is involved only to a minor degree in the metabolism of glucose. However, in case of hyperglycemia, glucose is rapidly converted by ALR2 to sorbitol, which cannot easily cross membranes and accumulates into cells, causing cell and tissue disfunction.8, 9 Additionally, the exhaustion of NADPH and the disturbance of NADH/NAD⁺ ratio can cause oxidative stress, which is also related to diabetic chronic complications.1, 9, 10, 11 Furthermore, fructose, via oxidation, gives intermediates that can lead to advanced glycation end products (AGEs), which are also considered responsible for diabetes’ chronic complications.10, 12 Finally, recent studies have shown that ALR2 is related to ischemic and inflammatory pathologic conditions,5, 13, 14 as well as to some particular types of cancer.5, 15

All the above evidence point out that ALR2 is an important pharmacological target and its inhibition could be the key for the treatment of many pathological conditions. Of course, this means that there is a continuously rising need for new and effective ALR2 inhibitors (ARIs), since today only epalrestat is on the market and only in Japan. Even though many active ARIs have been synthesized over the years, most of them are derivatives of the carboxylic acid or the hydantoin moiety, which have proved to have either poor bioavailability or serious adverse effects.¹⁶

In order to overcome the problematic pharmacokinetic profile of carboxylic acids, novel bioisosteric approaches have been implemented, as for example with the trifluoromethyl ketone substituted ARIs.¹⁷ In the present work, and in continuation of searching for new ARI chemotypes,⁴ we have prepared and in vitro tested the keto-pyrrolyl-difluorophenol derivatives 3a–c, 4a–c and 5 (Scheme 1). In these molecules 2,6-difluorophenol was used as a non-classical bioisosteric replacement of the acetic acid moiety,¹⁸ while the pyrrole ring was substituted by different keto-groups.

The biphenyl ring system, present in compounds 3a and 4a, is considered as a privileged scaffold, providing affinity, due to its rigid aromatic structure, which adapts well to protein hydrophobic pockets, where π-stacking with phenylalanine and tyrosine are commonly observed.¹⁹

The 4-bromo-2-fluoro-phenyl moiety, present in compounds 3b and 4b, has been shown to be correlated with ALR2 inhibition, since known ARIs contain this group (e.g., minalrestat⁶ and ranirestat²⁰). Our intention was to introduce it as a 4-bromo-2-fluoro-benzoyl substructure, which could be easily inserted into the pyrrole ring via a Friedel–Crafts acylation reaction.

The trifluoromethoxy moiety, present in compounds 3c and 4c, is considered not just a bioisosteric replacement of a methoxy group, since it attains vertical spatial disposition, it has a special electronic distribution, and the C–O bond acquires a character between a single and a double. Overall, it has a unique hydrogen bonding ability, critical to putative ligand–enzyme interactions.21, 22

The trifluoro-acetyl group, present in compound 5, was selected in an effort to minimize lipophilicity, while enhancing metabolic stability and retaining the capacity of hydrogen bond formation.²³

Section snippets

Chemistry

In a previous study⁴ in our laboratory we have utilized Friedel–Crafts aroylations on 2,6-difluoro-4-(1H-pyrrol-1-yl)phenyl arylcarboxylates in order to prepare C-α or C-β substituted keto-pyrrolyl-difluorophenol derivatives. In the present work we targeted to control the selectivity of the Friedel–Crafts aroylation on the phenol 1, without esterifying it. Thus, we systematically altered (Scheme 1) the equivalents (in respect to 1) of AlCl₃, the amount of solvent employed, and the reaction’s

Conclusions

In the present study seven novel ARIs (3a–c, 4a–c and 5) were synthesized with the implementation of an optimized and, partially, selective synthetic procedure. The synthesized ARIs were biologically evaluated for ALR2, as well as ALR1 inhibitory activities and SIs were calculated. The estimated values of IC₅₀^ALR2 ranged from 0.19 μM (in case of compound 3b) to 2.3 μM (in case of compound 4a), while the calculated values of SI ranged from 1 (in case of compound 3b) to 238 (in case of compound 3a

General notes

All reagents were purchased from Sigma–Aldrich and used without further purification, except for the solvents for flash chromatography and recrystallization, which were distilled. [1,1′-Biphenyl]-4-carbonyl chloride (2a) was obtained from Aldrich (product number: 161144) and 4-(trifluoromethoxy)benzoyl chloride (2c) was obtained from Fluka (product number: 91754). IR spectra were taken with a Perkin–Elmer FT–IR System Spectrum BX. ¹H NMR spectra were recorded on a Bruker AM 300 at 300 MHz, using

References and notes (34)

G. Danaei et al.
Lancet
(2011)
M. Chatzopoulou et al.
Bioorg. Med. Chem.
(2011)
D. Minehira et al.
Bioorg. Med. Chem.
(2012)
C. Darmanin et al.
Bioorg. Med. Chem.
(2004)
M.S. Ola et al.
J. Diabetes Complications
(2012)
R. Maccari et al.
Bioorg. Med. Chem.
(2010)
X. Chen et al.
Bioorg. Med. Chem.
(2011)
E.A. Adogla et al.
Tetrahedron Lett.
(2012)
C. Song et al.
Tetrahedron Lett.
(2004)
V. Carbone et al.
Eur. J. Med. Chem.
(2010)

O.A. Barski et al.

Genomics

(1999)

M. Stefek et al.

Bioorg. Med. Chem.

(2008)

K. Pegklidou et al.

Bioorg. Med. Chem.

(2010)

W.H. Tang et al.

Front. Pharmacol.

(2012)

D.W. Lam et al.

Curr. Opin. Endocr. Diabetes Obes.

(2012)

P. Alexiou et al.

Curr. Med. Chem.

(2009)

O. El-Kabbani et al.

J. Med. Chem.

(2005)

Cited by (20)

Highlights on U.S. FDA-approved fluorinated drugs over the past five years (2018–2022)
2023, European Journal of Medicinal Chemistry
The objective of this review is to provide an update on the fluorine-containing drugs approved by U.S. Food and Drug Administration in the span of past five years (2018–2022). The agency accepted a total of fifty-eight fluorinated entities to diagnose, mitigate and treat a plethora of diseases. Among them, thirty drugs are for therapy of various types of cancers, twelve for infectious diseases, eleven for CNS disorders, and six for some other diseases. These are categorized and briefly discussed based on their therapeutic areas. In addition, this review gives a glimpse about their trade name, date of approval, active ingredients, company developers, indications, and drug mechanisms. We anticipate that this review may inspire the drug discovery and medicinal chemistry community in both industrial and academic settings to explore the fluorinated molecules leading to the discovery of new drugs in the near future.
Aldose reductase and protein tyrosine phosphatase 1B inhibitors as a promising therapeutic approach for diabetes mellitus
2020, European Journal of Medicinal Chemistry
Diabetes mellitus is a metabolic disease characterized by high blood glucose levels and usually associated with several chronic pathologies. Aldose reductase and protein tyrosine phosphatase 1B enzymes have identified as two novel molecular targets associated with the onset and progression of type II diabetes and related comorbidities. Although many inhibitors against these enzymes have already found in the field of diabetic mellitus, the research for discovering more effective and selective agents with optimal pharmacokinetic properties continues. In addition, dual inhibition of these target proteins has proved as a promising therapeutic approach. A variety of diverse scaffolds are presented in this review for the future design of potent and selective inhibitors of aldose reductase and protein tyrosine phosphatase 1B based on the most important structural features of both enzymes. The discovery of novel dual aldose reductase and protein tyrosine phosphatase 1B inhibitors could be effective therapeutic molecules for the treatment of insulin-resistant type II diabetes mellitus. The methods used comprise a literature survey and X-ray crystal structures derived from Protein Databank (PDB). Despite the available therapeutic options for type II diabetes mellitus, the inhibitors of aldose reductase and protein tyrosine phosphatase 1B could be two promising approaches for the effective treatment of hyperglycemia and diabetes-associated pathologies. Due to the poor pharmacokinetic profile and low in vivo efficacy of existing inhibitors of both targets, the research turned to more selective and cell-permeable agents as well as multi-target molecules.
Novel quinolin-4(1H)-one derivatives as multi-effective aldose reductase inhibitors for treatment of diabetic complications: Synthesis, biological evaluation, and molecular modeling studies
2020, Bioorganic and Medicinal Chemistry Letters
A Study of the Electrophilic Aroylation of 1-Aryl-1H-pyrroles: An Improved Preparation of an Active and Selective Aldose Reductase Inhibitor
2019, Organic Preparations and Procedures International
Current anti-diabetic agents and their molecular targets: A review
2018, European Journal of Medicinal Chemistry
Diabetes mellitus is a medical condition characterized by the body's loss of control over blood sugar. The frequency of diagnosed cases and consequential increases in medical costs makes it a rapidly growing chronic disease that threatens human health worldwide. In addition, its unnerving statistical projections are perilous to both the economy of the nation and man's life expectancy. Type-I and type-II diabetes are the two clinical forms of diabetes mellitus. Type-II diabetes mellitus (T2DM) is illustrated by the abnormality of glucose homeostasis in the body, resulting in hyperglycemia. Although significant research attention has been devoted to the development of diabetes regimens, which demonstrates success in lowering blood glucose levels, their efficacies are unsustainable due to undesirable side effects such as weight gain and hypoglycemia. Over the years, heterocyclic scaffolds have been the basis of anti-diabetic chemotherapies; hence, in this review we consolidate the use of bioactive scaffolds, which have been evaluated for their biological response as inhibitors against their respective anti-diabetic molecular targets over the past five years (2012–2017). Our investigation reveals a diverse target set which includes; protein tyrosine phosphatase 1 B (PTP1B), dipeptidly peptidase-4 (DPP-4), free fatty acid receptors 1 (FFAR1), G protein-coupled receptors (GPCR), peroxisome proliferator activated receptor-γ (PPARγ), sodium glucose co-transporter-2 (SGLT2), α-glucosidase, aldose reductase, glycogen phosphorylase (GP), fructose-1,6-bisphosphatase (FBPase), glucagon receptor (GCGr) and phosphoenolpyruvate carboxykinase (PEPCK). This review offers a medium on which future drug design and development toward diabetes management may be modelled (i.e. optimization via structural derivatization), as many of the drug candidates highlighted show promise as an effective anti-diabetic chemotherapy.
Exploration of thioxothiazolidinone–sulfonate conjugates as a new class of aldehyde/aldose reductase inhibitors: A synthetic and computational investigation
2017, Bioorganic Chemistry
In the present study, the pharmacophore integration methodology provided an efficient access to a new library of thioxothiazolidinone–sulfonate conjugates (8a–r) from easily available synthetic precursors. The approach was excellently high yielding with flexible structural sites for chemical modifications. The designed hybrid scaffolds were assessed for aldehyde/aldose reductase inhibition activities. The results for the in vitro bioassays were promising with the identification of compound 8e as the lead and selective candidate for ALR2 inhibition with an IC₅₀ value of 0.468 ± 0.003 µM as compared to 3.1 ± 0.2 µM for the standard (sorbinil), whereas compound 8o demonstrated high inhibitory potency for both ALR2 and ALR1 enzymes. Molecular modeling analysis of the potent compounds provided further insight into the biological properties where detailed binding mode analysis revealed that the conjugates (8a–r) were found stabilized in the active site of the enzymes through the development of a number of interactions with catalytic residues.

View all citing articles on Scopus

View full text

Synthesis of derivatives of the keto-pyrrolyl-difluorophenol scaffold: Some structural aspects for aldose reductase inhibitory activity and selectivity

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Conclusions

General notes

Lancet

Bioorg. Med. Chem.

Bioorg. Med. Chem.

Bioorg. Med. Chem.

J. Diabetes Complications

Bioorg. Med. Chem.

Bioorg. Med. Chem.

Tetrahedron Lett.

Tetrahedron Lett.

Eur. J. Med. Chem.

Genomics

Bioorg. Med. Chem.

Bioorg. Med. Chem.

Front. Pharmacol.

Curr. Opin. Endocr. Diabetes Obes.

Curr. Med. Chem.

J. Med. Chem.