Design and synthesis of novel quinazolin-4(1H)-one derivatives as potent and selective inhibitors targeting AKR1B1.

Inhibition of aldose reductase (AKR1B1) is a promising option for the treatment of diabetic complications. However, most of the developed small molecule inhibitors lack selectivity or suffer from low bioactivity. To address this limitation, a novel series of quinazolin-4(1H)-one derivatives as potent and selective inhibitors of AKR1B1 were designed and synthesized.

Novel Hydroxychalcone-Based Dual Inhibitors of Aldose Reductase and α-Glucosidase as Potential Therapeutic Agents against Diabetes Mellitus and Its Complications.

We designed a novel series of bifunctional inhibitors of α-glucosidase and aldose reductase (ALR2) based on the structure of hydroxychalcone. The two enzymes relate to blood glucose level and anomalously elevated polyol pathway of glucose metabolism under hyperglycemia, respectively. Most compounds in the series exhibited a potent inhibitory activity for both enzymes, and a significant antioxidant property was shown.

Identification of 9H-purin-6-amine derivatives as novel aldose reductase inhibitors for the treatment of diabetic complications.

A series of 9H-purin-6-amine derivatives as aldose reductase (ALR) inhibitors were designed and synthesized. Most of these derivatives, having a C6-substituted benzylamine side chain and N9 carboxylic acid on the core structure, were found to be potent and selective ALR inhibitors, with submicromolar IC values against ALR2. Particularly, compound 4e was the most active with an IC value of 0.

Multifunctional agents based on benzoxazolone as promising therapeutic drugs for diabetic nephropathy.

Diabetic nephropathy (DN) is resulted from activations of polyol pathway and oxidative stress by abnormal metabolism of glucose, and no specific medication is available. We designed a novel class of benzoxazolone derivatives, and a number of individuals were found to have significant antioxidant activity and inhibition of aldose reductase of the key enzyme in the polyol pathway. The outstanding compound (E)-2-(7-(4-hydroxy-3-methoxystyryl)-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid was identified to reduce urinary proteins in diabetic mice suggesting an alleviation in the diabetic nephropathy, and this was confirmed by kidney hematoxylin-eosin staining.

Novel 3,4-dihydroquinolin-2(1H)-one derivatives as dual inhibitor targeting AKR1B1/ROS for treatment of diabetic complications: Design, synthesis and biological evaluation.

AKR1B1 (Aldose reductase) has been used as therapeutic intervention target for treatment of diabetic complications over 50 years, and more recently for inflammation and cancer. However, most developed small molecule inhibitors have the defect of low bioactivity. To address this limitation, novel series of 3,4-dihydroquinolin-2(1H)-one derivatives as dual inhibitor targeting AKR1B1/ROS (Reactive Oxygen Species) were designed and synthesized.

(5-Hydroxy-4-oxo-2-styryl-4-pyridin-1-yl)-acetic Acid Derivatives as Multifunctional Aldose Reductase Inhibitors.

As rate-limited enzyme of polyol pathway, aldose reductase (ALR2) is one of the key inhibitory targets for alleviating diabetic complications. To reduce the toxic side effects of the inhibitors and to decrease the level of oxidative stress, the inhibitory selectivity towards ALR2 against detoxicating aldehyde reductase (ALR1) and antioxidant activity are included in the design of multifunctional ALR2 inhibitors. Hydroxypyridinone derivatives were designed, synthesized and evaluated their inhibitory behavior and antioxidant activity.

Dihydrobenzoxazinone derivatives as aldose reductase inhibitors with antioxidant activity.

Dihydrobenzoxazinone based design and synthesis produced two series of compounds as aldose reductase (ALR2) inhibitor candidates. In particular, phenolic residues were embodied into the compounds for the combination of strengthening the inhibitory acitvity and antioxidant ability to retard the progression of diabetic complications. Most of the derivatives with styryl side chains exhibited excellent activities on selective ALR2 inhibition with IC values ranging from 0.

Organocatalytic asymmetric synthesis of arylindolyl indolin-3-ones with both axial and central chirality.

An efficient method for chiral phosphoric acid-catalyzed asymmetric synthesis of arylindolyl indolin-3-ones with both axial and central chirality has been developed via the reaction of 3-arylindoles with 2-aryl-3H-indol-3-ones, and the target products were obtained in high yields with excellent enantioselectivity and diastereoselectivity.

Identification of quinoxalin-2(1)-one derivatives as a novel class of multifunctional aldose reductase inhibitors.

Targeting aldose reductase and oxidative stress with quinoxalin-2(1)-one derivatives having a 1-hydroxypyrazole head as the bioisosteric replacement of carboxylic acid. Aldose reductase inhibition, selectivity and antioxidant potency of all the synthesized compounds were evaluated, and binding modes were studied by molecular docking. Most of the derivatives showed potent and selective aldose reductase inhibition, and among them was the most active (IC = 0.

Novel 2-phenoxypyrido[3,2-]pyrazin-3(4)-one derivatives as potent and selective aldose reductase inhibitors with antioxidant activity.

To develop multifunctional aldose reductase (AKR1B1) inhibitors for anti-diabetic complications, a novel series of 2-phenoxypyrido[3,2-]pyrazin-3(4)-one derivatives were designed and synthesised. Most of the derivatives were found to be potent and selective against AKR1B1, and 2-(7-chloro-2-(3,5-dihydroxyphenoxy)-3-oxopyrido[3,2-]pyrazin-4(3)-yl) acetic acid () was the most active with an IC value of 0.023 µM.

Superbase-promoted selective carbon-carbon bond cleavage driven by aromatization.

A novel selective carbon-carbon single bond cleavage has been disclosed through the copper-catalyzed reaction of 1-alkyl-3-alkylindolin-2-imine hydrochlorides with substituted 1-(bromomethyl)-2-iodobenzenes leading to fused N-heterocycles. Mechanistic studies showed that the intrinsic drive of aromatization and the action of the superbase derived from sodium tert-butoxide and dimethylsulfoxide were the key factors leading to the carbon-carbon single bond cleavage. Furthermore, the obtained N-heterocycles are indoloquinoline derivatives with wide biological activities.

Axially Chiral Cyclic Phosphoric Acid Enabled Enantioselective Sequential Additions.

Efficient axially chiral cyclic phosphoric acid catalyzed enantioselective sequential additions of 2-aryl-3 H-indol-3-ones, aldehydes, and diethyl 2-aminomalonate have been developed, and a new type of nitrogen-containing heterocyclic compounds, 2,3-dihydro-1 H-imidazo[1,5- a]indol-9(9a H)-one derivatives, were prepared in good yields and excellent ee values with a wide functional group tolerance, in which the reactivity and enantioselectivity of the substrates were enabled by our newly developed axially chiral cyclic phosphoric acid, ( R)-CYC-9-CPA. Furthermore, the corresponding 1 H-imidazo[1,5- a]indol-9(9a H)-ones were constructed through the easy oxidation of 2,3-dihydro-1 H-imidazo[1,5- a]indol-9(9a H)-one derivatives.

1-Alkyl-3-alkylindolin-2-imine hydrochlorides as useful building blocks in the copper-catalyzed synthesis of polycyclic indoline scaffolds.

A novel and efficient copper-catalyzed synthesis of dihydro-6-indolo[2,3-]quinoline derivatives has been developed by using 3-alkyl-1-alkylindolin-2-imine hydrochlorides as the building blocks. Furthermore, easy reduction of dihydro-6-indolo[2,3-]quinolines with diisobutylaluminum hydride provided tetrahydro-6-indolo[2,3-]quinoline derivatives in excellent yields. The present method shows some advantages including use of cheap cuprous chloride as the catalyst and tolerance of wide functional groups.

Designing of acyl sulphonamide based quinoxalinones as multifunctional aldose reductase inhibitors.

A series of quinoxalinone scaffold-based acyl sulfonamides were designed as aldose reductase inhibitors and evaluated for aldose reductase (ALR2)/aldehyde reductase (ALR1) inhibition and antioxidation. Compounds 9b-g containing styryl side chains at C3-side exhibited good ALR2 inhibitory activity and selectivity. Of them, 9g demonstrated the most potent inhibitory activity with an IC value of 0.

Axially Chiral Cyclic Diphosphine Ligand-Enabled Palladium-Catalyzed Intramolecular Asymmetric Hydroarylation.

In transition metal-catalyzed asymmetric synthesis, enantioselectivity strongly depends on the structures of chiral ligands, so the development of new chiral ligands is crucial. Here, an efficient and highly enantioselective palladium-catalyzed intramolecular hydroarylation has been developed, and a new kind of N-heterocycles, 1H-pyrazolo[5,1-a]isoindol-2(8H)-ones containing a quaternary stereocenter, was prepared in high yields and excellent enantiomeric excess values. The reaction was effectively catalyzed by palladium-diphosphine complexes with numerous functional group tolerance, in which the newly developed axially chiral cyclic diphosphine ligands played key roles in the reactivity and enantioselectivity of the substrates.

Synthesis and structure-activity relationship studies of phenolic hydroxyl derivatives based on quinoxalinone as aldose reductase inhibitors with antioxidant activity.

To enhance aldose reductase (ALR2) inhibition and add antioxidant ability, phenolic hydroxyl was introduced both to the quinoxalinone core and C3 side chain, resulting in a series of derivatives as ALR2 inhibitors. Biological activity tests suggested that most of the derivatives were potent and selective inhibitors with IC values ranging from 0.059 to 6.

A series of pyrido[2,3-b]pyrazin-3(4H)-one derivatives as aldose reductase inhibitors with antioxidant activity.

A series of pyrido[2,3-b]pyrazin-3(4H)-one based derivatives were designed as inhibitors of aldose reductase (ALR2), the enzyme which plays a key role in the development of diabetes complications as well as in the oxidative stress processes associated with diabetes and other pathologies. Most of the derivatives, having a substituted C2 aromatic group and a N4 acetic acid group on the core structure, were found to be potent and selective aldose reductase inhibitors with submicromolar IC50 values, and 9c was the most active with IC50 value 0.009 μM.

Synthesis of benzothiadiazine derivatives exhibiting dual activity as aldose reductase inhibitors and antioxidant agents.

Several multifunctional benzothiadiazine derivatives were synthesized and examined for their inhibition to the enzyme aldose reductase and in vitro antioxidant activity to identify novel drugs for diabetes and its complications. Most of them exhibited good inhibitory activity. Importantly, a number of compounds demonstrated strong antioxidant activity and one compound in particular was extremely active in the DPPH radical scavenging and MDA inhibition analysis.

Pyridothiadiazine derivatives as aldose reductase inhibitors having antioxidant activity.

A series of aldose reductase (ALR2) inhibitors based on pyridothiadiazine were prepared and evaluated for their activities in ALR2 inhibition, DPPH scavenging, and MDA inhibition. Comparison studies were carried out between analogs having either hydroxyl or methoxy groups substituted on the N2-benzyl side chains of the compounds. Most of the hydroxy-substituted compounds were found to be more potent compared to their methoxy-substituted analogs with respect to DPPH inhibition (>93%) and MDA inhibition (>73%).

Topical composition for treating diabetic cataracts: a patent evaluation (WO2015026380A1).

Diabetes mellitus is a major threat to global public health that requires long-term medical attention. In view of the potentially devastating effects of diabetes on ocular health, it highlights the urgent need of therapeutic drugs for the prevention and treatment of the diabetic complications. The patent described in this evaluation (WO2015026380A1) claimed a topical composition for treating diabetic cataracts both in animals and human beings.

Transition metal-free intramolecular regioselective couplings of aliphatic and aromatic C-H bonds.

Cross-dehydrogenative couplings of two different C-H bonds have emerged as an attractive goal in organic synthesis. However, achieving regioselective C-H activation is a great challenge because C-H bonds are ubiquitous in organic compounds. Actually, the regioselective couplings promoted by enzymes are a common occurrence in nature.

Phenolic 4-hydroxy and 3,5-dihydroxy derivatives of 3-phenoxyquinoxalin-2(1H)-one as potent aldose reductase inhibitors with antioxidant activity.

A group of novel quinoxalinone derivatives (4a-h) were prepared and investigated for their inhibitory activity against ALR2 and antioxidant activity. Most of them were found to be potent aldose reductase inhibitors with IC50 values ranging from 0.019 to 0.

Design and synthesis of potent and multifunctional aldose reductase inhibitors based on quinoxalinones.

Quinoxalin-2(1H)-one based design and synthesis produced several series of aldose reductase (ALR2) inhibitor candidates. In particular, phenolic structure was installed in the compounds for the combination of antioxidant activity and strengthening the ability to fight against diabetic complications. Most of the series 6 showed potent and selective effects on ALR2 inhibition with IC50 values in the range of 0.

Chiral resolution, determination of absolute configuration, and biological evaluation of (1,2-benzothiazin-4-yl)acetic acid enantiomers as aldose reductase inhibitors.

A novel series of (1,2-benzothiazin-4-yl)acetic acid enantiomers was prepared by chiral resolution, and their absolute configurations were determined using the PGME method. The biological evaluation of the racemate and single enantiomers has shown a remarkable difference for the aldose reductase inhibitory activity and selectivity. The (R)-(-)-enantiomer exhibited the strongest aldose reductase activity with an IC(50) value of 0.