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. Aldose reductase inhibitory activities of the novel compounds were characterized by IC50 values ranging from 0.015 to 31.497 µM. Markedly enhanced selectivity of these derivatives was also recorded, which was further supported by docking studies. Of these inhibitors, compound 5g exhibited the highest inhibition activity with selectivity indices reaching 1190.8. The structure-activity relationship highlighted the importance of N1-acetic acid and N3-benzyl groups with electron-withdrawing substituents on the quinazolin-4(1H)-one scaffold for the construction of efficient and selective AKR1B1 inhibitors.

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. Further in vivo studies of 11j and 14d using streptozotocin (STZ)-induced diabetic rats as a model found that 11j achieved not only good antihyperglycemic and glucose tolerance effect in a dose-dependent manner (p < 0.01) but also showed effective inhibition of polyol pathway. 14d significantly suppressed the maltose-induced postprandial glucose elevation. Additionally, they effectively improved lipid metabolisms and restored an antioxidant ability. Therefore, the two compounds may be promising agents for the prevention and treatment of diabetic complications.

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 IC50 values against ALR2. Particularly, compound 4e was the most active with an IC50 value of 0.038 µM, and it was also proved to be endowed with excellent inhibitory selectivity. The structure-activity relationship and molecular docking studies highlighted the importance of the carboxylic acid head group along with different halogen substituents on the C6 benzylamine side chain of the 9H-purin-6-amine scaffold for the construction of strong and selective ALR inhibitors.

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. Further investigations showed blood glucose normalization, declined in the polyol pathway and lipid peroxides, and raised glutathione and superoxide dismutase activity. Thus, we suggest a therapeutic function of the compound for DN which could be attributed to the combination of hypoglycemic, aldose reductase inhibition and antioxidant.

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. Most of these derivatives were found to be potent and selective against AKR1B1, and compound 8a was the most active with an IC50 value of 0.035 µM. Moreover, some prepared derivatives showed strong anti-ROS activity, and among them the phenolic 3,5-dihydroxyl compound 8b was proved to be the most potent, even comparable to that of the well-known antioxidant Trolox at a concentration of 100 µM. Thus the results suggested a success in the construction of potent dual inhibitor for the therapeutic intervention target of AKR1B1/ROS.

(5-Hydroxy-4-oxo-2-styryl-4H-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. Notably, {2-[2-(3,4-dihydroxy-phenyl)-vinyl]-5-hydroxy-4-oxo-4H-pyridin-1-yl}-acetic acid (7l) was the most potent, with IC50 values of 0.789 µM. Moreover, 7l showed excellent selectivity towards ALR2 with selectivity index 25.23, which was much higher than that of eparlestat (17.37), the positive control. More significantly, 7l performed powerful antioxidative action. At a concentration of 1 µM, phenolic compounds 7l scavenged DPPH radical with an inhibitory rate of 41.48%, which was much higher than that of the well-known antioxidant Trolox, at 11.89%. Besides, 7l remarkably suppressed lipid peroxidation with a rate of 88.76% at a concentration of 100 µM. The binding mode derived from molecular docking proved that the derivatives were tightly bound to the activate site, suggesting strongly inhibitory action of derivatives against ALR2. Therefore, these results provided an achievement of multifunctional ALR2 inhibitors capable with potency for both selective ALR2 inhibition and as antioxidants.

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 IC50 values ranging from 0.082 to 0.308 µM, and {8-[2-(4-hydroxy-phenyl)-vinyl]-2-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetic acid (3a) was the most potent. More significantly, most of dihydrobenzoxazinone compounds revealed not only good inhibitory effect on ALR2, but also showed powerful antioxidant activity. Notably, phenolic compound 3a was even comparable to the well-known antioxidant Trolox, confirming that the C8 p-hydroxystyryl substitution was key structure of lowering oxidative stress. Therefore, these results provided an achievement of multifunctional ALR2 inhibitors possessing capacities for both ALR2 inhibition and as antioxidants.

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

Aim: Targeting aldose reductase and oxidative stress with quinoxalin-2(1H)-one derivatives having a 1-hydroxypyrazole head as the bioisosteric replacement of carboxylic acid. Methodology & results: 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 13d was the most active (IC50 = 0.107 µM), suggesting success of the bioisosteric strategy. Phenolic 3,4-dihydroxyl compound 13f showed strong antioxidant ability even comparable to that of the well-known antioxidant Trolox. Conclusion: The present study identified the excellent bioisostere of the 1-hydroxypyrazole head group along with phenolic hydroxyl and vinyl spacer in C3 side chain on constructing quinoxalinone-based multifunctional aldose reductase inhibitors.

Novel 2-phenoxypyrido[3,2-b]pyrazin-3(4H)-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-b]pyrazin-3(4H)-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-b]pyrazin-4(3H)-yl) acetic acid (4k) was the most active with an IC50 value of 0.023 µM. Moreover, it was encouraging to find that some derivatives showed strong antioxidant activity, and among them, the phenolic 3,5-dihydroxyl compound 4l with 7-bromo in the core structure was proved to be the most potent, even comparable to that of the well-known antioxidant Trolox. Thus the results suggested success in the construction of potent and selective AKR1B1 inhibitors with antioxidant activity.

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.

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 IC50 value of 0.100 µM, and also exhibited excellent antioxidant activity, even comparable to the typical antioxidant Trolox. Compounds 9 had higher lipid-water partition coefficients relative to the carboxylic acid compounds 8, indicating that they may have better lipophilicity and membrane permeability. Structure-activity relationship (SAR) studies found that acyl trifluoromethanesulfonamide group at N1 and the C3-dihydroxystyryl side chain were the key structure for improving the aldose reductase inhibitory activity and antioxidant activity.

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-6H-indolo[2,3-b]quinoline derivatives has been developed by using 3-alkyl-1-alkylindolin-2-imine hydrochlorides as the building blocks. Furthermore, easy reduction of dihydro-6H-indolo[2,3-b]quinolines with diisobutylaluminum hydride provided tetrahydro-6H-indolo[2,3-b]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.

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. We believe that the cyclic diphosphine ligands with adjustable dihedral angles will find wide application in asymmetric synthesis.

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 IC50 values ranging from 0.059 to 6.825µM, and 2-(3-(4-hydroxystyryl)-7-methoxy-2-oxoquinoxalin-1(2H)-yl)acetic acid (6b) was the most active. Particularly, it was encouraging to find that some derivatives endowed with obvious antioxidant activity, and among them the phenolic 3,4-dihydroxyl compound 6f with 7-hydroxyl in the quinoxalinone core showed the most potent activity, even comparable with the well-known antioxidant Trolox. Structure-activity relationship and docking studies highlighted the importance of phenolic hydroxyl both in C3 side chain and the core structure for constructing potent ALR2 inhibitors with antioxidant activity.

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. Particularly, a number of the designed compounds bearing phenolic hydroxyl substituted C2-styryl side chain showed excellent not only in ALR2 inhibition but also in antioxidant, and among these 11i was proved to be the top one with an antioxidant ability even comparable to that of the well-known antioxidant Trolox. Structure-activity relationship and molecular docking studies highlighted the importance of phenolic hydroxyl substituents and vinyl spacer in C2 side chain of the scaffold for the construction of efficient and multifunctional ALR2 inhibitors.

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. The DPPH radical scavenging rate with this compound was 98.0%, 92.3% and 42.1% at concentrations of 100µM, 10µM, and 1µM, respectively, and the initial reaction rate was faster than Trolox at a concentration of 10µM.

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%). However, ALR2 inhibitory activity was found to be affected by the electron-withdrawing substituent at the C7 position in addition to the effect of the N2-substituted benzyl group. These results provide an array of multifunctional ALR2 inhibitors possessing capacities both for ALR2 inhibition and as antioxidants.