1,2-Benzothiazine 1,1-dioxide carboxylate derivatives as novel potent inhibitors of aldose reductase.

Due to the importance of aldose reductase (ALR2) as a potential drug target in the treatment of diabetic complications, there are increasing interests in design and synthesis of ALR2 inhibitors. Here, we prepared 1,2-benzothiazine 1,1-dioxide acetic acid derivatives and investigated their inhibition activity. Most of these derivatives were found to be active with IC(50) values ranging from 0.11 µM to 10.42 µM, and compound 8d, 2-[2-(4-bromo-2-fluorobenzyl)-1,1-dioxido-2H-1,2-benzothiazin-4(3H)-ylidene]acetic acid, showed the most potent inhibition activity. Further, SAR and docking studies suggest that in comparison with the α,ß-unsaturated derivatives, the saturated carboxylic acid derivatives had a greater binding affinity with the enzyme and thus an enhanced inhibition activity. Therefore, development of more powerful ARIs based on benzothiazine 1,1-dioxide by stereo-controlled synthesis could be expected.

Synthesis, characterization, and photoelectric properties of iridium(iii) complexes containing an N hetero-dibenzofuran C

In this study, three high-efficient green light iridium(iii) complexes were designed and synthesized, wherein 2-methyl-8-(2-pyridine) benzofuran [2,3-B] pyridine (MPBFP) is the main ligand and three ß-diketone derivatives, namely 3,7-diethyl-4,6-nondiazone (detd), 2,2,6,6-tetramethyl-3,5-heptyldione (tmd) and acetylacetone (acac), are ancillary ligands. The thermal stabilities, electrochemical properties, and electroluminescence (EL) performance of these three complexes, namely (MPBFP)2 Ir(detd), (MPBFP)2Ir(tmd) and (MPBFP)2Ir(acac), were investigated. The results show that the absorption peaks of the three complexes range from 260 to 340 nm, and the maximum emission wavelengths are 537 nm, 544 nm and 540 nm, respectively. The LUMO level is -2.18 eV, -2.20 eV, -2.21 eV, and the HOMO level is -5.30 eV, -5.25 eV, and -5.25 eV, respectively. The thermal decomposition temperatures of each of the three compounds are 359 °C, 389 °C and 410 °C respectively, with a weight loss of 5%. Green phosphorescent electroluminescent devices were prepared with the structure of ITO/HAT-CN/TAPC/TCTA/TCTA:X/Bepp2/LiF/Al, and the three complexes were dispersed in the organic light-emitting layer as the guest material X. The maximum external quantum efficiency of the devices is 17.2%, 16.7%, and 16.5%, respectively. The maximum brightness is 57 328 cd m-2, 69 267 cd m-2 and 69 267 cd m-2, respectively. With respect to the EL properties, (MPBFP)2Ir(detd) is the best performer among the three complexes. The different performances exhibited by these complexes were discussed from the view point of substituent effect on the ß-diketone ligands.

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 0.032-0.468 µM, and 2-(3-(2,4-dihydroxyphenyl)-7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid (6e) was the most active. More significantly, most of the series 8 revealed not only good activity in the ALR2 inhibition but also potent antioxidant activity, and 2-(3-(3-methoxy-4-hydroxystyryl)-2-oxoquinoxalin-1(2H)-yl)acetic acid (8d) was even as strong as the well-known antioxidant Trolox at a concentration of 100 µM, verifying the C3 p-hydroxystyryl side chain as the key structure for alleviating oxidative stress. These results therefore suggest an achievement of multifunctional ALR2 inhibitors having both potency for ALR2 inhibition and as antioxidants.

Synthesis and structure-activity relationship studies of quinoxaline derivatives as aldose reductase inhibitors.

ARIs for diabetes: A series of 2-(3-benzyl-2-oxoquinoxalin-1(2H)-yl)acetic acid derivatives were designed and synthesized as inhibitors of aldose reductase (AR), a novel target for the treatment of diabetes complications. Most of the derivatives proved to be potent and selective, with IC50 values in the low nanomolar to micromolar range.

Effect of C7 modifications on benzothiadiazine-1,1-dioxide derivatives on their inhibitory activity and selectivity toward aldose reductase.

The development and progression of chronic complications in diabetic patients, such as retinopathy, nephropathy, neuropathy, cataracts, and stroke, are related to the activation and/or overexpression of aldose reductase (ALR2), which is a member of the aldo-keto reductase superfamily. A structure-activity relationship study focused on the C7 position of 1,2,4-benzothiadiazine-1,1-dioxide derivatives was pursued in an attempt to discover ALR2 inhibitors with enhanced potency and selectivity. These studies led to a series of new C7-substituted compounds, which were evaluated for their inhibitory activity against ALR2; they exhibited IC(50) values in the range of 2.80-45.13 nM. Two compounds with a C7-dimethylcarbamoyl and a C7-diethylcarbamoyl substituent, respectively, were found to be the most active and presented excellent selectivity for ALR2 over aldehyde reductase (ALR1). The structure-activity relationship analyses and molecular modeling studies presented herein highlight the importance of hydrophobic and bulky groups at the C7 position for inhibitory activity and selectivity toward ALR2.

An efficient synthesis of quinoxalinone derivatives as potent inhibitors of aldose reductase.

A novel and facile synthesis of quinoxalinone derivatives was developed in which a wide range of 3-chloroquinoxalin-2(1H)-ones as key intermediates can be generated chemo- and regioselectively in good yields from corresponding quinoxaline-2,3(1H,4H)-diones. This new protocol is arguably superior, as it allows the design and preparation of a variety of bioactive quinoxaline-based compounds, which are particularly effective in the treatment of diabetes and its complications. Through this procedure, a new class of quinoxalinone-based aldose reductase inhibitors were synthesized successfully. Most of the inhibitors, with an N1-acetic acid head group and a substituted C3-phenoxy side chain, proved to be potent and selective. Their IC(50) values ranged from 11.4 to 74.8 nM. Among them, 2-(3-(4-bromophenoxy)-7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid and 2-(6-bromo-3-(4-bromophenoxy)-2-oxoquinoxalin-1(2H)-yl)acetic acid were the most active. Structure-activity relationship and molecular docking studies highlighted the importance of the ether spacer in the C3-phenoxy side chains, and provided clear guidance on the contribution of substitutions both at the core structure and the side chain to activity.

Design and synthesis of potent and selective aldose reductase inhibitors based on pyridylthiadiazine scaffold.

A series of pyrido[2,3-e]-[1,2,4]-thiadiazine 1,1-dioxide acetic acid derivatives were synthesized and tested for their inhibitory activity against aldose reductase (ALR2). These derivatives were found to be potent aldose reductase inhibitors with IC50 values ranging from 0.038 µM to 11.29 µM. Most but not all of them showed a strong ALR2 inhibition activity and significant selectivity, which were further supported by docking studies. Of these inhibitors, compound 7d exhibited highest inhibition activity. Structure-activity relationship studies indicate the requirement of N2-benzyl group with electron-withdrawing substituents and N4-acetic acid group in the pyridothiadiazine scaffold.

Acetic acid derivatives of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide as a novel class of potent aldose reductase inhibitors.

A series of novel benzothiadiazine 1,1-dioxide derivatives were synthesized and tested for their inhibitory activity against aldose reductase. Of these derivatives, 17 compounds, having a substituted N2-benzyl group and a N4-acetic acid group on the benzothiadiazine, were found to be potent and selective aldose reductase inhibitors in vitro with IC50 values ranging from 0.032 to 0.975 µM. 9m proved to be the most active in vitro. The eight top-scoring compounds coming from the in vitro test for ALR2 inhibition activity were then tested in vivo, whereby three derivatives, 9i, 9j, and 9m, demonstrated a significantly preventive effect on sorbitol accumulation in the sciatic nerve in the 5-day streptozotocin-induced diabetic rats in vivo. Structure-activity relationship and molecular docking studies highlighted the importance of substitution features of N4-acetic acid group and halogen-substituted N2-benzyl group in the benzothiadiazine scaffold and indicated that substitution with hallogen at C-7 had a remarkably strong effect on ALR2 inhibition potency.