Chaojun Jing

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.

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 IC50 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.

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,β-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.

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.

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.

Synthesis and characterization of sulfonated polyphosphazene-graft-polystyrene copolymers for proton exchange membranes

A novel series of polyphosphazene-graft-polystyrene (PP-g-PS) copolymers were successfully prepared by atom transfer radical polymerization (ATRP) of styrene monomers and brominated poly(bis(4-methylphenoxy)phosphazene) macroinitiator. The graft density and the graft length could be regulated by changing the bromination degree of the macroinitiator and the ATRP reaction time, respectively. The PP-g-PS copolymers readily underwent a regioselective sulfonation reaction, which occurred preferentially at the polystyrene sites, producing the sulfonated PP-g-PS copolymers with a range of ion exchange capacities. The resulting sulfonated PP-g-PS membranes prepared by solution casting showed high water uptake, low water swelling and considerable proton conductivity. They also exhibited good oxidative stability and high resistance to methanol crossover. Morphological studies of the membranes by transmission electron microscopy showed clear nanophase-separated structures resulted from hydrophobic polyphosphazene backbone and hydrophilic polystyrene sulfonic acid segments, indicating the formation of proton transferring tunnels. Therefore, these sulfonated copolymers may be candidate materials for proton exchange membranes in direct methanol fuel cell (DMFC) applications.

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 IC50 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.

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.

Synthesis and Characterization of Perfluoroalkyl Sulfonic Acid Functionalized Polyphosphazene for Proton-Conducting Membranes

Polyphosphazenes containing perfluoroalkyl sulfonic acids (PSA-P) were synthesized by the copper-catalyzed coupling reaction of poly[(4-bromophenoxy)(phenoxy)phosphazene] with potassium 1,1,2,2-tetrafluoro-2-(1,1,2,2-tetrafluoro-2-iodoethoxy) ethanesulfonate. Two synthetic protocols have been developed to obtain the polymers and 1, 10-phenanthroline was found benefit for improving the efficiency of the coupling reaction. The PSA-P membranes prepared by solution casting showed excellent thermal stability, oxidative stability and low swelling ratios. In addition, compared with the sulfonated poly[bis(phenoxy)phosphazene] membrane with similar IEC, the PSA-P membrane displayed significant superiority in proton conductivity, water resistance, oxidative and thermal stability, indicating that it is a good candidate for proton exchange membranes.