Changjin Zhu

A series of copolymers as anion exchange membrane materials were synthesized by the copolymerization of N,N-butylvinylimidazolium with p-methylstyrene and polybenzimidazole, and then the corresponding membranes were prepared and are abbreviated in this study as VIBx/PMSy/PBIz. The components of the three polymeric blocks were optimized in order to realize a good compromise between different properties. Membrane test results revealed that the percentage of a single polymeric block in the copolymer influenced directly the anion conductivity of the membrane. Comparing to the commercial membrane A201 Tokuyama, six of the present membranes had a better conductivity at high temperatures, and three displayed better conductivity at all temperatures. The best conductivity is observed for membrane VIB5/PMS1/PBI0.5 which reaches chloride conductivity of 26.3 mS cm−1 at 25 °C and 73.7 mS cm−1 at 100 °C. The membrane had an IEC of 2.6 mmol g−1 and a low activation energy of 6.62 kJ mol−1. Membrane VIB5/PMS2/PBI0.5 is also among the three membranes that had better conductivity, and had 10.77% swelling ratio and 6.66 kJ mol−1 of activation energy. Most membranes showed a low activation energy and in-plane swelling ratio. So far all membranes exhibit a linear Arrhenius behavior and are thermally stable up to 250 °C. The morphology study explored by TEM and AFM showed a well-developed bicontinuous phase distribution of hydrophilic and hydrophobic regions that confirmed a facile transport through the ion channels deduced after the finding of activation energy results.

Novel proton conducting membranes based on cross-linked sulfonated polyphosphazenes and poly(ether ether ketone)

Co-reporter:Shuitao Gao, Hulin Xu, Tianwei Luo, Yingfang Guo, Zhong Li, Amina Ouadah, Yanxia Zhang, Zeyu Zhang, Changjin Zhu

Journal of Membrane Science 2017 Volume 536(Volume 536) pp:

Publication Date(Web):15 August 2017

DOI:10.1016/j.memsci.2017.04.065

•Polyphosphazenes cross-linked with highly sulfonated poly(ether ether ketone) were designed and synthesized.•Hybrid membrane composed of sulfonated single-walled carbon nanotubes was prepared.•Hybrid membrane showed a conformation of complete homogeneity and compatibility.•Hybrid membrane exhibited low methanol permeability, satisfying proton conductivity and excellent selectivity.•Hybrid membrane disentangled the tradeoff between proton conductivity and dimensional stability for highly sulfonated PEEK.Two series of membranes A and B were designed and prepared by the following synthesis protocols where the cross-linked membranes were composed of highly sulfonated poly(ether ether ketone) (SPEEK) as the acidic component and polyphosphazenes backbone as the basic component. Membrane A was synthesized based on the graft-onto reaction between brominated poly[(4-methoxyphenoxy)(4-methylphenoxy)phosphazenes] (PMMP-Br) and SPEEK3 polymers, while membranes B were obtained by the reaction of bromomethyl groups of polyphosphazenes with triethylamine and simultaneously combined with various amounts of SPEEK3. All the membranes were characterized chemically, thermally, and mechanically by a set of technical means. Polyphosphazenes were found to constrain to a large extent the water uptake and swelling when blended with highly sulfonated PEEK providing sufficient mechanical strength without over-swelling. Specially, the advent of sulfonated single-walled carbon nanotubes (SCNT) in the membrane A led to the hybrid membrane A2:1-SCNT with favorable properties. It exhibited a satisfying proton conductivity of 0.132 S cm−1 at 80 °C and a very low methanol permeability of 2.16×10−7 cm2 s−1, and retained considerable thermal stability as well as mechanical strength. Also, the fuel cell performance of A2:1-SCNT at 25 °C was higher than that of recast membrane A2:1.

A series of poly(butylimidazolium) ionic liquid functionalized copolymers for anion exchange membranes

Co-reporter:Amina Ouadah, Hulin Xu, Tianwei Luo, Shuitao Gao, Xing Wang, Zhou Fang, Chaojun Jing, Changjin Zhu

Journal of Power Sources 2017 Volume 371(Volume 371) pp:

Publication Date(Web):15 December 2017

DOI:10.1016/j.jpowsour.2017.10.038

•High conductive b-VIB based DPEBI as AEM.•Low water uptake, swelling ratio and activation energy.•Drastically alkaline stability in 2M KOH.•Thermally stable up to 250 °C.•Well distinguished hydrophilic/hydrophobic nanophase separation.A new series of ionic liquid functionalized copolymers for anion exchange membranes (AEM) is prepared. Poly(butylvinylimidazolium)(b-VIB) is copolymerized with para-methyl styrene (p-MS) by the radical polymerization formed block copolymers b-VIB/p-MS, which is crosslinked with poly(diphenylether bibenzimidazole) (DPEBI) providing the desired materials b-VIB/p-MS/DPEBI. Structures are characterized via H1NMR, FTIR spectra and elemental analysis. The b-VIB blocks offer the anion conduction function while DPEBI moieties contribute to enhancing other properties. The prepared membranes display chloride conductivity as high as 19.5 mS/cm at 25 °C and 69.2 mS/cm at 100 °C-higher than that of the commercial membrane tokuyuama A201-. Their hydroxide conductivity reaches 35.7 Scm−1 at 25 °C and 73.1 Scm−1 at 100 °C. The membranes showed a linear Arrhenius behavior in the anion conduction, low activation energies and distinguished nanophase separation of hydrophilic/hydrophobic regions by the transmission electron microscopy (TEM) studies. Thermal investigations using TGA and DSC confirm that the membranes are stable up to 250 °C. Particularly, drastically alkaline stability due to no decrease in the hydroxide conductivity after 168 h of treatment with 2M KOH.Download high-res image (186KB)Download full-size image

Multifunctional aldose reductase inhibitors based on 2H-benzothiazine 1,1-dioxide

Co-reporter:Zhongfei Han, Xin Hao, Zehong Gao, Bing Ma and Changjin Zhu

RSC Advances 2016 vol. 6(Issue 16) pp:12761-12769

Publication Date(Web):25 Jan 2016

DOI:10.1039/C5RA25984C

A series of benzothiazine derivatives were designed and synthesized for the development of drug candidates for diabetic complications. A number of derivatives having a phenolic hydroxyl-substituted N2-aromatic side chain and a C4-acetic acid head group on the core structure were found to be potent and selective aldose reductase inhibitors. 8a with a phenolic 4-hydroxyl at N2-styryl side chain was proved to be the most active with an IC50 value of 0.094 μM. All compounds with the N2-styryl side chain showed good antioxidant activity using the DPPH radical scavenging test, and among them, compounds with phenolic hydroxyl-substituted N2-styryl were potent both in activities of ALR2 inhibition and antioxidation. The results suggest a success in the development of multifunctional aldose reductase inhibitors based on the benzothiazine framework.

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

Co-reporter:Shaojuan Zhu, Xin Hao, Shuzhen Zhang, Xiangyu Qin, Xin Chen, Changjin Zhu

Bioorganic & Medicinal Chemistry Letters 2016 Volume 26(Issue 12) pp:2880-2885

Publication Date(Web):15 June 2016

DOI:10.1016/j.bmcl.2016.04.047

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 100 μM, 10 μM, and 1 μM, respectively, and the initial reaction rate was faster than Trolox at a concentration of 10 μM.

Proton exchange membrane based on crosslinked sulfonated polyphosphazene containing pendent perfluorosulfonic acid groups with sulfonated poly(ether ether ketone)

Co-reporter:Yan Dong;Yan-Xia Zhang;Hu-Lin Xu;Tian-Wei Luo;Feng-Yan Fu;Chang-Jin Zhu

Journal of Applied Polymer Science 2016 Volume 133( Issue 23) pp:

Publication Date(Web):

DOI:10.1002/app.43492

ABSTRACT

A series of crosslinked membranes based on new sulfonated polyphosphazene bearing pendent perfluorosulfonic acid groups (PMFP-g-PS) and sulfonated poly (ether ether ketone) were prepared and evaluated as proton exchange membranes for direct methanol fuel cells (DMFCs). The structure of PMFP-g-PS was characterized by Fourier transform infrared spectroscopy, ¹H and ¹⁹F NMR spectra. In comparison with the pristine PMFP-g-PS membrane, the crosslinked membranes showed improved water uptakes and proton conductivities. The methanol permeability values of the membranes were in the range of 1.32 × 10⁻⁷ to 3.85 × 10⁻⁷ cm²/s, which were lower than Nafion 117 (12.1 × 10⁻⁷ cm²/s). The selectivity of all the membranes was much higher compared with Nafion 117. Furthermore, transmission electron microscopy observation revealed that clear phase-separated structures were well dispersed and connected to each other in the membranes. These membranes displayed high water uptakes and low swelling ratios, high proton conductivities, low methanol permeability values, good thermal, and oxidative stabilities. The results indicate that these membranes are potential candidate proton exchange membrane materials for DMFCs. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 43492.

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

Co-reporter:Zhongfei Han, Xin Hao, Bing Ma, Changjin Zhu

European Journal of Medicinal Chemistry 2016 121() pp: 308-317

Publication Date(Web):4 October 2016

DOI:10.1016/j.ejmech.2016.05.036

•A series of novel aldose reductase inhibitors were synthesized.•Compound 11i was proved to be a multifunctional ARI with antioxidant activity.•Structure-activity relationship and molecular docking studies were conducted.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.

Design of polyphosphazene-based graft copolystyrenes with alkylsulfonate branch chains for proton exchange membranes

Co-reporter:Fengyan Fu, Hulin Xu, Yan Dong, Minlan He, Zeyu Zhang, Tianwei Luo, Yanxia Zhang, Xin Hao, Changjin Zhu

Journal of Membrane Science 2015 Volume 489() pp:119-128

Publication Date(Web):1 September 2015

DOI:10.1016/j.memsci.2015.04.016

•Polyphosphazene graft copolystyrenes with alkylsulfonate chains were synthesized.•They were made into the proton exchange membranes with the cross-linker.•The proton conduction was comparable or superior to Nafion 117.•The proton conduction may attribute to the nanophase-separated morphology.•These membranes all could inhibit significantly the methanol diffusion.In order to develop efficient proton exchange membranes used for direct methanol fuel cells, we are focusing on the design and synthesis of polyphosphazene-based copolymers. In the present study, block polystyrenes were grafted onto polyphosphazenes by atom transfer radical polymerization (ATRP) of styrene and 4-acetoxystyrene, and then alkylated with 1,4-butanesultone to yield two series of graft copolymers having branch chains of alkylsulfonic acids. They were further made into the corresponding membranes with the assist of simultaneous cross-linking reaction with 2,6-bis(hydroxymethyl)-4-methylphenol (BHMP) as the cross-linker. High proton conductivities were found for the membrane series of M-PSx-PSBOSy in the range of 0.184–0.266 S/cm, and for F-PSx-PSBOSy in the range of 0.147–0.284 S/cm under fully hydrated conditions at 80 °C, respectively, and were supported by the nanophase-separated structures by the transmission electron microscopy (TEM) investigations. Also, the membranes showed good methanol resistance (1.60–10.4×10−7 cm2/s) and high oxidative stabilities. These results suggest a potential of the membranes for the DMFCs application.A novel polyphosphazene-based graft polystyrene with branch chains of alkylsulfonic acid copolymers for proton exchange membranes was synthesized to use in direct methanol fuel cells.

Design and Synthesis of Potent and Multifunctional Aldose Reductase Inhibitors Based on Quinoxalinones

Co-reporter:Xiangyu Qin; Xin Hao; Hui Han; Shaojuan Zhu; Yanchun Yang; Bobin Wu; Saghir Hussain; Shagufta Parveen; Chaojun Jing; Bing Ma

Journal of Medicinal Chemistry 2015 Volume 58(Issue 3) pp:1254-1267

Publication Date(Web):January 20, 2015

DOI:10.1021/jm501484b

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 properties of sulfonated poly(phosphazene)-graft-poly(styrene-co-N-benzylmaleimide) copolymers via atom transfer radical polymerization for proton exchange membrane

Co-reporter:Yan Dong;Hu-Lin Xu;Min-Lan He;Feng-Yan Fu;Chang-Jin Zhu

Journal of Applied Polymer Science 2015 Volume 132( Issue 29) pp:

Publication Date(Web):

DOI:10.1002/app.42251

ABSTRACT

A series of sulfonated poly(phosphazene)-graft-poly(styrene-co-N-benzylmaleimide) (PP-g-PSN) copolymers were prepared via atom transfer radical polymerization (ATRP), followed by regioselective sulfonation which occurred preferentially at the poly(styrene-co-N-benzylmaleimide) sites. The structures of these copolymers were confirmed by Fourier transform infrared (FTIR) spectroscopy, ¹H-NMR, and ³¹P-NMR, respectively. The resulting sulfonated PP-g-PSN membranes showed high water uptakes (WUs), low water swelling ratios (SWs), low methanol permeability coefficients, and proper proton conductivities. In comparison with non-grafting sulfonated poly(bis(phenoxy)phosphazene) (SPBPP) membrane previously reported, the present membranes displayed higher proton conductivity, significantly improved the thermal and oxidative stabilities. Transmission electron microscopy (TEM) observation showed clear phase-separated structures resulting from the difference in polarity between the hydrophobic polyphosphazene backbone and hydrophilic sulfonated poly(styrene-co-N-benzylmaleimide) side chains, indicating effective ionic pathway in these membranes. The results showed that these materials were promising candidate materials for proton exchange membrane (PEM) in direct methanol fuel cell (DMFC) applications. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 42251.

Polyphosphazene-based copolymers containing pendant alkylsulfonic acid groups as proton exchange membranes

Co-reporter:Fengyan Fu, Hulin Xu, Yan Dong, Minlan He, Tianwei Luo, Yanxia Zhang, Xin Hao, Tao Ma, Changjin Zhu

Solid State Ionics 2015 Volume 278() pp:58-64

Publication Date(Web):1 October 2015

DOI:10.1016/j.ssi.2015.05.018

•A series of polyphosphazene-based copolymers were prepared.•They were made into the corresponding membranes by the assist of the cross-linking reagent.•The membranes showed lower water uptake and dimensional swelling.•They displayed significant methanol resistance.•The proton conductivities up to 0.14 S/cm at 80 °C under fully hydrated conditions.A series of polyphosphazene-based copolymers containing alkylsulfonated side chains were prepared and made into the corresponding membranes by the reaction with 2,6-bis(hydroxymethyl)-4-methylphenol (BHMP) as the cross-linking reagent. All the cross-linked membranes showed lower water uptake and dimensional swelling. They displayed significant methanol resistance ranging from 1.35 to 7.18 × 10− 7 cm2/s and high oxidative stabilities. The individual membrane PFMPP1-r-PFSPP9 showed good proton conductivity (0.14 S/cm) under fully hydrated conditions at 80 °C.

Selective synthesis and comparative activity of olefinic isomers of 1,2-benzothiazine-1,1-dioxide carboxylates as aldose reductase inhibitors

Co-reporter:Shagufta Parveen, Saghir Hussain, Shaojuan Zhu, Xiangyu Qin, Xin Hao, Shuzhen Zhang, Jianglu Lu and Changjin Zhu

RSC Advances 2014 vol. 4(Issue 40) pp:21134-21140

Publication Date(Web):21 Mar 2014

DOI:10.1039/C4RA01016G

α,β- and β,γ-unsaturated carboxylate isomers of 1,2-benzothiazine-1,1-dioxide were selectively synthesized via the Wittig olefination reaction under various temperature conditions. At 40 °C, α,β-unsaturated esters with high Z-stereoselectivity (83–87%) were formed, while β,γ-unsaturated esters formed preferentially with moderate to excellent regioselectivity at 100–120 °C (77–96%). The acid isomers were found to inhibit aldose reductase in order of activity β,γ-unsaturated > Z-α,β-unsaturated > E-α,β-unsaturated isomers. The β,γ-unsaturated isomer 7b, 2-[2-(4-bromo-2-fluorobenzyl)-1,1-dioxido-2H-1,2-benzothiazin-4(3H)-ylidene]acetic acid, exhibited the most potent inhibition activity, with an IC50 value of 0.057 μM. This was further supported by docking studies.

Novel synthesis of nitro-quinoxalinone derivatives as aldose reductase inhibitors

Co-reporter:Saghir Hussain, Shagufta Parveen, Xiangyu Qin, Xin Hao, Shuzhen Zhang, Xin Chen, Changjin Zhu, Bing Ma

Bioorganic & Medicinal Chemistry Letters 2014 Volume 24(Issue 9) pp:2086-2089

Publication Date(Web):1 May 2014

DOI:10.1016/j.bmcl.2014.03.053

A novel, non-acid series of nitroquinoxalinone derivatives was synthesized and tested for their inhibitory activity against aldose reductase as targeting enzyme. All active compounds displayed an 8-nitro group, and showed significant activity in IC50 values ranging from 1.54 to 18.17 μM. Among them 6,7-dichloro-5,8-dinitro-3-phenoxyquinoxalin-2(1H)-one (7e), exhibited the strongest aldose reductase activity with an IC50 value of 1.54 μM and a good SAR (structure–activity relationship) profile.

Structure–activity relationships studies of quinoxalinone derivatives as aldose reductase inhibitors

Co-reporter:Saghir Hussain, Shagufta Parveen, Xin Hao, Shuzhen Zhang, Wei Wang, Xiangyu Qin, Yanchun Yang, Xin Chen, Shaojuan Zhu, Changjin Zhu, Bing Ma

European Journal of Medicinal Chemistry 2014 80() pp: 383-392

Publication Date(Web):

DOI:10.1016/j.ejmech.2014.04.047

Copper-Catalyzed Asymmetric Synthesis and Comparative Aldose Reductase Inhibition Activity of (+)/(−)-1,2-Benzothiazine-1,1-dioxide Acetic Acid Derivatives

Co-reporter:Shagufta Parveen, Saghir Hussain, Xiangyu Qin, Xin Hao, Shaojuan Zhu, Miao Rui, Shuzhen Zhang, Fengyan Fu, Bing Ma, Qun Yu, and Changjin Zhu

The Journal of Organic Chemistry 2014 Volume 79(Issue 11) pp:4963-4972

Publication Date(Web):May 2, 2014

DOI:10.1021/jo500338c

A copper catalyst system for the asymmetric 1,4-hydrosilylation of the α,β-unsaturated carboxylate class was developed by which synthesis of (+)- and (−)-enantiomers of 1,2-benzothiazine-1,1-dioxide acetates has been achieved with a good yield and an excellent level of enantioselectivity. A comparative structure–activity relationship study yielded the following order of aldose reductase inhibition activity: (−)-enantiomers > racemic > (+)-enantiomers. Further, a molecular docking study suggested that the (−)-enantiomer had significant binding affinity and thus increased inhibition activity.

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

Co-reporter:Min-lan He;Hu-lin Xu;Yan Dong;Jia-hong Xiao

Chinese Journal of Polymer Science 2014 Volume 32( Issue 2) pp:151-162

Publication Date(Web):2014 February

DOI:10.1007/s10118-014-1394-0

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.

Composite polyphosphazene membranes doped with phosphotungstic acid and silica

Co-reporter:Feng-yan Fu;Hu-lin Xu 徐虎林;Min-lan He;Yan Dong

Chinese Journal of Polymer Science 2014 Volume 32( Issue 8) pp:996-1002

Publication Date(Web):2014/08/01

DOI:10.1007/s10118-014-1459-0

Poly(bis(phenoxy)phosphazene) (SPBPP)/phosphotungstic acid (PWA)/silica composite membranes for fuel cells were prepared. The composite membranes were characterized by using FTIR, TGA and SEM techniquies. Incorporation of PWA particles and silica particles into the SPBPP polymer matrix and a specific interaction between them were confirmed by FTIR spectra. TGA results showed that the composite membranes had high thermal stability. Homogeneous distribution of PWA and silica particles within the SPBPP matrix was verified by SEM micrographs. The doped membranes showed increased water uptake and proton conductivity.

Synthesis and StructureActivity Relationship Studies of Quinoxaline Derivatives as Aldose Reductase Inhibitors

Co-reporter:Bobin Wu;Dr. Yanchun Yang;Dr. Xiangyu Qin;Dr. Shuzhen Zhang;Dr. Chaojun Jing;Dr. Changjin Zhu;Dr. Bing Ma

ChemMedChem 2013 Volume 8( Issue 12) pp:1913-1917

Publication Date(Web):

DOI:10.1002/cmdc.201300324

Effect of C7 Modifications on Benzothiadiazine-1,1-dioxide Derivatives on Their Inhibitory Activity and Selectivity toward Aldose Reductase

Co-reporter:Shuzhen Zhang;Xin Chen;Shagufta Parveen;Saghir Hussain;Yanchun Yang;Chaojun Jing ;Dr. Changjin Zhu

ChemMedChem 2013 Volume 8( Issue 4) pp:603-613

Publication Date(Web):

DOI:10.1002/cmdc.201200386

Abstract

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.

Inside Cover: Effect of C7 Modifications on Benzothiadiazine-1,1-dioxide Derivatives on Their Inhibitory Activity and Selectivity toward Aldose Reductase (ChemMedChem 4/2013)

Co-reporter:Shuzhen Zhang;Xin Chen;Shagufta Parveen;Saghir Hussain;Yanchun Yang;Chaojun Jing ;Dr. Changjin Zhu

ChemMedChem 2013 Volume 8( Issue 4) pp:

Publication Date(Web):

DOI:10.1002/cmdc.201390011

An Efficient Synthesis of Quinoxalinone Derivatives as Potent Inhibitors of Aldose Reductase

Co-reporter:Yanchun Yang;Shuzhen Zhang;Bobin Wu;Mingming Ma;Xin Chen;Xiangyu Qin;Minlan He;Saghir Hussain;Chaojun Jing;Bing Ma ;Dr. Changjin Zhu

ChemMedChem 2012 Volume 7( Issue 5) pp:823-835

Publication Date(Web):

DOI:10.1002/cmdc.201200054

Abstract

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.

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

Co-reporter:Xin Chen, Yanchun Yang, Bing Ma, Shuzhen Zhang, Minlan He, Dequan Gui, Saghir Hussain, Chaojun Jing, Changjin Zhu, Qun Yu, Yan Liu

European Journal of Medicinal Chemistry 2011 Volume 46(Issue 5) pp:1536-1544

Publication Date(Web):May 2011

DOI:10.1016/j.ejmech.2011.01.072

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.A series of pyrido[2,3-e]-[1,2,4]-thiadiazine derivatives were synthesized and found to be potent aldose reductase inhibitors with IC50 values ranging from 0.038 to 11.29 μM. Their structure–activity relationships were also discussed.Highlights► Aldose reductase links with the long-term diabetic complications. ► Aldose reductase inhibitors are a promising and an attractive therapeutic strategy. ► Design based on pyridothiadiazine scaffold leads to potent and selective inhibitors.

Acetic Acid Derivatives of 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxide as a Novel Class of Potent Aldose Reductase Inhibitors

Co-reporter:Xin Chen ; Changjin Zhu ; Fan Guo ; Xiaowei Qiu ; Yanchun Yang ; Shuzhen Zhang ; Minlan He ; Shagufta Parveen ; Chaojun Jing ; Yan Li ;Bing Ma

Journal of Medicinal Chemistry 2010 Volume 53(Issue 23) pp:8330-8344

Publication Date(Web):November 9, 2010

DOI:10.1021/jm100962a

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.

Preparation and evaluation of crosslinked sulfonated polyphosphazene with poly(aryloxy cyclotriphosphazene) for proton exchange membrane

Co-reporter:Yan Dong, Hulin Xu, Fengyan Fu, Changjin Zhu

Journal of Energy Chemistry (May 2016) Volume 25(Issue 3) pp:472-480

Publication Date(Web):1 May 2016

DOI:10.1016/j.jechem.2016.03.013

Several crosslinked proton exchange membranes with high proton conductivities and low methanol permeability coefficients were prepared, based on the sulfonated poly[(4-fluorophenoxy)(phenoxy)] phosphazene (SPFPP) and newly synthesized water soluble sulfonated poly(cyclophosphazene) (SPCP) containing clustered flexible pendant sulfonic acids. The structure of SPCP was characterized by fourier transform infrared spectroscopy (FTIR) and 1H NMR spectra. The membranes showed moderate proton conductivities and much lower methanol permeability coefficients when compared to Nafion 117. Transmission electron microscopy (TEM) results indicated the well-defined phase separation between the locally and densely sulfonated units and hydrophobic units, which induced efficient proton conduction. In comparison with SPFPP membrane, the proton conductivities, oxidative stabilities and mechanical properties of crosslinked membranes remarkably were improved. The selectivity values of all the crosslinked membranes were also much higher than that of Nafion 117 (0.74×105 S· s/cm3). These results suggested that the cSPFPP/SPCP membranes were promising candidate materials for proton exchange membrane in direct methanol fuel cells.Crosslinked sulfonated polyphosphazene with poly(aryloxycyclotriphosphazene) membranes were prepared, exhibiting high proton conductivity, low methanol permeability, excellent thermal stability, good oxidative and mechanical properties.Download full-size image

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

Co-reporter:Xin Hao, Zhongfei Han, Yang Li, Chenying Li, Xing Wang, Xin Zhang, Qin Yang, Bing Ma, Changjin Zhu

Bioorganic & Medicinal Chemistry Letters (15 February 2017) Volume 27(Issue 4) pp:

Publication Date(Web):15 February 2017

DOI:10.1016/j.bmcl.2017.01.006

•Novel aldose reductase inhibitors exhibiting antioxidant activity were designed and synthesized based on quinoxalin-2(1H)-one scaffold.•Phenolic hydroxyl containing compounds 6b and 6f exhibited not only significant ALR2 inhibition and selectivity but also antioxidant properties.•Structure-activity relationship and docking studies further confirmed the importance of phenolic hydroxyl for enhancing ALR2 inhibitory activity and adding an antioxidant property.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 6.825 μM, 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 novel series of phenolic hydroxyl containing quinoxalinone derivatives were designed and synthesized as potent aldose reductase inhibitors. Compounds 6b and 6f exhibited not only significant ALR2 inhibition and selectivity but also antioxidant properties. Structure-activity relationship and docking studies further confirmed the importance of phenolic hydroxyl for enhancing aldose reductase inhibition and adding antioxidant ability.