Synthesis of novel indenoquinoxaline derivatives as potent α-glucosidase inhibitors

Khan, Madiha Sahar; Munawar, Munawar Ali; Ashraf, Mohammad; Alam, Umber; Ata, Athar; Asiri, Abdullah M.; Kousar, Samina; Khan, Misbahul Ain

doi:10.1016/j.bmc.2013.12.024

Cited by 59 publications

(24 citation statements)

References 24 publications

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“…For example, several N-(11H-indeno [1,2-b]quinoxalin-11-ylidene)benzohydrazide derivatives with structures related to IQ-1S were recently reported as a-glucosidase inhibitors (Khan et al, 2014), and other structurally unrelated a-glucosidase inhibitors have been reported to have immunosuppressive and immunomodulatory properties (Willenborg et al, 1992;van den Broek et al, 1996). The indeno [1,2-b]quinoxaline nucleus of IQ-1S is a flat aromatic ring structure (Ghalib et al, 2010), and planar fused heterocyclic compounds can exhibit a wide variety of pharmacological activities, including DNA intercalation and inhibition of topoisomerases I/II (Deady et al, 1997;Moorthy et al, 2013).…”

Section: Foxp3mentioning

confidence: 99%

Anti-Inflammatory Effects and Joint Protection in Collagen-Induced Arthritis after Treatment with IQ-1S, a Selective c-Jun N-Terminal Kinase Inhibitor

Schepetkin

Kirpotina

Hammaker

et al. 2015

J Pharmacol Exp Ther

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c-Jun N-terminal kinases (JNKs) participate in many physiologic and pathologic processes, including inflammatory diseases. We recently synthesized the sodium salt of IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime) and demonstrated that it is a high-affinity JNK inhibitor and inhibits murine delayed-type hypersensitivity. Here we show that IQ-1S is highly specific for JNK and that its neutral form is the most abundant species at physiologic pH. Molecular docking of the IQ-1S syn isomer into the JNK1 binding site gave the best pose, which corresponded to the position of cocrystallized JNK inhibitor SP600125 (1,9-pyrazoloanthrone). Evaluation of the therapeutic potential of IQ-1S showed that it inhibited matrix metalloproteinase 1 and 3 gene expression induced by interleukin-1b in human fibroblast-like synoviocytes and significantly attenuated development of murine collagen-induced arthritis (CIA). Treatment with IQ-1S either before or after induction of CIA resulted in decreased clinical scores, and joint sections from IQ-1S-treated CIA mice exhibited only mild signs of inflammation and minimal cartilage loss compared with those from control mice. Collagen II-specific antibody responses were also reduced by IQ-1S treatment. By contrast, the inactive ketone derivative 11H-indeno[1,2-b]quinoxalin-11-one had no effect on CIA clinical scores or collagen II-specific antibody titers. IQ-1S treatment also suppressed proinflammatory cytokine and chemokine levels in joints and lymph node cells. Finally, treatment with IQ-1S increased the number of Foxp3 CD251 regulatory T cells in lymph nodes. Thus, IQ-1S can reduce inflammation and cartilage loss associated with CIA and can serve as a small-molecule modulator for mechanistic studies of JNK function in rheumatoid arthritis.

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Section: Foxp3mentioning

confidence: 99%

Anti-Inflammatory Effects and Joint Protection in Collagen-Induced Arthritis after Treatment with IQ-1S, a Selective c-Jun N-Terminal Kinase Inhibitor

Schepetkin

Kirpotina

Hammaker

et al. 2015

J Pharmacol Exp Ther

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“…Aldose (ALR2) Reductase Following the previously described procedure [25], aldose reductase (ALR2) extraction and purification; from the local slaughter house calf eyes were removed from a freshly slaughtered animal. Sample was kept frozen until used.…”

Section: Isolation and Purification Of Aldehyde (Alr1) Andmentioning

confidence: 99%

Benzopyrazines: Synthesis, Characterization and Evaluation as Aldose Reductase Inhibitors

Bhatti¹,

Zaheer²,

Tehseen³

et al. 2019

SJC

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Role of aldose reductase (ALR2) in diabetic complications such as retinopathy, nephropathy, neuropathy, and cataract etc. is well-evident. ALR2 in the first step of polyol pathway reduces glucose to sorbitol whose elevated level leads to diabetic cataract, characterize by clouding of the lens in the eye that affects vision. Inhibition of ALR2 enzyme with small molecules as inhibitor is a rapid approach for diabetic management. In the present study the synthetic route to synthesize desired benzopyrazines and a library of sixteen (16) methyl benzopyrazines were screened against aldose reductase. From the bioactivity results, the 3'-hydroxyphenyl benzopyrazine 6l was found most active (IC 50 = 1.34 ± 0.07 µM) while 3'bromophenyl analogue 6i showed comparable activity for ALR2 (IC 50 = 3.48 ± 0.66 µM) as compared to standard sorbinil (IC 50 = 3.14 ± 0.02 µM). Both compounds (6l and 6i) showed excellent selectivity for ALR2 over aldehyde reductase (ALR1) which has important role in detoxification of toxic aldehydes. The structure of two regio-isomers were fully characterize by 1 H and 13 C NMR two dimensional NMR techniques including COSY, NOESY, HSQC, and HMBC. Regio-isomers separation was proved to be difficult in different solvent systems. Only an isomer of 3'-bromo benzopyrazine 6i' was isolated that help to assign the structure of regioisomers from NMR data. All the benzopyrazines were fully characterized by using different spectral techniques including 1 H, 13 C NMR, IR spectroscopy, and mass spectrometry.

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“…P. guajava leaves contain flavonoids and other phenolic components which significantly restore the activities of carbohydrate metabolizing enzymes [ Table 1]. [159] Antidesma bunius The 80% aqueous ethanolic extracts were screened for their α-glucosidase enzyme inhibitory activity using yeast α-glucosidase enzyme. [160] Huanglian Wan is prescribed for the treatment of diabetes mellitus in the traditional Chinese medicine.…”

Section: Use Of Proper Nutraceuticalsmentioning

confidence: 99%

Untitled

2016

IJGP

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The present review explains the use of natural plant products for therapeutics of diabetes. It is a serious metabolic disorder that imposes multiple effects on human health. Although diabetes is curable, an erratic lifestyle always make panic and causes disease severity if proper medication is not being made available. Several ethnomedicines have been used by local people in form of crude extracts prepared from flowers, fruits, and roots of endemic plant species for cure of diabetes. There is a common usage of herbal parts for preparation of concoctions, syrups, vegetables, juices, green tea, from leaves, and roots for therapeutic purposes. This article explains antidiabetic effects of various plant secondary metabolites such as anthraquinones, flavonoids, secoiridoids, iridoids, flavanones, biophenols, triterpenes, benzoic acid derivatives, isochromans, and phytosterols. Daily meals containing good nutraceuticals such as protein and fiber can replace carbohydrate food that is a main source of glucose. Mainly, herbal foods rich in flavanols and polyphenols show hypoglycemic effects and can be used in the prevention of diabetes-induced vascular dysfunctions. Antidiabetic plant natural products restore insulin level and increase utilization of external glucose. Herbal dietary supplementation having diverse antioxidants, fibers, minerals, and antiglycants show inhibitory activity against α-amylase and α-glycosidase can easily control carbohydrate metabolism in humans. No doubt plant origin natural products can be used as alternative medicine for treatment of diabetes, but they must need proper composition and formulation before being used.

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Synthesis of novel indenoquinoxaline derivatives as potent α-glucosidase inhibitors

Cited by 59 publications

References 24 publications

Anti-Inflammatory Effects and Joint Protection in Collagen-Induced Arthritis after Treatment with IQ-1S, a Selective c-Jun N-Terminal Kinase Inhibitor

Anti-Inflammatory Effects and Joint Protection in Collagen-Induced Arthritis after Treatment with IQ-1S, a Selective c-Jun N-Terminal Kinase Inhibitor

Benzopyrazines: Synthesis, Characterization and Evaluation as Aldose Reductase Inhibitors

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