Benzopyrazines: Synthesis, Characterization and Evaluation as Aldose Reductase Inhibitors
Science Journal of Chemistry
Volume 7, Issue 5, October 2019, Pages: 90-97
Received: Sep. 14, 2019;
Accepted: Oct. 15, 2019;
Published: Oct. 24, 2019
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Huma Aslam Bhatti, Hussian Ebrahim Jamal Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
Qurat-Ul-Ain Zaheer, Hussian Ebrahim Jamal Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
Yildiz Tehseen, Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, Pakistan
Zahid Shaiq, Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, Pakistan
Khalid Mohammed Khan, Hussian Ebrahim Jamal Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
Abdul Hameed, Hussian Ebrahim Jamal Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
Jamshed Iqbal, Hussian Ebrahim Jamal Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
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 (IC50 = 1.34 ± 0.07 µM) while 3'-bromophenyl analogue 6i showed comparable activity for ALR2 (IC50 = 3.48 ± 0.66 µM) as compared to standard sorbinil (IC50 = 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 1H and 13C 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 1H, 13C NMR, IR spectroscopy, and mass spectrometry.
Huma Aslam Bhatti,
Khalid Mohammed Khan,
Benzopyrazines: Synthesis, Characterization and Evaluation as Aldose Reductase Inhibitors, Science Journal of Chemistry. Special Issue: Benzopyrazines: Synthesis, Characterization and Evaluation as Aldose Reductase Inhibitors.
Vol. 7, No. 5,
2019, pp. 90-97.
Tang, W, Martin, KA and Hwa, J, (2012), Aldose reductase, oxidative stress and diabetic mellitus, Front Pharmacol., 3.
Lorenzi, M, (2007), The polyol pathway as a mechanism for diabetic retinopathy: attractive, elusive, and resilient, J. Diabetes Res., 2007: 1-10.
Kinoshita, J, (1974), Mechanisms initiating cataract formation. Proctor Lecture, Invest. Ophthalmol. Vis., 13: 713-724.
Zhu, C, in Diabetes Mellitus - Insights and Perspectives, INTECH Open Access Publisher, 2013.
El-Kabbani, O, Wilson, DK, Petrash, M and Quiocho, FA, (1998), Structural features of the aldose reductase and aldehyde reductase inhibitor-binding sites, Mol. Vis., 4: 19-25.
Alexiou, P, Pegklidou, K, Chatzopoulou, M, Nicolaou, I and Demopoulos, VJ, (2009), Aldose reductase enzyme and its implication to major health problems of the 21st century, Curr. Med. Chem., 16: 734-752.
Qin, X, Hao, X, Han, H, Zhu, S, Yang, Y, Wu, B, Hussain, S, Parveen, S, Jing, C and Ma, B, (2015), Design and synthesis of potent and multifunctional aldose reductase inhibitors based on quinoxalinones, J. Med. Chem., 58: 1254-1267.
Parveen, S, Hussain, S, Qin, X, Hao, X, Zhu, S, Rui, M, Zhang, S, Fu, F, Ma, B and Yu, Q, (2014), Copper-Catalyzed Asymmetric Synthesis and Comparative Aldose Reductase Inhibition Activity of (+)/(−)-1, 2-Benzothiazine-1, 1-dioxide Acetic Acid Derivatives, J. Org. Chem., 79: 4963-4972.
Saeed, A, Tehseen, Y, Rafique, H, Furtmann, N, Bajorath, J, Flörke, U and Iqbal, J, (2014), Benzothiazolyl substituted iminothiazolidinones and benzamido-oxothiazolidines as potent and partly selective aldose reductase inhibitors, Med. Chem. Comm., 5: 1371-1380.
Stefek, M, Soltesova Prnova, M, Majekova, M, Rechlin, C, Heine, A and Klebe, G, (2015), Identification of Novel Aldose Reductase Inhibitors Based on Carboxymethylated Mercaptotriazinoindole Scaffold, J. Med. Chem., 58: 2649-2657.
Milackova, I, Prnova, MS, Majekova, M, Sotnikova, R, Stasko, M, Kovacikova, L, Banerjee, S, Veverka, M and Stefek, M, (2014), 2-Chloro-1, 4-naphthoquinone derivative of quercetin as an inhibitor of aldose reductase and anti-inflammatory agent, J. Enzyme Inhib. Med. Chem., 30: 107-113.
Maccari, R and Ottanà, R, (2014), Targeting aldose reductase for the treatment of diabetes complications and inflammatory diseases: new insights and future directions, J. Med. Chem., 58: 2047-2067.
Sestanj, K, Bellini, F, Fung, S, Abraham, N, Treasurywala, A, Humber, L, Simard-Dequesne, N and Dvornik, D, (1984), N-[[5-(Trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]-N-methylglycine (Tolrestat), a potent, orally active aldose reductase inhibitor, J. Med. Chem., 27: 255-256.
Ao, S, Shingu, Y, Kikuchi, C, Takano, Y, Nomura, K, Fujiwara, T, Ohkubo, Y, Notsu, Y and Yamaguchi, I, (1991), Characterization of a novel aldose reductase inhibitor, FR74366, and its effects on diabetic cataract and neuropathy in the rat, Metabolism, 40: 77-87.
Poulsom, R, (1986), Inhibition of hexonate dehydrogenase and aldose reductase from bovine retina by Sorbinil, Statil, M79175 and valproate, Biochem. Pharmacol., 35: 2955-2959.
Malamas, MS, Hohman, TC and Millen, J, (1994), Novel Spirosuccinimide Aldose Reductase Inhibitors Derived from Isoquinoline-1, 3-diones: 2-[(4-Bromo-2-fluorophenyl) methyl]-6-fluorospiro [isoquinoline-4 (11H), 3'-pyrrolidine]-1, 2', 3, 5'(2H)-tetrone and Congeners. 1, J. Med. Chem., 37: 2043-2058.
Ramirez, MA and Borja, NL, (2008), Epalrestat: an aldose reductase inhibitor for the treatment of diabetic neuropathy, Pharmacother., 28: 646-655.
Yang, Y, Zhang, S, Wu, B, Ma, M, Chen, X, Qin, X, He, M, Hussain, S, Jing, C, Ma, B and Zhu, C, (2012), An Efficient Synthesis of Quinoxalinone Derivatives as Potent Inhibitors of Aldose Reductase, Chem. Med. Chem., 7: 823-835.
Seitz, LE, Suling, WJ and Reynolds, RC, (2002), Synthesis and antimycobacterial activity of pyrazine and quinoxaline derivatives, Journal of medicinal chemistry, 45: 5604-5606.
Guillon, J, Forfar, I, Mamani-Matsuda, M, Desplat, V, Saliege, M, Thiolat, D, Massip, S, Tabourier, A, Léger, J-M and Dufaure, B, (2007), Synthesis, analytical behaviour and biological evaluation of new 4-substituted pyrrolo [1, 2-a] quinoxalines as antileishmanial agents, Bioorg. Med. Chem., 15: 194-210.
Desplat, V, Moreau, S, Gay, A, Fabre, SB, Thiolat, D, Massip, S, Macky, G, Godde, F, Mossalayi, D and Jarry, C, (2010), Synthesis and evaluation of the antiproliferative activity of novel pyrrolo [1, 2-a] quinoxaline derivatives, potential inhibitors of Akt kinase. Part II, J. Enzyme Inhib. Med. Chem., 25: 204-215.
Guillon, J, Grellier, P, Labaied, M, Sonnet, P, Léger, J-M, Déprez-Poulain, R, Forfar-Bares, I, Dallemagne, P, Lemaître, N and Péhourcq, F, (2004), Synthesis, antimalarial activity, and molecular modeling of new pyrrolo [1, 2-a] quinoxalines, bispyrrolo [1, 2-a] quinoxalines, bispyrido [3, 2-e] pyrrolo [1, 2-a] pyrazines, and bispyrrolo [1, 2-a] thieno [3, 2-e] pyrazines, J. Med. Chem., 47: 1997-2009.
Zeb, A, Hameed, A, Khan, L, Khan, I, Dalvandi, K, Iqbal Choudhary, M and Z Basha, F, (2014), Quinoxaline derivatives: Novel and selective butyrylcholinesterase inhibitors, Med. Chem., 10: 724-729.
Hameed, A, Zehra, ST, Shah, SJ, Khan, KM, Alharthy, RD, Furtmann, N, Bajorath, J, Tahir, MN and Iqbal, J, (2015), Syntheses, Cholinesterases Inhibition, and Molecular Docking Studies of Pyrido [2, 3-b] pyrazine Derivatives, Chem. Biol. Drug. Des., 86: 1115-1120.
Khan, MS, Munawar, MA, Ashraf, M, Alam, U, Ata, A, Asiri, AM, Kousar, S and Khan, MA, (2014), Synthesis of novel indenoquinoxaline derivatives as potent α-glucosidase inhibitors, Bioorg. Med. Chem., 22: 1195-1200.
Shah, CP, Dwivedi, C, Singh, KK, Kumar, M and Bajaj, PN, (2010), Riley oxidation: A forgotten name reaction for synthesis of selenium nanoparticles, Mater. Res. Bull., 45: 1213-1217.
Pohanka, M and Drtinova, L, (2013), Spectrophotometric methods based on 2,6-dichloroindophenol acetate and indoxylacetate for butyrylcholinesterase activity assay in plasma, Talanta, 106: 281-285.
Khalafy, J, Marjani, A and Haghipour, M, (2013), Regioselective synthesis of 3-arylpyrido[2,3-b]pyrazines by reaction of arylglyoxals with 2,3-diaminopyridine, Curr. Chem. Lett., 2: 21-26.
Iqbal, Z, Hameed, S, Ali, S, Tehseen, Y, Shahid, M and Iqbal, J, (2015), Synthesis, characterization, hypoglycemic and aldose reductase inhibition activity of arylsulfonylspiro [fluorene-9, 5′-imidazolidine]-2′, 4′-diones, Eur. J. Med. Chem., 98: 127-138.
Ali, S, Saeed, A, Abbas, N, Shahid, M, Bolte, M and Iqbal, J, (2012), Design, synthesis and molecular modelling of novel methyl[4-oxo-2-(aroylimino)-3-(substituted phenyl)thiazolidin-5-ylidene]acetates as potent and selective aldose reductase inhibitors, Med. Chem. Comm., 3: 1428-1434.
Hayman, S and Kinoshita, JH, (1965), Isolation and Properties of Lens Aldose Redutase, J. Biol. Chem., 240: 877-882.
Costantino, L, Rastelli, G, Gamberini, MC, Vinson, JA, Bose, P, Iannone, A, Staffieri, M, Antolini, L, Del Corso, A, Mura, U and Albasini, A, (1999), 1-Benzopyran-4-one Antioxidants as Aldose Reductase Inhibitors, J. Med. Chem., 42: 1881-1893.
Rees-Milton, KJ, Jia, Z, Green, NC, Bhatia, M, El-Kabbani, O and Flynn, TG, (1998), Arch. Biochem. Biophys., 335: 137-139.