Synthesis and Investigation on the Antidiabetic Effect of 3-aryl-1-(5-methylisoxazol-3-ylamino)-1-(4-nitrophenyl) Propan-1-one

Author(s): Jinyu Liu , Zuwen Zhou , Jian Liu , Jufang Yan , Li Fan , Xuemei Tang , Jie Liu , Feifei Chen , Dacheng Yang* .

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 8 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Diabetes mellitus is the third-largest non-communicable chronic disease worldwide. There are many effective drugs, but the long-term use of these clinical drugs may cause various side effects. Therefore, it is urgent to develop new antidiabetic molecules with higher efficacy and lower toxicity.

Methods: Fifteen new 3-aryl-1-(5-methylisoxazol-3-ylamino)-1-(4-nitrophenyl)propan-1-one were synthesized directly through the Mannich reaction of 4-nitroacetophenone, 3-amino-5- methylisoxazole and aromatic aldehydes catalyzed by concentrated hydrochloric acid. The molecular structures of the products were fully characterized by 1H NMR, 13C NMR, ESI MS and HRMS. The peroxisome proliferator-activated receptor (PPAR) response element and α-glucosidase inhibitory activity of these compounds were evaluated in vitro. Molecular docking, molecular physical parameters calculation, and molecular toxicity prediction were performed to analyze the structure- activity relationship and evaluate the druggability of these compounds theoretically.

Results: All compounds exhibited weak antidiabetic activities, but compound 15 showed promising as a high performance, dual-target antidiabetic lead compound with peroxisome proliferatoractivated receptor (PPAR) response element relative agonist activity of 99.55% at 27.2 nmol·mL−1 and α-glucosidase inhibitory activity of 35.21% at 13.6 nmol·mL−1. All compounds obtained may have no cardiotoxicity, no acute toxicity, no carcinogenic, and within safe range of mutagenic risk.

Conclusion: This study identified a potential PPAR lead molecule and presented an unusual strategy for antidiabetic drug development.

Keywords: Diabetes mellitus, α-glucosidase, protein tyrosine phosphatase 1B, peroxisome proliferator-activated receptor, mannich reaction, antidiabetic drug.

[1]
World Health Organization. Global report on diabetes. Available at:. www. who.int/diabetes/publications/grd-2016/en/ (Accessed January 1, 2018).
[2]
Zhang, X.H.; Yan, J.F.; Fan, L.; Wang, G.B.; Yang, D.C. Synthesis and antidiabetic of β-acetamido ketones. Acta Pharm. Sin. B, 2011, 2, 100-105.
[3]
Oguchi, M.; Wada, K.; Honma, H.; Tanaka, A.; Kaneko, T.; Sakakibara, S.; Ohsumi, J.; Serizawa, N.; Fujiwara, T.; Horikoshi, H.; Fujita, T. Molecular design, synthesis, and hypoglycemic activity of a series of thiazolidine-2,4-diones. J. Med. Chem., 2000, 43, 3052-3066.
[4]
Jorgensen, M.R.; Bhurruth-Alcor, Y.; Rost, T.; Bohov, P.; Müller, M.; Guisado, C.; Kostarelos, K.; Dyroy, E.; Berge, R.K.; Miller, A.D.; Skorve, J. Synthesis and analysis of novel glycerolipids for the treatment of metabolic syndrome. J. Med. Chem., 2009, 52, 1172-1179.
[5]
Fracchiolla, G.; Laghezza, A.; Piemontese, L.; Tortorella, P.; Mazza, F.; Montanari, R.; Pochetti, G.; Lavecchia, A.; Novellino, E.; Pierno, S.; Conte-Camerino, D.; Loiodice, F. New 2-aryloxy-3-phenyl -propanoic acids as peroxisome proliferator-activated receptors α/γ dual agonists with improved potency and reduced adverse effects on skeletal muscle function. J. Med. Chem., 2009, 52, 6382-6393.
[6]
Li, X.Q.; Xu, Q.; Luo, J.; Wang, L.J.; Jiang, B.; Zhang, R.S.; Shi, D.Y. Design, synthesis and biological evaluation of uncharged catechol derivatives as selective inhibitors of PTP1B. Eur. J. Med. Chem., 2017, 136, 348-359.
[7]
Guo, Y.S.; Guo, Z.R. Design of multiple targeted drugs. Acta. Pharm. Sin, 2009, 44, 276-281.
[8]
Jiang, F.C. The multi-target drugs and their design. Acta. Pharm. Sin, 2009, 44, 282-287.
[9]
Hall, I.H.; Lee, K.H.; Mar, E.C.; Starnes, C.O.; Waddell, T.G. Antitumor agents 21. A proposed mechanism of inhibition of cancer growth by tenulin and helenalin and related cyclopentenones. J. Med. Chem., 1977, 20, 333-337.
[10]
Masocha, W.; Kombian, S.B.; Edafiogho, I.O. Evaluation of the antinociceptive activities of enaminone compounds on the formalin and hot plate tests in mice. Sci. Rep., 2016, 6, 21582-21590.
[11]
Manna, K.; Ghosh, P.S.; Das, M.; Banik, U.; Das, A. 2-Amino-3-cyanopyridine: A bioactive scaffold. Int. J. Pharm. Sci. Res., 2014, 5, 2158-2163.
[12]
Zhou, C.; Wu, G.; Feng, Y.; Li, Q.; Su, H.; Mais, D.E.; Zhu, Y.; Li, N.; Deng, Y.; Yang, D.; Wang, M.W. Discovery and biological characterization of novel series of androgen receptor modulators. Br. J. Pharm., 2008, 154, 440-450.
[13]
Xu, J.; Yan, J.F.; Fan, L.; Song, X.L.; Tang, G.X.; Yang, D.C. Synthesis and α-glucosidase inhibitory activity of N-(1,5-diaryl-3-pentone-1-yl)-4-aminobenzoic acid. Acta. Pharm. Sin, 2009, 44, 48-55.
[14]
Song, X.L.; Yan, J.F.; Fan, L.; Chen, X.; Xu, J.; Zhou, Z.W.; Yang, D.C. Synthesis and preliminary evaluation of antidiabetic activity of 4-(1-Aryl-3-aryl/arylalkyl-3-oxpropylamino)-N-(5-methyl-3-isoxazolyl) bnzene sulfonamide. Chin. J. Org. Chem., 2009, 29, 606-613.
[15]
Zhang, Y.X.; Yan, J.F.; Fan, L.; Zhang, W.Y.; Zhou, Z.W.; Chen, X.; Su, X.Y.; Tang, X.M.; Yang, D.C. Synthesis and Preliminary evaluation of antidiabetic activity of 4-(3-(4-bromophenyl)-3-oxo- 1-arylpropyl amino)-N-(5-methylisoxazol-3-yl)benzenes ulfonamide. Acta. Pharm. Sin, 2009, 44, 1244-1251.
[16]
Liu, K.; Xu, L.B.; Berger, J.P.; Macnaul, K.L.; Zhou, G.; Doebber, T.W.; Forrest, M.J.; Moller, D.E.; Jones, A.B. Discovery of a novel series of peroxisome proliferator proliferator-activated receptor α/γ dual agonists for the treatment of type 2 diabetes and dyslipidemia. J. Med. Chem., 2005, 48, 2262-2265.
[17]
Aicher, T.D.; Balkan, B.; Bell, P.A.; Brand, L.J.; Cheon, S.H.; Deems, R.O.; Fell, J.B.; Fillers, W.S.; Fraser, J.D.; Gao, J.; Knorr, D.C.; Kahle, G.G.; Leone, C.L.; Nadelson, J.; Simpson, R.; Smith, H.C. Substituted tetrahydropyrrolo[2,1-b] oxazol-5(6H)-ones and tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones as hypoglycemic Agents. J. Med. Chem., 1998, 41, 4556-4566.
[18]
Kumar, A.; Maurya, R.A.; Sharma, S.; Ahmad, P.; Singh, A.B.; Tamrakar, A.K.; Srivastava, A.K. Design and synthesis of 3,5-diarylisoxazole derivatives as novel class of anti-hyperglycemic and lipid lowering agents. Bioorg. Med. Chem., 2009, 17, 5285-5292.
[19]
Naim, M.J.; Alam, M.J.; Nawaz, F.; Naidu, V.G.M.; Aaghaz, S.; Sahu, M.; Siddiqui, N.; Alam, O. Synthesis, molecular docking and anti-diabetic evaluation of 2,4-thiazolidinedione based amide derivatives. Bioorg. Chem., 2017, 73, 24-36.
[20]
Arend, M.; Westermann, B.; Risch, N. Modern variants of the Mannich reaction. Angew. Chem., 1998, 37, 1045-1070.
[21]
Yi, L.; Zou, J.H.; Lei, H.S.; Lin, X.M.; Zhang, M.X. The Mannich reaction of cyclic ketones, aromatic aldehydes and aromatic amines. Org. Prep. Proced. Int., 1991, 23, 673-676.
[22]
Yang, D.C.; Zhang, G.L.; Yang, Y.; Zhong, Y.G. The Mannich reaction of 4-methylacetophenone with aromatic aldehydes and aromatic amines. Chem. J. Chin. Univ., 2000, 21, 1694-1696.
[23]
Tang, G.X.; Yan, J.F.; Fan, L.; Xu, J.; Song, X.L.; Jiang, L.; Luo, L.F.; Yang, D.C. synthesis of novel β-amino ketones containing a p-aminobenzoic acid moiety and evaluation of their antidiabetic activities. Sci. China Chem., 2013, 4, 490-504.
[24]
Wang, H.; Yan, J.F.; Song, X.L.; Fan, L.; Xu, J.; Zhou, G.M.; Jiang, L.; Yang, D.C. Synthesis and antidiabetic performance of β-amino ketones containing nabumetone moiety. Bioorg. Med. Chem., 2012, 20, 2119-2130.
[25]
Tang, X.M.; Yan, J.F.; Zhang, Y.X.; Zhang, W.Y.; Su, X.Y.; Chen, X.; Zhou, Z.W.; Yang, D.C. Synthesis and preliminary study on α-glucosidase inhibitory activity of 4-[3-(4-bromophenyl)-3-oxo-1-arylpropyl amino]-N-(pyrimidin-2-yl) benzenesulfonamide. Youji Huaxue, 2009, 29, 1790-1798.
[26]
Zhang, K.; Yan, J.F.; Tang, X.M.; Liu, H.P.; Fan, L.; Zhou, G.M.; Yang, D.C. Synthesis of novel β-aminoalcohols containing nabumetone moiety with potential antidiabetic activity. Acta. Pharm. Sin, 2011, 46, 412-421.
[27]
Zhou, Z.W.; Yan, J.F.; Tang, X.M.; Zhang, W.Y.; Zhang, X.H.; Chen, X.; Yang, D.C. Synthesis and preliminary evaluation of antidiabetic activity for β-amino ketones containing isoxazole moiety. Chin. J. Org. Chem., 2010, 30, 582-589.
[28]
Müller, J.; Martins, A.; Csábi, J.; Fenyvesi, F.; Könczöl, Á.; Hunyadi, A.; Balogh, G.T. BBB penetration-targeting physicochemical lead selection: Ecdysteroids as chemo-sensitizers against CNS tumors. Eur. J. Pharm. Sci., 2017, 96, 571-577.
[29]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2001, 46, 3-26.
[30]
Mukhina, O.A.; Kuznetsov, D.M.; Cowger, T.M.; Kutateladze, A.G. Amino azaxylylenes photogenerated from o-amidoimines: Photoassisted access to complex spiro-poly-heterocycles. Angew. Chem., 2015, 54, 11516-11520.
[31]
Obermoser, V.; Urban, M.E.; Murgueitio, M.S.; Wolber, G.; Kintscher, U.; Gust, R. New telmisartan- derived PPARγ agonists: Impact of the 3D-binding mode on the pharmacological profile. Eur. J. Med. Chem., 2016, 124, 138-152.
[32]
Huigens, R.W.; Morrison, K.C.; Hicklin, R.W.; Flood, T.A.; Richter, M.F.; Hergenrother, P.J. A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products. Nat. Chem., 2013, 5, 195-202.
[33]
Veber, D.F.; Johnson, S.R.; Cheng, H.Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 2002, 45, 2615-2623.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 8
Year: 2019
Page: [835 - 845]
Pages: 11
DOI: 10.2174/1570180815666180608101529
Price: $58

Article Metrics

PDF: 23
HTML: 1