Login Register Cart 0
Generic placeholder image

Mini-Reviews in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Design, Synthesis and Biological Evaluation of Spiro Cyclohexane-1,2- Quinazoline Derivatives as Potent Dipeptidyl Peptidase IV Inhibitors

Author(s): Yasmin M. Syam, Somaia S. Abd El-Karim, Tamer Nasr*, Samia A. Elseginy, Manal M. Anwar*, Mohsen M. Kamel and Hanan F. Ali

Volume 19, Issue 3, 2019

Page: [250 - 269] Pages: 20

DOI: 10.2174/1389557517666170828121018

Price: $65

Abstract

Objective: Inhibition of dipeptidyl peptidase IV (DPP-4) is currently one of the most valuable and potential chemotherapeutic regimes for the medication of Type 2 Diabetes Mellitus (T2DM).

Method: Based on linagliptin, this study discusses the design, synthesis and biological evaluation of spiro cyclohexane-1,2'-quinazoline scaffold hybridized with various heterocyclic ring systems through different atomic spacers as a highly potent DPP-4 inhibitors. DPP-4 enzyme assay represented that most of the target compounds are 102-103 folds more active than the reference drug linagliptin (IC50: 0.0005-0.0089 nM vs 0.77 nM; respectively). Moreover, in vivo oral hypoglycemic activity assay revealed that most of the tested candidates were more potent than the reference drug, sitagliptin, producing rapid onset with long duration of activity that extends to 24 h. Interestingly, the derivatives 11, 16, 18a and 23 showed evidence of mild cytochrome P450 3A4 (CYP3A4) inhibition (IC50; > 210 µM) and their acute toxicity (LD50) was more than 1.9 gm/kg. Molecular simulation study of the new quinazoline derivatives explained the obtained biological results.

Conclusion: Finally, we conclude that our target compounds could be highly beneficial for diabetic patients in the clinic.

Keywords: Antidiabetic agents, linagliptin, DPP-4 inhibition, molecular docking, Quinazoline, Gewald reaction.

« Previous
Graphical Abstract

[1]
Miyamoto, Y.; Banno, Y.; Yamashita, T.; Fujimoto, T.; Oi, S.; Moritoh, Y.; Asakawa, T.; Kataoka, O.; Takeuchi, K.; Suzuki, N.; Ikedo, K.; Kosaka, T.; Tsubotani, S.; Tani, A.; Funami, M.; Amano, M.; Yamamoto, Y.; Aertgeerts, K.; Yano, J.; Maezaki, H. Design and synthesis of 3-pyridylacetamide derivatives as dipeptidyl peptidase IV (DPP-4) inhibitors targeting a bidentate interaction with Arg125. Bioorg. Med. Chem., 2011, 19, 172-185.
[2]
(a)Scully, T. Diabetes in numbers. Nat. Outlook, 2012, S2-S3.
(b)Shetty, P. Public health: India’s diabetes time bomb. Nat. Outlook, 2012, 485, S14-S16.
[3]
Deacon, C.F. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: A comparative review. Diabetes Obes. Metab., 2011, 13, 7-18.
[4]
Deacon, C.F. Therapeutic strategies based on glucagon-like peptide 1. Diabetes, 2004, 53, 2181-2189.
[5]
Zander, M.; Madsbad, S.; Madsen, J.L.; Holst, J.J. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: a parallel-group study. Lancet, 2002, 359, 824-830.
[6]
Kjems, L.L.; Holst, J.J.; Volund, A.; Madsbad, S. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on β-cell sensitivity in type 2 and non diabetic subjects. Diabetes, 2003, 52, 380-386.
[7]
Schirra, J.; Wank, U.; Arnold, R.; Goke, B.; Katschinski, M. Effects of glucagon-like peptide-1 (7-36) amideon motility and sensation of the proximal stomach in humans. Gut, 2002, 50, 341-348.
[8]
Lai, Z.; Li, C.; Liu, J.; Kong, L.; Wen, X.; Sun, H. Discovery of highly potent DPP-4 inhibitors by hybrid compound design based on linagliptin and alogliptin. Eur. J. Med. Chem., 2014, 83, 547-560.
[9]
D.J, Drucker. Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes: Preclinical biology and mechanisms of action. Diabetes Care, 2007, 30, 1335-1343.
[10]
Charbonnel, B.; Karasik, A.; Liu, J.; Wu, M.; Meininger, G. Sitagliptin study 020 group, Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care, 2006, 29, 2638-2643.
[11]
Mulakayala, N.; Reddy, C.H. U.; Iqbal, J.; Pal, M. Synthesis of dipeptidylpeptidase- 4-inhibitors: A brief overview. Tetrahedron, 2010, 66, 4919-4938.
[12]
Keating, M.G. Alogliptin: A review of its use in patients with Type 2 diabetes mellitus. Drugs, 2015, 75, 777-796.
[13]
Said, S.; Nwosu, C.A.; Mukherjee, D.; Hernandez, T.G.A. A Review of a New Dipeptidyl Peptidase-4 (DPP-4) inhibitor for the treatment of Type 2 diabetes mellitus. Cardio. Vasc. Hematol. Discord. Drug Targets, 2014, 14(1), 64-70.
[14]
Parsa, V.L.K.; Pal, M. Preclinical development of dipeptidyl peptidase IV inhibitor alogliptin: a brief overview. Expert Opin. Drug Discov., 2011, 6(8), 855-869.
[15]
Scott, L.J. Alogliptin: A review of its use in the management of type 2 diabetes mellitus. Drugs, 2010, 70(15), 2051-2072.
[16]
Augustyns, K.; Van der Veken, P.; Senten, K.; Haerners, A. Dipeptidyl peptidase IV inhibitors as new therapeutic agents for the treatment of Type 2 diabetes. Expert Opin. Ther. Pat., 2003, 13, 499-510.
[17]
Kim, H.J.; Kwak, W.Y.; Min, J.P.; Lee, J.Y.; Yoon, T.H.; Kim, H.D.; Shin, C.Y.; Kim, M.K.; Choi, S.H.; Kim, H.S.; Yang, E.K.; Cheong, Y.H.; Chae, Y.N.; Park, K.J.; Jang, J.M.; Choi, S.J.; Son, M.H.; Kim, S.H.; Yoo, M.; Lee, B.J. Discovery of DA-1229: A potent, long acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes. Bioorg. Med. Chem. Lett., 2011, 21, 3809-3812.
[18]
Ghate, M.D.; Baksariya, A.; Gupta, N.; Patel, B.D. Pharmacophore mapping, virtual screening and molecular docking studies of DPP-IV inhibitors. Int. J. Drug Des. Discov., 2013, 4, 1231-1248.
[19]
Craddy, P.; Palin, H.J.; Ian Johnson, K. Comparative effectiveness of dipeptidyl peptidase-4 inhibitors in type 2 Diabetes: A systematic review and mixed treatment comparison. Diabetes Ther., 2014.
[http://dx.doi.org/10.1007/s13300-014-0061-3]
[20]
Deacon, C.F.; Lebovitz, H.E. Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas. Diabetes Obes. Metab., 2016, 18, 333-347.
[21]
Karagiannis, T.; Boura, P.; Tsapas, A. Safety of dipeptidyl peptidase 4 inhibitors: A perspective review. Ther. Adv. Drug Saf., 2014, 5(3), 138-146.
[22]
Gupta, R.; Walunj, S.S.; Tokala, R.K.; Parsa, K.V.L.; Singh, S.K.; Pal, M. Emerging Drug Candidates of Dipeptidyl Peptidase IV (DPP IV) Inhibitor Class for the Treatment of Type 2 Diabetes. Curr. Drug Targets, 2009, 10, 71.
[23]
Kuhn, B.; Hennig, M.; Mattei, P. Molecular recognition of ligands in dipeptidyl peptidase IV. Curr. Top. Med. Chem., 2007, 7, 609-619.
[24]
Zettl, H.; Schubert-Zsilavecz, M.; Steinhilber, D. Medicinal chemistry of incretin mimetics and DPP-4 inhibitors. ChemMedChem, 2010, 5, 179-185.
[25]
Patel, B.D.; Ghate, M.D. Recent approaches to medicinal chemistry and therapeutic potential of dipeptidyl peptidase-4 (DPP-4) inhibitors. Eur. J. Med. Chem., 2014, 74, 574-605.
[26]
Shrikanth, H.H.; Manojit, P. Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase-4 for the treatment of type 2 diabetes. Bioorg. Med. Chem., 2009, 17, 1783-1802.
[27]
Kanstrup, A.B.; Sams, C.K.; Lundbeck, J.M.; Christiansen, L.B.; Kristiansen, M. DPP-4 inhibiting purine derivatives for the treatment of diabetes. , 2003, WO 2003004496 A1..
[28]
Meng, W.; Brigance, R.P.; Chao, H.J.; Fura, A.; Harrity, T.; Marcinkeviciene, J.; O’Connor, S.P.; Tamura, J.K.; Xie, D.; Zhang, Y.; Klei, H.E.; Kish, K.; Weigelt, C.A.; Turdi, H.; Wang, A.; Zahler, R.; Kirby, M.S.; Hamann, L.G. Discovery of 6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo [1,2-a]pyrimidine-2- carbox-amides as potent, selective dipeptidyl peptidase-4 (DPP4) inhibitors. J. Med. Chem., 2010, 53, 5620-5628.
[29]
Wallace, M.B.; Feng, J.; Zhang, Z.; Skene, R.J. Structure-based design and synthesis of benzimidazole derivatives as dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett., 2008, 18, 2362-2367.
[30]
Rambabu, D.; Raja, G.; Yogi Sreenivas, B.; Seerapu, G.P.K.; Lalith Kumar, K.; Deora, G.S.; Haldar, D.; Basaveswara Rao, M.V.; Pal, M. Spiro heterocycles as potential inhibitors of SIRT1: Pd/C-mediated synthesis of novel N-indolylmethyl spiroindoline-3,2′-quinazolines. Bioorg. Med. Chem. Lett., 2013, 23, 1351-1357.
[31]
Markosyan, I.I.; Gabrielyan, S.A.; Panosyan, G.A.; Arsenyan, F.G.; Garibdzhanyan, B.T. Synthesis and antitumor properties of new spiro(benzo[h]quinazoline-7,1′-cyclohexane) derivatives. Pharm. Chem. J., 2008, 42, 56-59.
[32]
Amin, K.M.; Anwar, M.M.; Syam, Y.M.; Khedr, M.; Kamel, M.M.; Kassem, E.M.M. A novel class of Ssubstituted spiro [quinazoline-2,1′-cyclohexane] Dderivatives as effective PARP-1 inhibitors: Molecular modeling, synthesis, cytotoxic and enzyme assay evaluation. Acta. Pol. Pharm. Drug Res., 2013, 70, 687-708.
[33]
Amin, K.M.; Anwar, M.M.; Kamel, M.M.; Kassem, E.M.M.; Syam, Y.M.; Elseginy, S.A. Synthesis, cytotoxic evaluation and molecular docking study of novel quinazoline derivatives as PARP-1 inhibitors. Acta Pol. Pharm. Drug Res., 2013, 70, 833-849.
[34]
Zhang, X-H.; Yan, J.; Fan, L.; Wang, G-b.; Yang, D. Synthesis and antidiabetic activity of β-acetamido ketones. Acta Pharm. Sin. B, 2011, 1, 100-105.
[35]
Vats, V.; Yadav, S.P.; Grover, J.K. Ethanolic extract of Ocimum sanctum leaves partially attenuates streptozotocin-induced alterations in glycogen content and carbohydrate metabolism in rats. J. Ethnopharmacol., 2004, 90, 155-160.
[36]
SAKR. H.F. Effect of sitagliptin on the working memory and reference memory in type 2 diabetic sprague-dawley rats: Possible role of adiponectin receptors 1. J. Physiol. Pharmacol., 2013, 64, 613-623.
[37]
Trinder, P. Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann. Clin. Biochem., 1969, 1, 624-627.
[38]
Austen, K.F.; Brocklehurst, W.E. Anaphylaxis in chopped guinea pig lung. I. Effect of peptidase substrates and inhibitors. J. Exp. Med., 1961, 113, 521-539.
[39]
Molecular Operating Environment (MOE), 2008, Chemical Computing Group Inc., 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A2R7,. 2008.
[40]
Nabeno, M. Akahoshi, F.; Kishida, H.; Miyaguchi, I.; Tanaka, Y.; Ishii, S.; Kadowaki, T. A comparative study of the binding modes of recently launched dipeptidyl peptidase IV inhibitors in the active site. Biochem. Biophys. Res. Commun., 2013, 434, 191-196.
[41]
Molecular Operating Environment (MOE), 2008., Chemical Computing Group Inc., 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A2R7, 2008.
[42]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. J. Adv. Drug Deliv. Rev., 2001, 46(3), 3-26.
[43]
Walters, W.P.; Stahl, M.T.; Murcko, M.A. Virtual screening–an overview. Drug Discov. Today, 1998, 3, 160-178.

Rights & Permissions Print Cite
Article Metrics
33
3
© 2024 Bentham Science Publishers | Privacy Policy