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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Letter Article

Design and Synthesis of Echitamine-inspired Hybrid Analogues Containing Thiazolidinediones as Potential Pancreatic Lipase Inhibitors

Author(s): Ginson George, Prashant S. Auti, Pracheta Sengupta and Atish T. Paul*

Volume 19, Issue 11, 2022

Published on: 10 May, 2022

Page: [956 - 968] Pages: 13

DOI: 10.2174/1570180819666220314094820

Price: $65

Abstract

Background: Obesity is a multifactorial metabolic disease characterised by excessive accumulation of triglycerides. The prevalence and morbidity rates associated with obesity are increasing tremendously, posing a significant risk to society. Pancreatic lipase (PL) is a key enzyme responsible for the digestion of dietary triglycerides; hence its inhibition is considered an attractive target in obesity.

Methods: In this present work, a new series of echitamine-inspired indole-based thiazolidinedione hybrid analogues were designed, synthesized, and evaluated for their in vitro PL inhibitory potential. The nature of inhibition has been identified by enzyme kinetic analysis, whereas in silico molecular modelling tools (molecular docking and dynamic studies) were used for the identification of the mode of action at the catalytic site of PL (PDB ID: 1LPB). Fluorescence quenching was used for the identification of the interaction between the potent analogues with PL.

Results: The condensation reaction of substituted indole derivatives with TZD in the presence of aqueous KOH resulted in the formation of the titled analogues. Analogues 7k and 7p displayed a potential PL inhibitory activity (IC50 = 11.36 and 11.87 μM, respectively). A competitive mode of PL inhibition was revealed in the enzyme kinetic analysis. A static quenching mechanism was exhibited by the screened agents on PL. The obtained MolDock scores were aligned with the in vitro PL inhibitory activity (Pearson’s r - 0.7575, p < 0.05). Moreover, the PL-ligand complexes were stable in the dynamic conditions.

Conclusion: Analogue 7k exerted the potential activity, and further studies might result in novel lead molecules.

Keywords: Obesity, pancreatic lipase, enzyme inhibition, fluorescence spectroscopy, molecular docking, thiazolidinediones.

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[1]
EASO. The obesity policy engagement network. Facilitating an open debate on obesity., Available from: https://obesityopen.org.
[2]
EASO. Centers for disease control and prevention. Obesity, race/ethnicity, and COVID-19., Available from: https://www.cdc.gov/obesity/data/obesity-and-covid-19.html.
[3]
Leitner, D.R.; Frühbeck, G.; Yumuk, V.; Schindler, K.; Micic, D.; Woodward, E.; Toplak, H. Clinical information obesity and type 2 diabetes: Two Diseases with a need for combined treatment strategies-EASO can lead the way. Obes. Facts, 2017, 10(5), 483-492.
[http://dx.doi.org/10.1159/000480525] [PMID: 29020674]
[4]
World Health Organisation (WHO). Obesity, Available from: https://www.who.int/health-topics/obesity#tab=tab_1.
[5]
Srivastava, G.; Apovian, C.M. Current pharmacotherapy for obesity. Nat. Rev. Endocrinol., 2018, 14(1), 12-24.
[http://dx.doi.org/10.1038/nrendo.2017.122] [PMID: 29027993]
[6]
Pilitsi, E.; Farr, O.M.; Polyzos, S.A.; Perakakis, N.; Nolen-Doerr, E.; Papathanasiou, A.E.; Mantzoros, C.S. Pharmacotherapy of obesity: Available medications and drugs under investigation. Metabolism, 2019, 92, 170-192.
[http://dx.doi.org/10.1016/j.metabol.2018.10.010] [PMID: 30391259]
[7]
Egloff, M.P.; Marguet, F.; Buono, G.; Verger, R.; Cambillau, C.; van Tilbeurgh, H. The 2.46 A resolution structure of the pancreatic lipase-colipase complex inhibited by a C11 alkyl phosphonate. Biochemistry, 1995, 34(9), 2751-2762.
[http://dx.doi.org/10.1021/bi00009a003] [PMID: 7893686]
[8]
United States Food and Drug Administration. Orlistat (marketed as Alli and Xenical) Information., Available from: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/orlistat-marketed-alli-and-xenical.
[9]
McNeely, W.; Benfield, P.; Drent, L.; Pi-Sunyer, F.X. Orlistat. Drugs, 1998, 56(2), 241-249.
[http://dx.doi.org/10.2165/00003495-199856020-00007] [PMID: 9711448]
[10]
NIH. Orlistat., Available from: https://pubchem.ncbi.nlm.nih.gov/compound.
[11]
Kitadokoro, K.; Tanaka, M.; Hikima, T.; Okuno, Y.; Yamamoto, M.; Kamitani, S. Crystal structure of pathogenic Staphylococcus aureus lipase complex with the anti-obesity drug orlistat. Sci. Reports, 2020, 10, 1-13.
[http://dx.doi.org/10.1038/s41598-020-62427-8] [PMID: 32214208]
[12]
Filippatos, T.D.; Derdemezis, C.S.; Gazi, I.F.; Nakou, E.S.; Mikhailidis, D.P.; Elisaf, M.S. Orlistat-associated adverse effects and drug interactions: a critical review. Drug Saf., 2008, 31(1), 53-65.
[http://dx.doi.org/10.2165/00002018-200831010-00005] [PMID: 18095746]
[13]
Sridhar, S.N.C.; George, G.; Verma, A.; Paul, A.T. Natural products-based pancreatic lipase inhibitors for obesity treatment. In: Natural Bio-active Compounds; Springer: Singapore, 2019; pp. 149-191.
[http://dx.doi.org/10.1007/978-981-13-7154-7_6]
[14]
Rajan, L.; Palaniswamy, D.; Mohankumar, S.K. Targeting obesity with plant-derived pancreatic lipase inhibitors: A comprehensive review. Pharmacol. Res., 2020, 155, 104681.
[http://dx.doi.org/10.1016/j.phrs.2020.104681] [PMID: 32045666]
[15]
George, G.; Dileep, P.S.; Paul, A.T. Development and validation of a new hptlc-hrms method for the quantification of a potent pancreatic lipase inhibitory lead echitamine from Alstonia scholaris. Nat. Prod. Res., 2021, 22(35), 4680-4.
[http://dx.doi.org/10.1080/14786419.2019.1705817] [PMID: 31872775]
[16]
Salian, V.V.; Narayana, B.; Sarojini, B.K.; Kodandoor, S.C.; Lobo, A.G. Design, synthesis, docking and computational pharmacokinetic profiling of new pyrazolinyl thiazolinone biheterocycles as potent antimicrobial agents. Lett. Drug Des. Discov., 2020, 17(11), 1342-1354.
[http://dx.doi.org/10.2174/1570180817999200623115049]
[17]
Maji, D.; Samanta, S.; Patil, V.M. In silico ADMET and docking studies of thiazolidinedione-acetic-acid hybrids as antidiabetics with cardioprotection. Lett. Drug Des. Discov., 2020, 17(12), 1475-1484.
[http://dx.doi.org/10.2174/1570180817999200618103328]
[18]
Yang, B.; Si, H.; Zhai, H. QSAR studies on the ic50 of a class of thiazolidinone/thiazolide based hybrids as antitrypanosomal agents. Lett. Drug Des. Discov., 2020, 18(4), 406-415.
[http://dx.doi.org/10.2174/1570180817999201102200015]
[19]
Ranganathan, S.; Kern, P.A. Thiazolidinediones inhibit lipoprotein lipase activity in adipocytes. J. Biol. Chem., 1998, 273(40), 26117-26122.
[http://dx.doi.org/10.1074/jbc.273.40.26117] [PMID: 9748292]
[20]
Sridhar, S.N.C.; Bhurta, D.; Kantiwal, D.; George, G.; Monga, V.; Paul, A.T. Design, synthesis, biological evaluation and molecular modelling studies of novel diaryl substituted pyrazolyl thiazolidinediones as potent pancreatic lipase inhibitors. Bioorg. Med. Chem. Lett., 2017, 27(16), 3749-3754.
[http://dx.doi.org/10.1016/j.bmcl.2017.06.069] [PMID: 28705641]
[21]
Stefanucci, A.; Dimmito, M.P.; Zengin, G.; Luisi, G.; Mirzaie, S.; Novellino, E.; Mollica, A. Discovery of novel amide tripeptides as pancreatic lipase inhibitors by virtual screening. New J. Chem., 2019, 43(7), 3208-3217.
[http://dx.doi.org/10.1039/C8NJ05884A]
[22]
Sridhar, S.N.C.; Palawat, S.; Paul, A.T. Design, synthesis, biological evaluation and molecular modelling studies of conophylline inspired novel indolyl oxoacetamides as potent pancreatic lipase inhibitors. New J. Chem., 2020, 44, 12355-12369.
[http://dx.doi.org/10.1039/D0NJ02622K]
[23]
Corigliano, D.M.; Syed, R.; Messineo, S.; Lupia, A.; Patel, R.; Reddy, C.V.R.; Dubey, P.K.; Colica, C.; Amato, R.; De Sarro, G.; Alcaro, S.; Indrasena, A.; Brunetti, A. Indole and 2,4-Thiazolidinedione conjugates as potential anticancer modulators. PeerJ, 2018, 6, e5386.
[http://dx.doi.org/10.7717/peerj.5386] [PMID: 30123711]
[24]
Lineweaver, H.; Burk, D. The determination of enzyme dissociation constants. J. Am. Chem. Soc., 1934, 56(3), 658-666.
[http://dx.doi.org/10.1021/ja01318a036]
[25]
Burlingham, B.T.; Widlanski, T.S. An intuitive look at the relationship of Ki and IC50: A more general use for the dixon plot. J. Chem. Educ., 2003, 80(2), 214.
[http://dx.doi.org/10.1021/ed080p214]
[26]
Li, S.; Pan, J.; Hu, X.; Zhang, Y.; Gong, D.; Zhang, G. Kaempferol inhibits the activity of pancreatic lipase and its synergistic effect with orlistat. J. Funct. Foods, 2020, 72, 104041.
[http://dx.doi.org/10.1016/j.jff.2020.104041]
[27]
Yan, L.Q.; Yang, P.; Gao, F.; Zhang, Z.W.; Wu, B. Probing the interaction between 3 flavonoids and pancreatic lipase by methods of fluorescence spectroscopy and enzymatic kinetics. Eur. Food Res. Technol., 2011, 233(1), 63-69.
[http://dx.doi.org/10.1007/s00217-011-1491-z]
[28]
Thomsen, R.; Christensen, M.H. MolDock: A new technique for high-accuracy molecular docking. J. Med. Chem., 2006, 49(11), 3315-3321.
[http://dx.doi.org/10.1021/jm051197e] [PMID: 16722650]
[29]
Abraham, M.J.; Murtola, T.; Schulz, R.; Páll, S.; Smith, J.C.; Hess, B.; Lindah, E.; Lindahl, E.; Lindah, E. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX, 2015, 1, 19-25.
[http://dx.doi.org/10.1016/j.softx.2015.06.001]
[30]
MacKerell, A.D., Jr; Banavali, N.; Foloppe, N. Development and current status of the CHARMM force field for nucleic acids. Biopolymers, 2000-2001, 56(4), 257-265.
[http://dx.doi.org/10.1002/1097-0282(2000)56:4<257::AID-BIP10029>3.0.CO;2-W] [PMID: 11754339]
[31]
Zoete, V.; Cuendet, M.A.; Grosdidier, A.; Michielin, O. SwissParam: a fast force field generation tool for small organic molecules. J. Comput. Chem., 2011, 32(11), 2359-2368.
[http://dx.doi.org/10.1002/jcc.21816] [PMID: 21541964]
[32]
Khaldoun, K.; Safer, A.; Boukabcha, N.; Dege, N.; Ruchaud, S.; Souab, M.; Bach, S.; Chouaih, A.; Saidi-Besbes, S. Synthesis and evaluation of new isatin-aminorhodanine hybrids as pim1 and clk1 kinase inhibitors. J. Mol. Struct., 2019, 1192, 82-90.
[http://dx.doi.org/10.1016/j.molstruc.2019.04.122]
[33]
Abo-Ashour, M.F.; Eldehna, W.M.; George, R.F.; Abdel-Aziz, M.M.; Elaasser, M.M.; Abdel Gawad, N.M.; Gupta, A.; Bhakta, S.; Abou-Seri, S.M. Novel indole-thiazolidinone conjugates: Design, synthesis and whole-cell phenotypic evaluation as a novel class of antimicrobial agents. Eur. J. Med. Chem., 2018, 160, 49-60.
[http://dx.doi.org/10.1016/j.ejmech.2018.10.008] [PMID: 30317025]
[34]
Huo, P.C.; Hu, Q.; Shu, S.; Zhou, Q-H.; He, R-J.; Hou, J.; Guan, X-Q.; Tu, D-Z.; Hou, X-D.; Liu, P.; Zhang, N.; Liu, Z-G.; Ge, G-B. Design, synthesis and biological evaluation of novel chalcone-like compounds as potent and reversible pancreatic lipase inhibitors. Bioorg. Med. Chem., 2021, 29, 115853.
[http://dx.doi.org/10.1016/j.bmc.2020.115853] [PMID: 33214035]
[35]
Martinez-Gonzalez, A.I.; Alvarez-Parrilla, E.; Díaz-Sánchez, Á.G.; de la Rosa, L.A.; Núñez-Gastélum, J.A.; Vazquez-Flores, A.A.; Gonzalez-Aguilar, G.A. In vitro inhibition of pancreatic lipase by polyphenols: A kinetic, fluorescence spectroscopy and molecular docking study. Food Technol. Biotechnol., 2017, 55(4), 519-530.
[http://dx.doi.org/10.17113/ftb.55.04.17.5138] [PMID: 29540986]
[36]
Lakowicz, J.R. Quenching of fluorescence. In: Principles of Fluorescence Spectroscopy; Springer Science & Business Media: Boston, MA, 2006; pp. 277-330.
[http://dx.doi.org/10.1007/978-0-387-46312-4_8]
[37]
Ladokhin, A.S. Fluorescence spectroscopy in peptide and protein analysis. In: Encyclopedia of Analytical Chemistry; John Wiley & Sons, Ltd: Chichester, UK, 2000; pp. 277-330.
[http://dx.doi.org/10.1002/9780470027318.a1611]
[38]
Zhu, Y.T.; Jia, Y.W.; Liu, Y.M.; Liang, J.; Ding, L.S.; Liao, X. Lipase ligands in Nelumbo nucifera leaves and study of their binding mechanism. J. Agric. Food Chem., 2014, 62(44), 10679-10686.
[http://dx.doi.org/10.1021/jf503687e] [PMID: 25328123]
[39]
Lowe, M.E. Pancreatic triglyceride lipase and colipase: Insights into dietary fat digestion. Gastroenterology, 1994, 107(5), 1524-1536.
[http://dx.doi.org/10.1016/0016-5085(94)90559-2] [PMID: 7926517]
[40]
Birari, R.B.; Gupta, S.; Mohan, C.G.; Bhutani, K.K. Antiobesity and lipid lowering effects of Glycyrrhiza chalcones: Experimental and computational studies. Phytomedicine, 2011, 18(8-9), 795-801.
[http://dx.doi.org/10.1016/j.phymed.2011.01.002] [PMID: 21315569]
[41]
Spahi, S.; Mutlu, O.; Sariyer, E.; Kocer, S.; Ugurel, E.; Turgut-Balik, D. Hit identification against peptidyl-prolyl isomerase of Theileria annulata by combined virtual high-throughput screening and molecular dynamics simulation approach. Comput. Biol. Chem., 2020, 89, 107398.
[http://dx.doi.org/10.1016/j.compbiolchem.2020.107398] [PMID: 33059132]

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