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Protein & Peptide Letters

Author(s): Mandeep Kumar Gupta*, Rajnish Srivastava, Sushil Kumar, Krishna Kumar Varshney and Hariram Singh

DOI: 10.2174/0929866529666220829090810

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GLP-1 Targeted Novel 3-phenyl-7-hydroxy Substituted Coumarins Mitigate STZ-induced Pancreatic Damage and Improve Glucose Homeostasis in OGTT Method

Page: [979 - 992] Pages: 14

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Abstract

Background: Worldwide, type 2 diabetes mellitus accounts for a considerable burden of disease, with an estimated global cost of >800 billion USD annually. For this reason, the search for more effective and efficient therapeutic anti-diabetic agents is continuing. Recent studies support the search for coumarins or related compounds with potential blood glucose-lowering properties.

Aim: The study aims to design, synthesize and evaluate the hypoglycemic activity of a new class of 7-hydroxy coumarin derivatives.

Objective: To explore and establish the in-silico-driven pharmacological role of a new class of 7- hydroxy coumarin derivatives as the therapeutic strategies against type 2 diabetes mellitus.

Methods: A new class of 7-hydroxy coumarin derivatives was designed by assessment of their physicochemical properties and molecular docking against the Glucagon-like peptide-1 (GLP-1) receptor. Two novel series of 30 compounds were synthesized. The chemical structures of all the synthesized analogues have been elucidated by spectral studies of IR, 1H-NMR, and mass spectroscopy. After considering the molecular docking score and their physicochemical properties, the compounds were screened out for the evaluation of their hypoglycemic potential. The compounds were investigated for their hypoglycemic activity using a streptozotocin (STZ) induced diabetic model and an oral glucose tolerance test (OGTT) method at different dose levels.

Results: The molecular docking studies of synthesized derivatives reveal significant molecular interaction with the various amino acid residues of the GLP-1 receptor. IR spectral analysis revealed a strong band of -NH stretching in the range of 3406.7-3201.61 cm-1 and one strong band for the lactone carbonyl group of the coumarin ring in the range of 1722.0-1703.5 cm-1, confirming the chemical structure of all produced compounds. The synthesized coumarin analogues with the best docking score exhibited remarkable hypoglycemic potential as assessed by the STZ model and the OGTT method.

Conclusion: Coumarin derivatives explored a good structure-activity relationship (SAR) and produced significant hypoglycemic potential.

Keywords: Coumarin, Molecular docking; Hypoglycemic activity; Streptozotocin; Structure-activity relationship; Glucagon-like peptide-1.

Graphical Abstract

[1]
Ismael, R.; Mustafa, Y.; Al-Qazaz, H. Coumarin-based products: Their biodiversity and pharmacology. Iraqi J. Pharm., 2022, 18(2), 162-179.
[http://dx.doi.org/10.33899/iphr.2022.170405]
[2]
Razaq, A.F.; Mohammed, M.J. Synthesis and studying of the biological activity of some new coumarin-3-carboxylic acid heterocyclic derivatives. Egypt. J. Chem., 2022, 65(2), 35-40.
[3]
Dorababu, A. Pharmacological report of recently designed multifunctional coumarin and coumarin-heterocycle derivatives. Arch. Pharm. (Weinheim), 2022, 355(2), 2100345.
[http://dx.doi.org/10.1002/ardp.202100345] [PMID: 34693550]
[4]
Mollazadeh, M.; Mohammadi-Khanaposhtani, M.; Valizadeh, Y.; Zonouzi, A.; Faramarzi, M.A.; Kiani, M.; Biglar, M.; Larijani, B.; Hamedifar, H.; Mahdavi, M.; Hajimiri, M.H. Novel coumarin containing dithiocarbamate derivatives as potent α-glucosidase inhibitors for management of type 2 diabetes. Med. Chem., 2021, 17(3), 264-272.
[http://dx.doi.org/10.2174/1573406416666200826101205] [PMID: 32851964]
[5]
Bruneton, J. Pharmacognosy, phytochemistry, medicinal plants. Carbohydr. Polym., 1999, 42(4), 428-429.
[6]
Gupta, M.K.; Kumar, S.; Chaudhary, S. Coumarins: A unique scaffold with versatile biological behavior. Asian J. Pharm. Clin. Res., 2019, 12, 27-38.
[http://dx.doi.org/10.22159/ajpcr.2019.v12i3.30635]
[7]
Nauck, M.A.; Quast, D.R.; Wefers, J.; Meier, J.J. GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol. Metab., 2021, 46, 101102.
[http://dx.doi.org/10.1016/j.molmet.2020.101102] [PMID: 33068776]
[8]
Kobayati, A.; Haidar, A.; Tsoukas, M.A. GLP‐1 receptor agonists as adjunctive treatment for type 1 diabetes: Renewed opportunities through tailored approaches? Diabetes Obes. Metab., 2022. Epub ahead of print
[http://dx.doi.org/10.1111/dom.14637]
[9]
De Block, C.E.; Dirinck, E.; Verhaegen, A.; Van Gaal, L.F. Efficacy and safety of high‐dose GLP‐1, GLP‐1/GIP and GLP‐1/glucagon receptor agonists in type 2 diabetes. Diabetes Obes. Metab., 2022. Epub ahead of print
[http://dx.doi.org/10.1111/dom.14640]
[10]
Sharma, D.; Mir, N.A.; Biswas, A.; Deo, C. Performance enhancing, immunomodulatory, anti-hyperlipidaemic, and antimicrobial properties of bael (Aegle marmelos) leaf powder in broiler chicken. Trop. Anim. Health Prod., 2022, 54(1), 56.
[http://dx.doi.org/10.1007/s11250-022-03054-5] [PMID: 35031883]
[11]
Kılıç, CS Herbal coumarins in healthcare. In: Herbal Biomolecules in Healthcare Applications; Academic Press: USA, 2022; pp. 363-380.
[12]
Lin, H.C.H.; Paul, C.R.; Kuo, C.H.; Chang, Y.H.; Chen, W.S.T.; Ho, T.J.; Day, C.H.; Velmurugan, B.K.; Tsai, Y.; Huang, C.Y. Glycyrrhiza uralensis root extract ameliorates high glucose‐induced renal proximal tubular fibrosis by attenuating tubular epithelial‐myofibroblast transdifferentiation by targeting TGF‐β1/Smad/Stat3 pathway. J. Food Biochem., 2022, 46(5), e14041.
[http://dx.doi.org/10.1111/jfbc.14041] [PMID: 35064587]
[13]
G, A.C.; Gondru, R.; Li, Y.; Banothu, J. Coumarin-benzimidazole hybrids: A review of developments in medicinal chemistry. Eur. J. Med. Chem., 2022, 227, 113921.
[http://dx.doi.org/10.1016/j.ejmech.2021.113921] [PMID: 34715585]
[14]
Mendelson, W.L.; Hayden, S. Preparation of 2, 4-dihydroxybenzaldehyde by the Vilsmeier-Haack reaction. Synth. Commun., 1996, 26(3), 603-610.
[http://dx.doi.org/10.1080/00397919608003654]
[15]
Mann, F.G.; Saunders, B.C. Practical Organic Chemistry; Orient Blackswan, 1975.
[16]
Hari Krishna, M.; Thriveni, P. Synthesis of coumarins via Pechmann reaction using Cr(NO3)3. 9H2O as a Catalyst under microwave irradiation. Der Pharma Chem., 2016, 8(9), 94.
[17]
Liu, G.L.; Hu, Y.; Chen, X.H.; Wang, G.X.; Ling, F. Synthesis and anthelmintic activity of coumarin-imidazole hybrid derivatives against Dactylogyrus intermedius in goldfish. Bioorg. Med. Chem. Lett., 2016, 26(20), 5039-5043.
[http://dx.doi.org/10.1016/j.bmcl.2016.08.090] [PMID: 27617878]
[18]
Srivastava, R.; Choudhury, P.K.; Dev, S.K.; Rathore, V. Formulation and evaluation of α-pinene loaded self-emulsifying nanoformulation for in vivo anti-parkinson’s activity. Recent Pat. Nanotechnol., 2022, 16(27), 139-159.
[PMID: 33781196]
[19]
Srivastava, R.; Tripathi, L.; Swain, S.R.; Singh, J. Neuroprotective validation of pectin in T2DM-induced allodynia and hyperalgesia in diabetic peripheral neuropathic pain. Arch. Physiol. Biochem., 2021, 2021, 1884725.
[http://dx.doi.org/10.1080/13813455.2021.1884725] [PMID: 33618606]
[20]
Gundala, N.K.V.; Naidu, V.G.M.; Das, U.N. Amelioration of streptozotocin-induced type 2 diabetes mellitus in Wistar rats by arachidonic acid. Biochem. Biophys. Res. Commun., 2018, 496(1), 105-113.
[http://dx.doi.org/10.1016/j.bbrc.2018.01.007] [PMID: 29309791]
[21]
Gupta, M.K.; Kumar, S.; Chaudhary, S. Synthesis and Investigation of antidiabetic response of new coumarin derivatives against streptozotocin induced diabetes in experimental rats. Pharm. Chem. J., 2020, 53(12), 1122-1127.
[http://dx.doi.org/10.1007/s11094-020-02134-w]
[22]
Santos-Pardo, I.; Lagerqvist, B.; Ritsinger, V.; Witt, N.; Norhammar, A.; Nyström, T. Risk of stent failure in patients with diabetes treated with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors: A nationwide observational study. Int. J. Cardiol., 2021, 330, 23-29.
[http://dx.doi.org/10.1016/j.ijcard.2021.02.011] [PMID: 33621623]
[23]
Gaur, A.; Lewis, E.L.; Hergarden, A.C.; Sheridan, S.E.; He, L.; Whistler, J.L. Effects of naturally occurring genetic variations in incretin receptors on glucose homeostasis. Metabolism, 2021, 116, 154530.
[24]
Hussain, M.A.; Laimon-Thomson, E.; Mustafa, S.M.; Deck, A.; Song, B. Detour ahead: incretin hormone signaling alters its intracellular path as β-cell failure progresses during diabetes. Front. Endocrinol. (Lausanne), 2021, 12, 665345.
[http://dx.doi.org/10.3389/fendo.2021.665345] [PMID: 33935974]
[25]
Bianchini, G.; Nigro, C.; Sirico, A.; Novelli, R.; Prevenzano, I.; Miele, C.; Beguinot, F.; Aramini, A. A new synthetic dual agonist of GPR120/GPR40 induces GLP-1 secretion and improves glucose homeostasis in mice. Biomed. Pharmacother., 2021, 139, 111613.
[http://dx.doi.org/10.1016/j.biopha.2021.111613] [PMID: 33895521]
[26]
Nakajima, Y.; Ito, S.; Asakura, M.; Min, K.D.; Fu, H.Y.; Imazu, M.; Hitsumoto, T.; Takahama, H.; Shindo, K.; Fukuda, H.; Yamazaki, S.; Asanuma, H.; Kitakaze, M. A dipeptidyl peptidase-IV inhibitor improves diastolic dysfunction in Dahl salt-sensitive rats. J. Mol. Cell. Cardiol., 2019, 129, 257-265.
[http://dx.doi.org/10.1016/j.yjmcc.2019.03.009] [PMID: 30880253]
[27]
Cheng, C.; Jabri, S.; Taoka, B.M.; Sinz, C.J. Small molecule glucagon receptor antagonists: An updated patent review (2015-2019). Expert Opin. Ther. Pat., 2020, 30(7), 509-526.
[http://dx.doi.org/10.1080/13543776.2020.1769600] [PMID: 32552241]
[28]
Martins, F.L.; Bailey, M.A.; Girardi, A.C.C. Endogenous activation of glucagon-like peptide-1 receptor contributes to blood pressure control: Role of proximal tubule Na+/H+ exchanger isoform 3, renal angiotensin II, and insulin sensitivity. Hypertension, 2020, 76(3), 839-848.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14868] [PMID: 32755467]
[29]
Ahmed, S.; Islam, N.; Shahinozzaman, M.; Fakayode, S.O.; Afrin, N.; Halim, M.A. Virtual screening, molecular dynamics, density functional theory and quantitative structure activity relationship studies to design peroxisome proliferator-activated receptor-γ agonists as anti-diabetic drugs. J. Biomol. Struct. Dyn., 2021, 39(2), 728-742.
[http://dx.doi.org/10.1080/07391102.2020.1714482] [PMID: 31916505]
[30]
Kaneto, H.; Kimura, T.; Obata, A.; Shimoda, M.; Kaku, K. Multifaceted mechanisms of action of metformin which have been unraveled one after another in the long history. Int. J. Mol. Sci., 2021, 22(5), 2596.
[http://dx.doi.org/10.3390/ijms22052596] [PMID: 33807522]
[31]
Cortez, I.; Hernandez, C.M.; Dineley, K.T. Enhancement of select cognitive domains with rosiglitazone implicates dorsal hippocampus circuitry sensitive to PPARγ agonism in an Alzheimer’s mouse model. Brain Behav., 2021, 11(2), e01973.
[http://dx.doi.org/10.1002/brb3.1973] [PMID: 33382528]
[32]
Guo, J.; Chen, J.; Ren, W.; Zhu, Y.; Zhao, Q.; Zhang, K.; Su, D.; Qiu, C.; Zhang, W.; Li, K. Citrus flavone tangeretin is a potential insulin sensitizer targeting hepatocytes through suppressing MEK-ERK1/2 pathway. Biochem. Biophys. Res. Commun., 2020, 529(2), 277-282.
[http://dx.doi.org/10.1016/j.bbrc.2020.05.212] [PMID: 32703423]
[33]
Matumba, M.; Ayeleso, A.; Nyakudya, T.; Erlwanger, K.; Chegou, N.; Mukwevho, E. Long-term impact of neonatal intake of oleanolic acid on the expression of AMP-activated protein kinase, adiponectin and inflammatory cytokines in rats fed with a high fructose diet. Nutrients, 2019, 11(2), 226.
[http://dx.doi.org/10.3390/nu11020226] [PMID: 30678182]
[34]
Shaheen, A.; Ashiq, U.; Jamal, R.A.; Khan, K.M.; Gul, S.; Yousuf, S.; Ali, S.T. Design and synthesis of fluoroquinolone derivatives as potent α‐glucosidase inhibitors: In vitro inhibitory screening with in silico docking studies. ChemistrySelect, 2021, 6(10), 2483-2491.
[http://dx.doi.org/10.1002/slct.202003956]
[35]
Jarosinski, M.A.; Dhayalan, B.; Rege, N.; Chatterjee, D.; Weiss, M.A. ‘Smart’ insulin-delivery technologies and intrinsic glucose-responsive insulin analogues. Diabetologia, 2021, 64(5), 1016-1029.
[http://dx.doi.org/10.1007/s00125-021-05422-6] [PMID: 33710398]
[36]
Pan, Y.; Liu, T.; Wang, X.; Sun, J. Research progress of coumarins and their derivatives in the treatment of diabetes. J. Enzyme Inhib. Med. Chem., 2022, 37(1), 616-628.
[http://dx.doi.org/10.1080/14756366.2021.2024526] [PMID: 35067136]
[37]
Mayendraraj, A.; Rosenkilde, M.M.; Gasbjerg, L.S. GLP-1 and GIP receptor signaling in beta cells - A review of receptor interactions and co-stimulation. Peptides, 2022, 151, 170749.
[http://dx.doi.org/10.1016/j.peptides.2022.170749] [PMID: 35065096]
[38]
Laurindo, L.F.; Barbalho, S.M.; Guiguer, E.L.; da Silva Soares de Souza, M.; de Souza, G.A.; Fidalgo, T.M.; Araújo, A.C.; de Souza Gonzaga, H.F.; de Bortoli Teixeira, D.; de Oliveira Silva Ullmann, T.; Sloan, K.P.; Sloan, L.A. GLP-1a: Going beyond traditional use. Int. J. Mol. Sci., 2022, 23(2), 739.
[http://dx.doi.org/10.3390/ijms23020739] [PMID: 35054924]
[39]
Spezani, R.; Mandarim-de-Lacerda, C.A. The current significance and prospects for the use of dual receptor agonism GLP-1/Glucagon. Life Sci., 2022, 288, 120188.
[http://dx.doi.org/10.1016/j.lfs.2021.120188] [PMID: 34861287]
[40]
Nidhar, M.; Khanam, S.; Sonker, P.; Gupta, P.; Mahapatra, A.; Patil, S.; Yadav, B.K.; Singh, R.K.; Kumar Tewari, A. Click inspired novel pyrazole-triazole-persulfonimide & pyrazole-triazole-aryl derivatives; Design, synthesis, DPP-4 inhibitor with potential anti-diabetic agents. Bioorg. Chem., 2022, 120, 105586.
[http://dx.doi.org/10.1016/j.bioorg.2021.105586] [PMID: 35051706]
[41]
Shah, B.M.; Modi, P.; Trivedi, P. Recent medicinal chemistry approach for the development of dipeptidyl peptidase IV inhibitors. Curr. Med. Chem., 2021, 28(18), 3595-3621.
[http://dx.doi.org/10.2174/0929867327666201012153255] [PMID: 33045957]
[42]
Lambert, L. Focus on Saxenda® solution for injection. J. Endocrinol. Metabol. Diabetes South Africa, 2021, 26(1), 8-10.
[43]
Nebbioso, M.; Lambiase, A.; Armentano, M. 0 Tucciarone, G.; Sacchetti, M.; Greco, A.; Alisi, L. Diabetic retinopathy, oxidative stress, and sirtuins: An in depth look in enzymatic patterns and new therapeutic horizons. Surv. Ophthalmol., 2022, 67(1), 168-183.
[http://dx.doi.org/10.1016/j.survophthal.2021.04.003] [PMID: 33864872]
[44]
Pelkonen, O.; Raunio, H.; Rautio, A.; Pasanen, M.; Lang, M. The metabolism of coumarins. In: Coumarins: Biology, Applications and mode of action; Wiley: Hoboken, NJ, 1997.
[45]
Killard, A.J.; Keating, G.J.; Kennedy, R.O. Production and characterization of anti-coumarin scFv antibodies. Biochem. Soc. Trans., 1998, 26(1), S33.
[http://dx.doi.org/10.1042/bst026s033] [PMID: 10909791]
[46]
Dempsey, E.; O’Sullivan, C.; Smyth, M.R.; Egan, D.; O’Kennedy, R.; Wang, J. Development of an antibody-based amperometric biosensor to study the reaction of 7-hydroxycoumarin with its specific antibody. Analyst (Lond.), 1993, 118(4), 411-413.
[http://dx.doi.org/10.1039/an9931800411] [PMID: 8494174]
[47]
Han, J.; Sun, L.; Huang, X.; Li, Z.; Zhang, C.; Qian, H.; Huang, W. Novel coumarin modified GLP-1 derivatives with enhanced plasma stability and prolonged in vivo glucose-lowering ability. Br. J. Pharmacol., 2014, 171(23), 5252-5264.
[http://dx.doi.org/10.1111/bph.12843] [PMID: 25039358]
[48]
Ruegsegger, G.N.; Creo, A.L.; Cortes, T.M.; Dasari, S.; Nair, K.S. Altered mitochondrial function in insulin-deficient and insulin-resistant states. J. Clin. Invest., 2018, 128(9), 3671-3681.
[http://dx.doi.org/10.1172/JCI120843] [PMID: 30168804]
[49]
Onyango, A.N. Cellular stresses and stress responses in the pathogenesis of insulin resistance. Oxid. Med. Cell. Longev., 2018, 2018, 4321714.
[http://dx.doi.org/10.1155/2018/4321714] [PMID: 30116482]
[50]
Wang, N.; Zhang, J.; Qin, M.; Yi, W.; Yu, S.; Chen, Y.; Guan, J.; Zhang, R. Amelioration of streptozotocin induced pancreatic β cell damage by morin: Involvement of the AMPK FOXO3 catalase signaling pathway. Int. J. Mol. Med., 2018, 41(3), 1409-1418.
[http://dx.doi.org/10.3892/ijmm.2017.3357]
[51]
Lu, W.; Cui, Y.; Zhang, L. Isofraxidin exerts anti-diabetic, antilipidemic, and antioxidant effects and protects renal tissues via inhibition of NF-ĸB in Streptozotocin-induced diabetic rats.Mol. Cell. Toxicol; , 2022, pp. 1-11.
[http://dx.doi.org/10.1007/s13273-021-00204-y]