DESIGN, SYNTHESIS, AND BIO PROFILING OF 2, 3-DIHYDROQUINAZOLIN-4(1H)-ONE DERIVATIVE AS TYPE II DIABETES AGENTS: A COMPREHENSIVE IN SILICO, IN VITRO, AND IN VIVO STUDY

MINCY MATHEW; D. KILIMOZHI; SANTHOSH M. MATHEWS; ANTON SMITH

doi:10.22159/ijap.2024v16i6.51705

Authors

MINCY MATHEW Department of Pharmacy, Faculty of Engineering and Technology, Annamalai University, Tamilnadu, India https://orcid.org/0000-0002-2118-8810
D. KILIMOZHI Department of Pharmacy, Faculty of Engineering and Technology, Annamalai University, Tamilnadu, India
SANTHOSH M. MATHEWS Department of Pharmaceutics, Pushpagiri College of Pharmacy, Kerala, India
ANTON SMITH Department of Pharmacy, Faculty of Engineering and Technology, Annamalai University, Tamilnadu, India https://orcid.org/0000-0002-6698-3965

DOI:

https://doi.org/10.22159/ijap.2024v16i6.51705

Keywords:

Diabetes mellitus, Type 2 diabetes mellitus, Antidiabetic, Drug design, 2,3-Dihydroquinazolin-4(1H)-One

Abstract

Objective: Diabetes mellitus is a significant global health challenge, with Type 2 Diabetes Mellitus (T2DM) being a leading cause of mortality worldwide, demanding the need for effective interventions by developing innovative therapeutic strategies or novel antidiabetic agents. This study explores in silico, in vitro, and in vivo approaches to identify the most potent 2,3-Dihydroquinazolin-4(1H)-One derivative molecule with antidiabetic activity.
Methods: Eleven new derivatives were designed, studied in silico to identify the most promising compounds, synthesized, studied spectrally to describe them, and evaluated for both in vitro and in vivo investigations. Alpha amylase and alpha-glucosidase inhibitory activities were investigated in vitro. The endogenous suppression of glucose synthesis in Hepatoblastoma cell line 2(HepG2) cells and the in vitro glucose absorption assay on cultivated L6 cell lines were conducted. To assess the ability of the newly synthesized compounds to prevent diabetes, in vivo investigations were conducted on Streptozotocin (STZ)-induced diabetic rats and the effects on various biochemical parameters were identified.
Results: Leveraging computational methods, the QZ9 molecule was identified with stable interactions with key biomolecules associated with T2DM. Subsequent in vitro assays confirmed the inhibitory effects of QZ2, QZ8, and QZ9 on alpha-amylase and alpha-glucosidase activities, suggesting their potential as enzyme inhibitors. Additionally, QZ8 and QZ9 demonstrated enhanced glucose uptake and production inhibition in HepG2 cells, indicating their role in improving glucose homeostasis. In vitro, the top-ranked molecules QZ2, QZ8, and QZ9 were analyzed to validate the in silico findings and assess their potential as therapeutic agents for T2DM. The inhibition of α-amylase activity by QZ2, QZ8, and QZ9 was dose-dependent, with maximum inhibition observed at 1000 µg/ml: 57.33% for QZ2, 52.21% for QZ8, and 87.16% for QZ9. Similarly, α-glucosidase inhibition at 1000 µg/ml was 59.96% for QZ2, 53.50% for QZ8, and 81.51% for QZ9. Both QZ8 and QZ9 significantly increased glucose uptake and inhibited glucose production in HepG2 cells, with maximum glucose production inhibition at 100 µg/ml: 62.22% for QZ8 and 62.35% for QZ9. These findings suggest that QZ8 and QZ9 contribute to glucose homeostasis. QZ9 demonstrated superior enzyme inhibition compared to QZ2 and QZ8, with α-amylase and α-glucosidase inhibition up to 87.16% and 81.51%, respectively, at 1000 µg/ml. In vivo investigations in Diabetic rat models further confirmed the efficacy of these compounds by showing significant reductions in blood glucose levels. These results suggests the potentiality of QZ9 as a promising novel Antidiabetic agent.
Conclusion: Combining computational predictions with experimental validations, this integrated approach highlights the promise of 2,3-Dihydroquinazolin-4(1H)-One derivative QZ9 as a novel antidiabetic agent, warranting further investigation for clinical translation.

Downloads

Download data is not yet available.

References

Daina A, Michielin O, Zoete V. Swiss ADME: a free web tool to evaluate pharmacokinetics drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017 Mar 3;7:42717. doi: 10.1038/srep42717, PMID 28256516.

Haghighatpanah M, Nejad AS, Haghighatpanah M, Thunga G, Mallayasamy S. Factors that correlate with poor glycemic control in type 2 diabetes mellitus patients with complications. Osong Public Health Res Perspect. 2018;9(4):167-74. doi: 10.24171/j.phrp.2018.9.4.05, PMID 30159222.

LI M, Chi X, Wang Y, Setrerrahmane S, Xie W, XU H. Trends in insulin resistance: insights into mechanisms and therapeutic strategy. Signal Transduct Target Ther. 2022;7(1):216. doi: 10.1038/s41392-022-01073-0, PMID 35794109.

Tran N, Pham B, LE L. Bioactive compounds in anti-diabetic plants: from herbal medicine to modern drug discovery. Biology (Basel). 2020;9(9):1-31. doi: 10.3390/biology9090252, PMID 32872226.

Buggana SJ, Paturi MC, Rajendra Prasad VV. Design and synthesis of Novel 2, 3-disubstituted quinazolines: evaluation of in vitro anticancer activity and in silico studies. Asian J Pharm Clin Res. 2019;13(1):174-9. doi: 10.22159/ajpcr.2020.v13i1.36215.

Dash B, Dash S, Laloo D. Design and synthesis of 4-substituted quinazoline derivatives for their anticonvulsant and CNS depressant activities. Int J Pharm Pharm Sci. 2016;9(1):165. doi: 10.22159/ijpps.2017v9i1.15492.

M. WS, MA M, SA Y, G DR. Biological activity of quinazolinone derivatives: a review. Int J Curr Pharm Res. 2023;15(1):15-8.

Pisal P, Deodhar M, Kale A, Nigade G, Pawar S. Design synthesis docking studies and biological evaluation of 2-phenyl-3-(substituted benzo[d] thiazol-2-ylamino)-quinazoline-4(3h) one derivatives as antimicrobial agents. Int J Pharm Pharm Sci. 2018;10(10):57. doi: 10.22159/ijpps.2018v10i10.28480.

Daina A, Michielin O, Zoete V. Swiss ADME: a free web tool to evaluate pharmacokinetics drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017 Mar 3;7:42717. doi: 10.1038/srep42717, PMID 28256516.

Pires DE, Blundell TL, Ascher DB. PkCSM: predicting small molecule pharmacokinetic and toxicity properties using graph based signatures. J Med Chem. 2015 May 14;58(9):4066-72. doi: 10.1021/acs.jmedchem.5b00104, PMID 25860834.

Katelia R, Jauhar MM, Syaifie PH, Nugroho DW, Ramadhan D, Arda AG. In silico investigation of xanthone derivative potency in inhibiting carbonic anhydrase II (Ca Ii) using molecular docking and molecular dynamics (MD) simulation. Int J App Pharm. 2022;14(5):190-8. doi: 10.22159/ijap.2022v14i5.45388.

Trott O, Olson AJ. Auto dock vina: improving the speed and accuracy of docking with a new scoring function efficient optimization and multithreading. J Comput Chem. 2010;31(2):455-61. doi: 10.1002/jcc.21334, PMID 19499576.

Whitcomb DC, Lowe ME. Human pancreatic digestive enzymes. Dig Dis Sci. 2007;52(1):1-17. doi: 10.1007/s10620-006-9589-z, PMID 17205399.

Stiefel DJ, Keller PJ. Preparation and some properties of human pancreatic amylase, including a comparison with human parotid amylase. Biochim Biophys Acta. 1973;302(2):345-61. doi: 10.1016/0005-2744(73)90163-0, PMID 4699244.

Brissenden JE, Ullrich A, Francke U. Human chromosomal mapping of genes for insulin-like growth factors I and II and epidermal growth factor. Nature. 1984;310(5980):781-4. doi: 10.1038/310781a0, PMID 6382023.

Proks P, Reimann F, Green N, Gribble F, Ashcroft F. Sulfonylurea stimulation of insulin secretion. Diabetes. 2002 Dec 1;51 Suppl 3:S368-76. doi: 10.2337/diabetes.51.2007.s368, PMID 12475777.

Mathieu C, Dupret JM, Rodrigues Lima F. The structure and the regulation of glycogen phosphorylases in brain. Adv Neurobiol. 2019;23:125-45. doi: 10.1007/978-3-030-27480-1_4, PMID 31667807.

Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)-UpToDate.

Wang L, LI J, DI LJ. Glycogen synthesis and beyond a comprehensive review of GSK3 as a key regulator of metabolic pathways and a therapeutic target for treating metabolic diseases. Med Res Rev. 2022;42(2):946-82. doi: 10.1002/med.21867, PMID 34729791.

Rohrborn D, Wronkowitz N, Eckel J. DPP4 in diabetes. Front Immunol. 2015 Jul 27;6:386. doi: 10.3389/fimmu.2015.00386, PMID 26284071.

Tyagi S, Gupta P, Saini AS, Kaushal C, Sharma S. The peroxisome proliferator-activated receptor: a family of nuclear receptors role in various diseases. J Adv Pharm Technol Res. 2011;2(4):236-40. doi: 10.4103/2231-4040.90879, PMID 22247890.

Abraham MJ, Murtola T, Schulz R, Pall S, Smith JC, Hess B. Gromacs: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 2015 Sep;1-2:19-25. doi: 10.1016/j.softx.2015.06.001.

Markidis S, Laure E. Solving software challenges for exascale: international conference on exascale applications and software. Lect Notes Comput Sci. 2014;8759:3–27.

Valdes Tresanco MS, Valdes Tresanco ME, Valiente PA, Moreno E. Gmx_MMPBSA: a new tool to perform end-state free energy calculations with GROMACS. J Chem Theory Comput. 2021 Oct 12;17(10):6281-91. doi: 10.1021/acs.jctc.1c00645, PMID 34586825.

Barmak A, Niknam K, Mohebbi G. Synthesis structural studies and α-glucosidase inhibitory antidiabetic and antioxidant activities of 2,3-dihydroquinazolin-4(1h) ones derived from pyrazol-4-carbaldehyde and anilines. ACS Omega. 2019;4(19):18087-99. doi: 10.1021/acsomega.9b01906, PMID 31720511.

Zhang J, Cheng P, MA Y, Liu J, Miao Z, Ren D. An efficient nano CuO catalyzed synthesis and biological evaluation of quinazolinone schiff base derivatives and bis-2,3-dihydroquinazolin-4(1H) ones as potent antibacterial agents against streptococcus lactis. Tetrahedron Lett. 2016 Nov 23;57(47):5271-7. doi: 10.1016/j.tetlet.2016.10.047.

Dabiri M, Salehi P, Otokesh S, Baghbanzadeh M, Kozehgary G, Mohammadi AA. Efficient synthesis of mono and disubstituted 2,3-dihydroquinazolin-4(1H) ones using KAl(SO4)2.12H2O as a reusable catalyst in water and ethanol. Tetrahedron Lett. 2005 Sep 5;46(36):6123-6. doi: 10.1016/j.tetlet.2005.06.157.

Badolato M, Aiello F, Neamati N. 2,3-Dihydroquinazolin-4(1: H) badolato M Aiello F Neamati N 2,3-Dihydroquinazolin-4(1H) one as a privileged scaffold in drug design. RSC Adv. 2018;8(37):20894-921. doi: 10.1039/c8ra02827c, PMID 35542353.

Wickramaratne MN, Punchihewa JC, Wickramaratne DB. In vitro alpha amylase inhibitory activity of the leaf extracts of adenanthera pavonina. BMC Complement Altern Med. 2016;16(1):466. doi: 10.1186/s12906-016-1452-y, PMID 27846876.

Ouassou H, Zahidi T, Bouknana S, Bouhrim M, Mekhfi H, Ziyyat A. Inhibition of α-glucosidase intestinal glucose absorption and antidiabetic properties by caralluma europaea. Evid Based Complement Alternat Med. 2018 Aug 29;2018:9589472. doi: 10.1155/2018/9589472, PMID 30228829.

Guo L, Zheng X, Liu J, Yin Z. Geniposide suppresses hepatic glucose production via AMPK in hepG2 cells. Biol Pharm Bull. 2016;39(4):484-91. doi: 10.1248/bpb.b15-00591, PMID 26830672.

Yamamoto N, Ueda Wakagi M, Sato T, Kawasaki K, Sawada K, Kawabata K. measurement of glucose uptake in cultured cells. Curr Protoc Pharmacol. 2015;71(1):12.14.1-12.14.26. doi: 10.1002/0471141755.ph1214s71, PMID 26646194.

Zhou F, Furuhashi K, Son MJ, Toyozaki M, Yoshizawa F, Miura Y. Antidiabetic effect of enterolactone in cultured muscle cells and in type 2 diabetic model db/db mice. Cytotechnology. 2017;69(3):493-502. doi: 10.1007/s10616-016-9965-2, PMID 27000262.

Asagba SO, Kadiri HE, Ezedom T. Biochemical changes in diabetic rats treated with ethanolic extract of Chysophyllum albidum fruit skin. The Journal of Basic and Applied Zoology. 2019;80(1). doi: 10.1186/s41936-019-0118-y.

Poovitha S, Parani M. In vitro and in vivo α-amylase and α-glucosidase inhibiting activities of the protein extracts from two varieties of bitter gourd (Momordica charantia L.). BMC Complement Altern Med. 2016;16 Suppl 1:185. doi: 10.1186/s12906-016-1085-1, PMID 27454418.

Gopal V, Mandal V, Tangjang S, Mandal SC. Serum biochemical histopathology and SEM analyses of the effects of the Indian traditional herb wattakaka volubilis leaf extract on wistar male rats. J Pharmacopuncture. 2014;17(1):13-9. doi: 10.3831/KPI.2014.17.002, PMID 25780685.

Ozougwu O. The pathogenesis and pathophysiology of type 1 and type 2 diabetes mellitus. J Physiol Pathophysiol. 2013;4(4):46-57. doi: 10.5897/JPAP2013.0001.

Bell RH, Hye RJ. Animal models of diabetes mellitus: physiology and pathology. J Surg Res. 1983;35(5):433-60. doi: 10.1016/0022-4804(83)90034-3, PMID 6314046.

Lenzen S. The mechanisms of alloxan and streptozotocin-induced diabetes. Diabetologia. 2008;51(2):216-26. doi: 10.1007/s00125-007-0886-7, PMID 18087688.

Tomlinson KC, Gardiner SM, Hebden RA, Bennett T. Functional consequences of streptozotocin-induced diabetes mellitus with particular reference to the cardiovascular system. Pharmacol Rev. 1992;44(1):103-50. PMID 1557425.

Gandhi GR, Sasikumar P. Antidiabetic effect of Merremia emarginata Burm. F. in streptozotocin induced diabetic rats. Asian Pac J Trop Biomed. 2012;2(4):281-6. doi: 10.1016/S2221-1691(12)60023-9, PMID 23569914.

Andallu B, Vinay Kumar AV, Varadacharyulu NCh. Lipid abnormalities in streptozotocin diabetes: amelioration by Morus indica L. cv suguna leaves. Int J Diabetes Dev Ctries. 2009;29(3):123-8. doi: 10.4103/0973-3930.54289, PMID 20165649.

Hollenbeck CB, Chen YD, Greenfield MS, Lardinois CK, Reaven GM. Reduced plasma high-density lipoprotein cholesterol concentrations need not increase when hyperglycemia is controlled with insulin in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1986;62(3):605-8.

Pandhare RB, Sangameswaran B, Mohite PB, Khanage SG. Anti-hyperglycaemic and lipid-lowering potential of Adenanthera pavonina Linn. in streptozotocin-induced diabetic rats. Orient Pharm Exp Med. 2012;12(3):197-203. doi: 10.1007/s13596-012-0074-2, PMID 22924034.

Wang J, WU T, Fang L, Liu C, Liu X, Li H. Anti-diabetic effect by walnut (Juglans mandshurica Maxim.) derived peptide LPLLR through inhibiting α-glucosidase and α-amylase and alleviating insulin resistance of hepatic HepG2 cells. J Funct Foods. 2020 Jun 1;69:103944. doi: 10.1016/j.jff.2020.103944.

Aladejana AE, Bradley G, Afolayan AJ. In vitro evaluation of the antidiabetic potential of Helichrysum petiolare hilliard and B. L. Burtt using HepG2. 1240; C3A and L6 cell lines. F1000 Research. 2021;9.

Khan I, Rehman W, Rahim F, Hussain R, Khan S, Rasheed L. Synthesis and in vitro α-amylase and α-glucosidase dual inhibitory activities of 1,2,4-triazole-bearing bis-hydrazone derivatives and their molecular docking study. ACS Omega. 2023;8(25):22508-22. doi: 10.1021/acsomega.3c00702, PMID 37396210.

Yousefnejad F, Mohammadi Moghadam Goozali M, Sayahi MH, Halimi M, Moazzam A, Mohammadi Khanaposhtani M. Design synthesis in vitro and in silico evaluations of benzo[d]imidazole-amide-1,2,3-triazole-N-arylacetamide hybrids as new antidiabetic agents targeting α-glucosidase. Sci Rep. 2023;13(1):12397. doi: 10.1038/s41598-023-39424-8, PMID 37524733.

Toumi A, Boudriga S, Hamden K, Sobeh M, Cheurfa M, Askri M. Synthesis antidiabetic activity and molecular docking study of rhodanine substitued spirooxindole pyrrolidine derivatives as novel α-amylase inhibitors. Bioorg Chem. 2021;106:104507. doi: 10.1016/j.bioorg.2020.104507, PMID 33288322.

Barmak A, Niknam K, Mohebbi G. Synthesis structural studies and α-glucosidase inhibitory antidiabetic and antioxidant activities of 2,3-dihydroquinazolin-4(1H) ones derived from pyrazol-4-carbaldehyde and anilines. ACS Omega. 2019;4(19):18087-99. doi: 10.1021/acsomega.9b01906, PMID 31720511.