Discovery of thymol-fused chalcones as new competitive \(\alpha\)-glucosidase inhibitors: Design, synthesis, biological evaluation, and molecular modeling studies
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Abstract
This study aims to synthesize and evaluate the inhibitory activity of thymol derivatives targeting ?-glucosidase using in vitro and in silico studies. Ten thymol derivatives (2-11) including five new thymol-fused chalcones (7-11) were successfully synthesized. Among them, four compounds (4, 8, 9, 11) showed the best inhibitory activity with IC50 values of 18.45, 13.75, 8.86, and 10.67µM compared with acarbose (IC50 = 832.82 µM), respectively. The kinetic study of three new thymol-fused chalcones (8, 9, 11) exhibited a competitive inhibition. Molecular docking demonstrated the predicted interactions between ligand (8, 9, 11) and ?-glucosidase, which are responsible for inhibiting the enzyme's catalytic abilities. Furthermore, molecular dynamics simulation of the enzyme-ligand 9 complex indicated that this complex was stable in aqueous condition. This research contributes significantly to the understanding of thymol-fused chalcones that may have therapeutic potential and their possible application in the treatment of type 2 diabetes mellitus (T2DM) for further study.
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Danova, A., Hermawati, E., Chavasiri, W., Mujahidin, D., Alni, A., & Roswanda, R. (2024). Discovery of thymol-fused chalcones as new competitive \(\alpha\)-glucosidase inhibitors: Design, synthesis, biological evaluation, and molecular modeling studies. Communications in Science and Technology, 9(2), 322-330. https://doi.org/10.21924/cst.9.2.2024.1497
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References
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11. Trapero A, Llebaria A. A Prospect for Pyrrolidine Iminosugars as Antidiabetic ?-Glucosidase Inhibitors. J. Med. Chem. 2012;55:10345-6.
12. Kim DK, Lee B-H. New glucogenesis inhibition model based on complete ?-glucosidases from rat intestinal tissues validated with various types of natural and pharmaceutical inhibitors. J. Sci. Food Agric. 2022;102:4419-24.
13. Salani B, Rio AD, Marini C, Sambuceti G, Cordera R, Maggi D. Metformin, cancer and glucose metabolism. Endocr. Relat. Cancer. 2014;21(6):R461-R71.
14. Zhao Y, Xu L, Tian D, Xia P, Zheng H, Wang L, et al. Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid level: A meta-analysis of randomized controlled trials. Diabetes Obes. Metab. 2018;20(2):458-62.
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29. Dias DA, Urban S, Roessner U. A Historical Overview of Natural Products in Drug Discovery. Metabolites. 2012, p. 303-36.
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31. Kachur K, Suntres Z. The antibacterial properties of phenolic isomers, carvacrol and thymol. Crit. Rev. Food Sci. Nutr. 2020;60:3042-53.
32. Wang K, Jiang S, Yang Y, Fan L, Su F, Ye M. Synthesis and antifungal activity of carvacrol and thymol esters with heteroaromatic carboxylic acids. Nat. Prod. Res. 2019;33:1924-30.
33. López V, Cascella M, Benelli G, Maggi F, Gómez-Rincón C. Green drugs in the fight against Anisakis simplex—larvicidal activity and acetylcholinesterase inhibition of Origanum compactum essential oil. Parasitol Res. 2018;117:861-7.
34. Araújo LX, Novato TPL, Zeringota V, Matos RS, Senra TOS, Maturano R, et al. Acaricidal activity of thymol against larvae of Rhipicephalus microplus (Acari: Ixodidae) under semi-natural conditions. Parasitol Res. 2015;114:3271-6.
35. Jairajpuri DS, Khan S, Anwar S, Hussain A, Alajmi MF, Hassan I. Investigating the role of thymol as a promising inhibitor of pyruvate dehydrogenase kinase 3 for targeted cancer therapy. Int. J. Biol. Macromol. 2024;259:129314.
36. Dominguez-Uscanga A, Aycart DF, Li K, Witola WH, Andrade Laborde JE. Anti-protozoal activity of Thymol and a Thymol ester against Cryptosporidium parvum in cell culture. Int. J. Parasitol. Drugs Drug Resist. 2021;15:126-33.
37. Kurt BZ, Gazioglu I, Dag A, Salmas RE, Kay?k G, Durdagi S, et al. Synthesis, anticholinesterase activity and molecular modeling study of novel carbamate-substituted thymol/carvacrol derivatives. Bioorg. Med. Chem. 2017;25:1352-63.
38. Rajput JD, Bagul SD, Bendre RS. Design, synthesis, biological screenings and docking simulations of novel carvacrol and thymol derivatives containing acetohydrazone linkage. Res. Chem. Intermed. 2017;43:4893-906.
39. Nagle PS, Pawar YA, Sonawane AE, Bhosale SM, More DH. Synthesis and evaluation of antioxidant and antimicrobial properties of thymol containing pyridone moieties. Med. Chem. Res. 2012;21:1395-402.
40. Raghuvanshi DS, Verma N, Singh SV, Khare S, Pal A, Negi AS. Synthesis of thymol-based pyrazolines: An effort to perceive novel potent-antimalarials. Bioorg. Chem. 2019;88:102933.
41. Salazar MO, Osella MI, Arcusin DEJ, Lescano LE, Furlan RLE. New ?-glucosidase inhibitors from a chemically engineered essential oil of Origanum vulgare L. Ind. Crop. Prod. 2020;156:112855.
42. Singh A, Singh K, Kaur K, Sharma A, Mohana P, Prajapati J, et al. Discovery of triazole tethered thymol/carvacrol-coumarin hybrids as new class of ?-glucosidase inhibitors with potent in vivo antihyperglycemic activities. Eur. J. Med. Chem. 2024;263:115948.
43. Bachelet J, Cavier R, Lemoine J, Rigothier M, Gayral P, Royer R. Comparison of the antibacterial, antiparasitic and molluscicidal properties of halogenoacylamide or halogenoacyl derivatives of thymol.NA. Eur. J. Med. Chem. 1979;14:321-4.
44. Hengphasatporn K, Garon A, Wolschann P, Langer T, Yasuteru S, Huynh TNT, et al. Multiple Virtual Screening Strategies for the Discovery of Novel Compounds Active Against Dengue Virus: A Hit Identification Study. Sci. Pharm. 2020.
45. Danova A, Pattanapanyasat K, Hengphasatporn K, Shigeta Y, Rungrotmongkol T, Hermawati E, et al. Unlocking E-arylidene Steroid Derivatives as Promising ?-Glucosidase Inhibitors. ChemistrySelect. 2024;9(9):e202303887.
46. Jakubec D, Skoda P, Krivak R, Novotny M, Hoksza D. PrankWeb 3: accelerated ligand-binding site predictions for experimental and modelled protein structures. Nucleic Acids Res. 2022;50(W1):W593-W7.
47. Yamamoto K, Miyake H, Kusunoki M, Osaki S. Steric hindrance by 2 amino acid residues determines the substrate specificity of isomaltase from Saccharomyces cerevisiae. J. Biosci. Bioeng. 2011;112:545-50.
48. Dallakyan S, Olson AJ. Small-Molecule Library Screening by Docking with PyRx. In: Hempel JE, Williams CH, Hong CC, editors. Chemical Biology: Methods and Protocols, New York, NY: Springer New York; 2015, p. 243-50.
49. Trott O, Olson AJ. AutoDock 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.
50. Duan Y, Wu C, Chowdhury S, Lee MC, Xiong G, Zhang W, et al. A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations. J. Comput. Chem. 2003;24:1999-2012.
51. Krieger E, Darden T, Nabuurs SB, Finkelstein A, Vriend G. Making optimal use of empirical energy functions: Force-field parameterization in crystal space. Proteins. 2004;57:678-83.
52. Krieger E, Vriend G. New ways to boost molecular dynamics simulations. J. Comput. Chem. 2015;36:996-1007.
53. Al-ghulikah HA, Mughal EU, Elkaeed EB, Naeem N, Nazir Y, Alzahrani AY, Sadiq A, Shah SW. Discovery of chalcone derivatives as potential ?-glucosidase and cholinesterase inhibitors: Effect of hyperglycemia in paving a path to dementia. J. Mol. Struct. 2023;1275:134658.
54. Hosseini Nasab N, Raza H, Eom YS, Shah FH, Kwak JH, Kim SJ. Exploring chalcone-sulfonyl piperazine hybrids as anti-diabetes candidates: design, synthesis, biological evaluation, and molecular docking study. Mol. Divers. 2024;22:1-7.
55. Hu CM, Luo YX, Wang WJ, Li JP, Li MY, Zhang YF, Xiao D, Lu L, Xiong Z, Feng N, Li C. Synthesis and evaluation of coumarin-chalcone derivatives as ?-glucosidase inhibitors. Front. Chem. 2022;10:926543.
56. He XF, Chen JJ, Li TZ, Hu J, Zhang XM, Geng CA. Diarylheptanoid-chalcone hybrids with PTP1B and ?-glucosidase dual inhibition from Alpinia katsumadai. Bioorg. Chem. 2021;108:104683.
57. Halim SA, Jabeen S, Khan A, Al-Harrasi A. Rational Design of Novel Inhibitors of ?-Glucosidase: An Application of Quantitative Structure Activity Relationship and Structure-Based Virtual Screening. Pharmaceuticals. 2021.
58. Ardiansah B, Rohman N, Nasution MAF, Tanimoto H, Cahyana AH, Fadlan A, et al. Synthesis, ?-Glucosidase Inhibitory Activity and Molecular Docking Study of Chalcone Derivatives Bearing a 1H-1,2,3-Triazole Unit. Chem. Pharm. Bull. 2023;71:342-8.
2. Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res. Clin. Pract. 2019;157:107843.
3. Gaziano TA, Bitton A, Anand S, Abrahams-Gessel S, Murphy A. Growing Epidemic of Coronary Heart Disease in Low- and Middle-Income Countries. Curr. Probl. Cardiol. 2010;35:72-115.
4. Lam AA, Lepe A, Wild SH, Jackson C. Diabetes comorbidities in low-and middle-income countries: an umbrella review. J. Glob. Health. 2021;11.
5. Hu FB. Globalization of Diabetes: The role of diet, lifestyle, and genes. Diabetes Care. 2011;34:1249-57.
6. Yen F-S, Wei JC-C, Shih Y-H, Hsu C-C, Hwu C-M. The Risk of Nephropathy, Retinopathy, and Leg Amputation in Patients With Diabetes and Hypertension: A Nationwide, Population-Based Retrospective Cohort Study. Front. Endocrinol. 2021;12. endo.2021.756189.
7. Aras RA, Lestari T, Nugroho HA, Ardiyanto I. Segmentation of retinal blood vessels for detection of diabetic retinopathy: A review. Commun. Sci. Technol. 2016;1(1).
8. Yulyanti V, Adi Nugroho H, Ardiyanto I, Oktoeberza, WK. Dark lesion elimination based on area, eccentricity and extent features for supporting haemorrhages detection. Commun. Sci. Technol. 2019;4(1):7-11.
9. American Diabetes A. Diagnosis and Classification of Diabetes Mellitus. Diabetes Care .2010;33:S62-S9.
10. El-Abhar HS, Schaalan MF. Phytotherapy in diabetes: Review on potential mechanistic perspectives. World J. Diabetes. 2014;5:176.
11. Trapero A, Llebaria A. A Prospect for Pyrrolidine Iminosugars as Antidiabetic ?-Glucosidase Inhibitors. J. Med. Chem. 2012;55:10345-6.
12. Kim DK, Lee B-H. New glucogenesis inhibition model based on complete ?-glucosidases from rat intestinal tissues validated with various types of natural and pharmaceutical inhibitors. J. Sci. Food Agric. 2022;102:4419-24.
13. Salani B, Rio AD, Marini C, Sambuceti G, Cordera R, Maggi D. Metformin, cancer and glucose metabolism. Endocr. Relat. Cancer. 2014;21(6):R461-R71.
14. Zhao Y, Xu L, Tian D, Xia P, Zheng H, Wang L, et al. Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid level: A meta-analysis of randomized controlled trials. Diabetes Obes. Metab. 2018;20(2):458-62.
15. Fitchett D. A safety update on sodium glucose co-transporter 2 inhibitors. Diabetes Obes. Metab. 2019;21:34-42.
16. Herrington WG, Savarese G, Haynes R, Marx N, Mellbin L, Lund LH, et al. Cardiac, renal, and metabolic effects of sodium–glucose co-transporter 2 inhibitors: a position paper from the European Society of Cardiology ad-hoc task force on sodium–glucose co-transporter 2 inhibitors. Eur. J. Heart Fail. 2021;23:1260-75.
17. Grygiel-Górniak B. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications - a review. Nutr. J. 2014;13:17.
18. Janani C, Ranjitha Kumari BD. PPAR gamma gene – A review. Diabetes Metabol Syndr: Clin. Res. Rev. 2015;9:46-50.
19. Derosa G, Maffioli P. Management of diabetic patients with hypoglycemic agents
?-Glucosidase inhibitors and their use in clinical practice. Arch. Med. Sci. 2012;8:899-906.
20. Vanderlaan EL, Nolan JK, Sexton J, Evans-Molina C, Lee H, Voytik-Harbin SL. Development of electrochemical Zn2+ sensors for rapid voltammetric detection of glucose-stimulated insulin release from pancreatic ?-cells. Biosens. Bioelectron. 2023;235:115409.
21. Altunta? Y. Postprandial reactive hypoglycemia. ?i?li Etfal Hastanesi tip Bülteni. 2019;53:215-20.
22. Chawla A, Chawla R, Jaggi S. Microvasular and macrovascular complications in diabetes mellitus: Distinct or continuum?. Indian J. Endocrinol. Metab. 2016;20.
23. Monnier L, Mas E, Ginet C, Michel F, Villon L, Cristol J-P, et al. Activation of Oxidative Stress by Acute Glucose Fluctuations Compared With Sustained Chronic Hyperglycemia in Patients With Type 2 Diabetes. JAMA. 2006;295:1681-7.
24. Wright LA-C, Hirsch IB. Metrics Beyond Hemoglobin A1C in Diabetes Management: Time in Range, Hypoglycemia, and Other Parameters. Diabetes Technol. Ther. 2017;19:S-16-S-26. https://doi.org/10.1089/dia.2017.0029.
25. Hossain U, Das AK, Ghosh S, Sil PC. An overview on the role of bioactive ?-glucosidase inhibitors in ameliorating diabetic complications. Food Chem. Toxicol. 2020;145:111738.
26. Ghani U. Re-exploring promising ?-glucosidase inhibitors for potential development into oral anti-diabetic drugs: Finding needle in the haystack. Eur. J. Med. Chem. 2015;103:133-62.
27. Padhi S, Nayak AK, Behera A. Type II diabetes mellitus: a review on recent drug based therapeutics. Biomed. Pharmacother. 2020;131:110708.
28. Singh A, Singh K, Sharma A, Kaur K, Kaur K, Chadha R, et al. Recent developments in synthetic ?-glucosidase inhibitors: A comprehensive review with structural and molecular insight. J. Mol. Struct. 2023;1281:135115.
29. Dias DA, Urban S, Roessner U. A Historical Overview of Natural Products in Drug Discovery. Metabolites. 2012, p. 303-36.
30. Youssefi MR, Moghaddas E, Tabari MA, Moghadamnia AA, Hosseini SM, Farash BR, et al. In Vitro and In Vivo Effectiveness of Carvacrol, Thymol and Linalool against Leishmania infantum. Molecules. 2019.
31. Kachur K, Suntres Z. The antibacterial properties of phenolic isomers, carvacrol and thymol. Crit. Rev. Food Sci. Nutr. 2020;60:3042-53.
32. Wang K, Jiang S, Yang Y, Fan L, Su F, Ye M. Synthesis and antifungal activity of carvacrol and thymol esters with heteroaromatic carboxylic acids. Nat. Prod. Res. 2019;33:1924-30.
33. López V, Cascella M, Benelli G, Maggi F, Gómez-Rincón C. Green drugs in the fight against Anisakis simplex—larvicidal activity and acetylcholinesterase inhibition of Origanum compactum essential oil. Parasitol Res. 2018;117:861-7.
34. Araújo LX, Novato TPL, Zeringota V, Matos RS, Senra TOS, Maturano R, et al. Acaricidal activity of thymol against larvae of Rhipicephalus microplus (Acari: Ixodidae) under semi-natural conditions. Parasitol Res. 2015;114:3271-6.
35. Jairajpuri DS, Khan S, Anwar S, Hussain A, Alajmi MF, Hassan I. Investigating the role of thymol as a promising inhibitor of pyruvate dehydrogenase kinase 3 for targeted cancer therapy. Int. J. Biol. Macromol. 2024;259:129314.
36. Dominguez-Uscanga A, Aycart DF, Li K, Witola WH, Andrade Laborde JE. Anti-protozoal activity of Thymol and a Thymol ester against Cryptosporidium parvum in cell culture. Int. J. Parasitol. Drugs Drug Resist. 2021;15:126-33.
37. Kurt BZ, Gazioglu I, Dag A, Salmas RE, Kay?k G, Durdagi S, et al. Synthesis, anticholinesterase activity and molecular modeling study of novel carbamate-substituted thymol/carvacrol derivatives. Bioorg. Med. Chem. 2017;25:1352-63.
38. Rajput JD, Bagul SD, Bendre RS. Design, synthesis, biological screenings and docking simulations of novel carvacrol and thymol derivatives containing acetohydrazone linkage. Res. Chem. Intermed. 2017;43:4893-906.
39. Nagle PS, Pawar YA, Sonawane AE, Bhosale SM, More DH. Synthesis and evaluation of antioxidant and antimicrobial properties of thymol containing pyridone moieties. Med. Chem. Res. 2012;21:1395-402.
40. Raghuvanshi DS, Verma N, Singh SV, Khare S, Pal A, Negi AS. Synthesis of thymol-based pyrazolines: An effort to perceive novel potent-antimalarials. Bioorg. Chem. 2019;88:102933.
41. Salazar MO, Osella MI, Arcusin DEJ, Lescano LE, Furlan RLE. New ?-glucosidase inhibitors from a chemically engineered essential oil of Origanum vulgare L. Ind. Crop. Prod. 2020;156:112855.
42. Singh A, Singh K, Kaur K, Sharma A, Mohana P, Prajapati J, et al. Discovery of triazole tethered thymol/carvacrol-coumarin hybrids as new class of ?-glucosidase inhibitors with potent in vivo antihyperglycemic activities. Eur. J. Med. Chem. 2024;263:115948.
43. Bachelet J, Cavier R, Lemoine J, Rigothier M, Gayral P, Royer R. Comparison of the antibacterial, antiparasitic and molluscicidal properties of halogenoacylamide or halogenoacyl derivatives of thymol.NA. Eur. J. Med. Chem. 1979;14:321-4.
44. Hengphasatporn K, Garon A, Wolschann P, Langer T, Yasuteru S, Huynh TNT, et al. Multiple Virtual Screening Strategies for the Discovery of Novel Compounds Active Against Dengue Virus: A Hit Identification Study. Sci. Pharm. 2020.
45. Danova A, Pattanapanyasat K, Hengphasatporn K, Shigeta Y, Rungrotmongkol T, Hermawati E, et al. Unlocking E-arylidene Steroid Derivatives as Promising ?-Glucosidase Inhibitors. ChemistrySelect. 2024;9(9):e202303887.
46. Jakubec D, Skoda P, Krivak R, Novotny M, Hoksza D. PrankWeb 3: accelerated ligand-binding site predictions for experimental and modelled protein structures. Nucleic Acids Res. 2022;50(W1):W593-W7.
47. Yamamoto K, Miyake H, Kusunoki M, Osaki S. Steric hindrance by 2 amino acid residues determines the substrate specificity of isomaltase from Saccharomyces cerevisiae. J. Biosci. Bioeng. 2011;112:545-50.
48. Dallakyan S, Olson AJ. Small-Molecule Library Screening by Docking with PyRx. In: Hempel JE, Williams CH, Hong CC, editors. Chemical Biology: Methods and Protocols, New York, NY: Springer New York; 2015, p. 243-50.
49. Trott O, Olson AJ. AutoDock 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.
50. Duan Y, Wu C, Chowdhury S, Lee MC, Xiong G, Zhang W, et al. A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations. J. Comput. Chem. 2003;24:1999-2012.
51. Krieger E, Darden T, Nabuurs SB, Finkelstein A, Vriend G. Making optimal use of empirical energy functions: Force-field parameterization in crystal space. Proteins. 2004;57:678-83.
52. Krieger E, Vriend G. New ways to boost molecular dynamics simulations. J. Comput. Chem. 2015;36:996-1007.
53. Al-ghulikah HA, Mughal EU, Elkaeed EB, Naeem N, Nazir Y, Alzahrani AY, Sadiq A, Shah SW. Discovery of chalcone derivatives as potential ?-glucosidase and cholinesterase inhibitors: Effect of hyperglycemia in paving a path to dementia. J. Mol. Struct. 2023;1275:134658.
54. Hosseini Nasab N, Raza H, Eom YS, Shah FH, Kwak JH, Kim SJ. Exploring chalcone-sulfonyl piperazine hybrids as anti-diabetes candidates: design, synthesis, biological evaluation, and molecular docking study. Mol. Divers. 2024;22:1-7.
55. Hu CM, Luo YX, Wang WJ, Li JP, Li MY, Zhang YF, Xiao D, Lu L, Xiong Z, Feng N, Li C. Synthesis and evaluation of coumarin-chalcone derivatives as ?-glucosidase inhibitors. Front. Chem. 2022;10:926543.
56. He XF, Chen JJ, Li TZ, Hu J, Zhang XM, Geng CA. Diarylheptanoid-chalcone hybrids with PTP1B and ?-glucosidase dual inhibition from Alpinia katsumadai. Bioorg. Chem. 2021;108:104683.
57. Halim SA, Jabeen S, Khan A, Al-Harrasi A. Rational Design of Novel Inhibitors of ?-Glucosidase: An Application of Quantitative Structure Activity Relationship and Structure-Based Virtual Screening. Pharmaceuticals. 2021.
58. Ardiansah B, Rohman N, Nasution MAF, Tanimoto H, Cahyana AH, Fadlan A, et al. Synthesis, ?-Glucosidase Inhibitory Activity and Molecular Docking Study of Chalcone Derivatives Bearing a 1H-1,2,3-Triazole Unit. Chem. Pharm. Bull. 2023;71:342-8.