Medicinal Chemistry Research

, Volume 26, Issue 5, pp 916–928 | Cite as

Synthesis of 2-phenyl-1H-imidazo[4,5-b]pyridine as type 2 diabetes inhibitors and molecular docking studies

  • Muhammad TahaEmail author
  • Nor Hadiani Ismail
  • Syahrul Imran
  • Izzatul Ainaa
  • Manikandan Selvaraj
  • Mohd syukri baharudin
  • Muhammad Ali
  • Khalid Mohammed Khan
  • Nizam Uddin
Original Research


A series of imidazo[4,5-b]pyridines (332) was synthesized and evaluated for their ability to inhibit Baker’s yeast α-glucosidase enzyme. The IC50 values for all compounds were in the range of 13.5–93.7 µM with compound 15, a 2,4-dihydroxy-substituted analog, displayed the most potent activity potential. Structure–activity relationship strongly suggested the presence of hydroxyl group at aromatic side chain as the main contributing factor towards the inhibitory potential. Findings also suggested that compounds having hydroxyl groups at ortho and para positions are able to inhibit α-glucosidase enzyme efficiently. This experimental observation was further supported by docking studies carried out on human intestinal maltase-glucoamylase enzyme (PDB ID: 3TOP). The –NH– group of imidazo-pyridine of compound 15 formed H-bond with Asp1526, while both hydroxyls of catechol formed H-bond with Asp1279. Imidazo-pyridine ring was well stabilized by ππ stacking with Phe1560, and other hydrophobic interactions involving side chain of Pro1159, Tyr1167, Asp1157, Met1421, Trp1369, Pro1318, and Lys1460. The catechol ring also forms several hydrophobic interactions with Phe1560, Trp1523, Trp1418, His1584, Try1251, Ile1218 and Trp1355.


Imidazo[4,5-b]pyridine Type-2 Diabetes Pharmacokinetic prediction Molecular docking 



Dr. Muhammad Taha would like to acknowledge the Ministry of Higher Education for financial support under the Fundamental Research Grant Scheme (FRGS) with sponsorship reference numbers FRGS/1/2016/STG01/UiTM/02/2 and Universiti Teknologi MARA for the financial support under LESTARI grant 600-RMI/DANA /5/3/ lestari (54/2013). The author (Dr. M.A.) is also grateful to HEC Pakistan for providing a research grant vide 20-1933/NRPU/R&D/HEC/12/5017.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interest.

Supplementary material

44_2017_1806_MOESM1_ESM.pdf (2.9 mb)
Supplementary Information


  1. Adisakwattana S, Sookkongwaree K, Roengsumran S, Petsom A, Ngamrojnavanich N, Chavasiri W, Deesamer S, Yibchok-anun S (2004) Structure–activity relationships of trans-cinnamic acid derivatives on α-glucosidase inhibition. Bioorg Med Chem Lett 14:2893–2896CrossRefPubMedGoogle Scholar
  2. Asano N, Oseki K, Tomioka E, Kizu H, Matsui K (1994) N-containing sugars from Morus alba and their glycosidase inhibitory activities. Carbohydr Res 259:243–255CrossRefPubMedGoogle Scholar
  3. Brownson C, Hipkiss A (2000) Carnosine reacts with a glycated protein. Free Radic Biol Med 28:1564–1570CrossRefPubMedGoogle Scholar
  4. Bukowski L, Kaliszan R (1991) Imidazo [4, 5‐b] pyridine derivatives of potential tuberculostatic activity, II: synthesis and bioactivity of designed and some other 2‐cyanomethylimidazo [4, 5‐b] pyridine derivatives. Arch Pharm 324:537–542CrossRefGoogle Scholar
  5. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110CrossRefPubMedGoogle Scholar
  6. Charron MJ, Dubin RA, Michels CA (1986) Structural and functional analysis of the MAL1 locus of Saccharomyces cerevisiae. Mol Cell Biol 6:3891–3899CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chen YG, Li P, Li P, Yan R, Zhang XQ, Wang Y, Zhang XT, Ye WC, Zhang QW (2013) α-Glucosidase inhibitory effect and simultaneous quantification of three major flavonoid glycosides in Microctis folium. Molecules 18:4221–4232CrossRefPubMedGoogle Scholar
  8. Clark RL, Pessolano AA, Shen TY, Jacobus DP, Jones H, Lotti VJ, Flataker LM (1978) Synthesis and analgesic activity of 1, 3-dihydro-3-(substituted phenyl) imidazo [4, 5-b] pyridin-2-ones and 3-(substituted phenyl)-1, 2, 3-triazolo [4, 5-b] pyridines. J Med Chem 2:965–978CrossRefGoogle Scholar
  9. Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ, Lin JK, Farzadfar F, Khang YH, Stevens GA, Rao M, Ali MK, Riley LM, Robinson CA, Ezzati M (2011) Global burden of metabolic risk factors of chronic diseases collaborating group (blood glucose). Lancet 378:31–40CrossRefPubMedGoogle Scholar
  10. Duffy EM, Jorgensen WL (2000) Prediction of properties from simulations: free energies of solvation in hexadecane, octanol, and water. J Am Chem 122:2878–2888CrossRefGoogle Scholar
  11. Hsiao SH, Liao LH, Cheng PN, Wu TJ (2006) Hepatotoxicity associated with acarbose therapy. Ann Pharmacother 40:151–154CrossRefPubMedGoogle Scholar
  12. Hollander P (1992) Safety profile of acarbose, an α-glucosidase inhibitor. Drugs 44:47–53CrossRefPubMedGoogle Scholar
  13. Humphries MJ, Matsumoto K, White SL, Olden K (1986) Inhibition of experimental metastasis by castanospermine in mice: blockage of two distinct stages of tumor colonization by oligosaccharide processing inhibitors. Cancer Res 46:5215–5222PubMedGoogle Scholar
  14. Imran S, Taha M, Ismail NH, Fayyaz S, Khan KM, Choudhary MI (2015a) Synthesis, biological evaluation, and docking studies of novel thiourea derivatives of bisindolylmethane as carbonic anhydrase II inhibitor. Bioorg Chem 62:83–93CrossRefPubMedGoogle Scholar
  15. Imran S, Taha M, Ismail NH, Kashif SM, Rahim F, Jamil W, Hariono M, Yusuf M, Wahab H (2015b) Synthesis of novel flavone hydrazones: in-vitro evaluation of α-glucosidase inhibition, QSAR analysis and docking studies. Eur J Med Chem 105:156–170CrossRefPubMedGoogle Scholar
  16. Imran S, Taha M, Ismail NH, Kashif SM, Rahim F, Jamil W, Wahab H, Khan KM (2015c) Synthesis, in vitro and docking studies of new flavone ethers as α‐glucosidase inhibitors. Chem Biol Drug Des 87:361–373CrossRefPubMedGoogle Scholar
  17. Kumar S, Narwal S, Kumar V, Prakash O (2011) α-glucosidase inhibitors from plants: a natural approach to treat diabetes. Pharmacogn Rev 5:19–29CrossRefPubMedPubMedCentralGoogle Scholar
  18. Lavanya P, Suresh M, Kotaiah Y, Harikrishna N, Rao CV (2011) Synthesis, antibacterial, antifungal and antioxidant activity studies on 6-bromo-2-substitutedphenyl-1H-imidazo [4, 5-b] pyridine. Asian J Pharm Clin Res 4:69–73Google Scholar
  19. Lefebvre P, Scheen A (1994) The use of acarbose in the prevention and treatment of hypoglycaemia. Eur J Clin Invest 24:40–44CrossRefPubMedGoogle Scholar
  20. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliver Rev 23:3–25CrossRefGoogle Scholar
  21. Loriga M, Paglietti G, Piras S, Sparatore F, Anania V, Demontis MP, Varoni MV, Fattaccio MC (1992) Synthesis and evaluation of gastroprotective and antiulcer activity of some 2-substituted-1H-imidazo [4, 5-b] pyridines and-1H-benzimidazoles. Farmaco 47:287–303PubMedGoogle Scholar
  22. Luo H, Imoto T, Hiji Y, World J (2001) Inhibitory effect of voglibose and gymnemic acid on maltose absorption in vivo. World J Gastroenterol 7:270–274CrossRefPubMedPubMedCentralGoogle Scholar
  23. Mallemula VR, Sanghai NN, Himabindu V, Chakravarthy AK (2013) Synthesis and characterization of antibacterial 2-(pyridin-3-yl)-1H-benzo [d] imidazoles and 2-(pyridin-3-yl)-3H-imidazo [4, 5-b] pyridine derivatives. Res Chem Intermed 4:2125–2138Google Scholar
  24. Matsuo T, Odaka H, Ikeda H, Am (1992) Effect of an intestinal disaccharidase inhibitor (AO-128) on obesity and diabetes. J Clin Nutr 55:314S–317SGoogle Scholar
  25. Narasimhan B, Sharma D, Kumar P (2011) Biological importance of imidazole nucleus in the new millennium. Med Chem Res 20:1119–1140CrossRefGoogle Scholar
  26. NY L, Molecular Graphics System USA (2010) PyMOL New York, USGoogle Scholar
  27. O’Dea K, Turton J (1985) Optimum effectiveness of intestinal alpha-glucosidase inhibitors: importance of uniform distribution through a meal. Am J Clin Nutr 41:511–516PubMedGoogle Scholar
  28. Park H, Hwang KY, Oh KH, Kim YH, Lee JY, Kim K (2008) Discovery of novel α-glucosidase inhibitors based on the virtual screening with the homology-modeled protein structure. Bioorg Med Chem 16:284–292CrossRefPubMedGoogle Scholar
  29. Plant TD, Henquin JC (1990) Phentolamine and yohimbine inhibit ATP‐sensitive K+ channels in mouse pancreatic β‐cells. British J Pharmacol 101:115–120CrossRefGoogle Scholar
  30. Puls W, Keup U, Krause HP, Thomas G, Hoffiester F (1977) Glucosidase inhibition. Naturwisenschaften 64:536–537CrossRefGoogle Scholar
  31. Reuser AJ, Wisselaar HA (1994) An evaluation of the potential side‐effects of α‐glucosidase inhibitors used for the management of diabetes mellitus. Eur J Clin Invest 24:19–24CrossRefPubMedGoogle Scholar
  32. Samad AH, Willing TST, Alberti KGM, Taylor R (1988) Effects of BAYm 1099. New alpha-glucosidase inhibitor on acute metabolic responses and metabolic control in NIDDM over 1 month. Diabetes Care 11:337–344CrossRefPubMedGoogle Scholar
  33. Scheen AJ (2003) Is there a role for α-glucosidase inhibitors in the prevention of type 2 diabetes mellitus? Drugs 63:933–951CrossRefPubMedGoogle Scholar
  34. Schmidt D, Frommer W, Junge B, Muller L, Wingender W, Truscheit E, Schäfer D (1977) alpha-glucosidase inhibitors. New complex oligosaccharides of microbial origin. Naturwissenschaften 64:535–536CrossRefPubMedGoogle Scholar
  35. Schrödinger Release 2015-1: Maestro, version 10.1, Schrödinger LLC, (2015) New York, NYGoogle Scholar
  36. Scott LJ, Spencer CM (2000) Miglitol. Drugs 59:521–549CrossRefPubMedGoogle Scholar
  37. Shim YJ, Doo HK, Ahn SY, Kim YS, Seong JK, Park IS, Kim BH (2003) Inhibitory effect of aqueous extract from the gall of Rhus chinensis on alpha-glucosidase activity and postprandial blood glucose. J Etnhopharmacology 85:283–287CrossRefGoogle Scholar
  38. Storr SJ, Royle L, Chapman CJ, Hamid UMA, Robertson JF, Murray A, Dwek RA, Rudd PM (2008) The O-linked glycosylation of secretory/shed MUC1 from an advanced breast cancer patient’s serum. Glycobiology 18:456–462CrossRefPubMedGoogle Scholar
  39. Taha M, Ismail NH, Imran S, Ali M, Jamil W, Uddin N, Kashif SM (2016a) Identification of bisindolylmethane–hydrazone hybrids as novel inhibitors of β-glucuronidase, DFT, and in silico SAR intimations. RSC Adv 6:3276–3289CrossRefGoogle Scholar
  40. Taha M, Ismail NH, Imran S, Selvaraj M, Rahim F (2016b) Synthesis of novel inhibitors of β-glucuronidase based on the benzothiazole skeleton and their molecular docking studies. RSC Adv 6:3003–3012CrossRefGoogle Scholar
  41. Taha M, Ismail NH, Javaid K, Imran S, Wadood A, Ali M, Khan KM, Saad SM, Rahim F, Choudhary MI (2015a) Evaluation of 2-indolcarbohydrazones as potent α-glucosidase inhibitors, in silico studies and DFT based stereochemical predictions. Bioorg Chem 63:24–35CrossRefPubMedGoogle Scholar
  42. Taha M, Ismail NH, Lalani S, Fatmi MQ, Siddiqui S, Khan KM, Imran S, Choudhary MI (2015b) Synthesis of novel inhibitors of α-glucosidase based on the benzothiazole skeleton containing benzohydrazide moiety and their molecular docking studies. Eur J Med Chem 92:387–400CrossRefPubMedGoogle Scholar
  43. Taha M, Ismail NH, Imran S, Wadood A, Rahim F, Ali M, Rehman AU (2015c) Novel quinoline derivatives as potent in vitro α-glucosidase inhibitors: in silico studies and SAR predictions. Med Chem Comm 6:1826–1836CrossRefGoogle Scholar
  44. Taha M, Ismail NH, Imran S, Rahim Mohamad MH, Wadood A, Rahim F, Saad SM, Rehman A, Khan KM (2016) Synthesis, α-glucosidase inhibitory, cytotoxicity and docking studies of 2-Aryl-7-methylbenzimidazoles. Bioorg Chem 65:100–109CrossRefPubMedGoogle Scholar
  45. Tang PC, Lin ZG, Wang Y, Yang FL, Wang Q, Fu JH, Zhang L, Gong AS, Luo JJ, Dai J, She GH, Si DD, Feng J (2010) Design and synthesis of DPP-4 inhibitor for the treatment of type 2 diabetes. Chin Chem Lett 21:253–256CrossRefGoogle Scholar
  46. Taylor SI, Accili D, Imai Y (1994) Insulin resistance or insulin deficiency. Diabetes 43:735–740CrossRefPubMedGoogle Scholar
  47. Porte Jr. D (1991) Beta-cells in type II diabetes mellitus. Diabetes 40:166–180CrossRefPubMedGoogle Scholar
  48. Temple Jr. C, Rose JD, Comber RN, Rene GA (1987) Synthesis of potential anticancer agents: imidazo [4, 5-c] pyridines and imidazo [4, 5-b] pyridines. J Med Chem 30:1746–1751CrossRefPubMedGoogle Scholar
  49. Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD (2003) Improved protein-ligand docking using GOLD. Proteins 52:609–623CrossRefPubMedGoogle Scholar
  50. Wang YF, Yang ZW, Wei XL (2010) Sugar compositions, α-glucosidase inhibitory and amylase obtained by different extraction methods. Int J Biol Macromol 47:534–539CrossRefPubMedGoogle Scholar
  51. Wehmeier UF, Piepersberg W (2004) Biotechnology and molecular biology of the α-glucosidase inhibitor acarbose. Appl Microbiol Biotech 63:613–625CrossRefGoogle Scholar
  52. Whiting DR, Guariguata L, Weil C, Shaw J, ( (2011) IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 94:311–321CrossRefPubMedGoogle Scholar
  53. Wu YH (2007) Synthesis of (S) 2-ethoxy-3-phenylpropanoic acid derivatives and their insulin sensitizing activity. Chin J Chem 25:265–267CrossRefGoogle Scholar
  54. Zawawi NKNA, Taha M, Ahmat N, Ismail NH, Wadood A, Rahim F (2017) Synthesis, molecular docking studies of hybrid benzimidazole as α-glucosidase inhibitor. Bioorg Chem doi: 10.1016/j.bioorg.2016.12.009

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Muhammad Taha
    • 1
    • 2
    Email author
  • Nor Hadiani Ismail
    • 1
    • 2
  • Syahrul Imran
    • 1
    • 2
  • Izzatul Ainaa
    • 2
  • Manikandan Selvaraj
    • 3
    • 4
  • Mohd syukri baharudin
    • 1
    • 2
  • Muhammad Ali
    • 5
  • Khalid Mohammed Khan
    • 6
  • Nizam Uddin
    • 7
  1. 1.Atta-ur-Rahman Institute for Natural Product DiscoveryUniversiti Teknologi MARA (UiTM), Puncak Alam CampusBandar Puncak AlamMalaysia
  2. 2.Faculty of Applied Science Universiti Teknologi MARA (UiTM)Shah AlamMalaysia
  3. 3.Integrative Pharmacogenomics Institute (iPROMISE)Universiti Teknologi MARA (UiTM), Puncak Alam CampusBandar Puncak AlamMalaysia
  4. 4.Faculty of PharmacyUniversiti Teknologi MARA (UiTM), Puncak Alam CampusBandar Puncak AlamMalaysia
  5. 5.Department of ChemistryCOMSATS Institute of Information TechnologyAbbottabadPakistan
  6. 6.H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological SciencesUniversity of KarachiKarachiPakistan
  7. 7.Batterje Medical College for Science & TechnologyJeddahKingdom of Saudi Arabia

Personalised recommendations