Design of Some Benzimidazoles as Target for α-Glucosidase Inhibitors
Diabetes mellitus is rising globally touching more than 180 million people worldwide. This is prevailing mostly in type 2 diabetes and according to WHO report the incidence is likely to be more than doubled by 2030. α-Glucosidase inhibitors work by reducing the amount of glucose that the intestines absorb from food. In this work, forty-five benzimidazole analogues were studied using 3D QSAR, HQSAR, pharmacophore mapping and based on their results 60 compounds were designed. The results show that the best Comparative Molecular Field Analysis (CoMFA) model has q2 = 0.742 and r2 = 0.973, and the best Comparative Molecular Similarity Indices Analysis (CoMSIA) model has q2 = 0.679 and r2 = 0.918. For HQSAR the best model has q2 = 0.773 and r2 = 0.964. The r2 value for boostrap for CoMFA and CoMSIA are 0.98 and 0.97 respectively. Pharmacophore mapping revealed varied bioactive regions of ligand. Thus, these compounds could be used as lead for designing the synthesis of potent alpha-glucosidase inhibitors.
Keywords: Acarbose, Alpha-glucosidase inhibition, Benzimidazoles, Molecular modelling, Post-prandial hyperglycemia
2. Mathers CD, Loncar D. Projections of global mortality and burden of diseases from 2002 to 2030. Plos Med, 2006; 3 (11):442.
3. Alberti K, Zimmet Z. Definition, diagnosis and classification of diabetes mellitus and its complications: Report of a WHO Consultation. 1999; 1:125.
4. Kalra S. Alpha glucosidase inhibitors. J. Pak Med. Assoc. 2014; 64(4):474-476.
5. Hanefeld M, Schaper F. The role of Alpha-Glucosidase Inhibitors (Acarbose). Pharmacotherapy of Diabetes: New Developments. Diabetes: Endocrinology. US Springer, 2007; 143-52.
6.A.N. Aziz, M. Taha, N.H. Ismail, E.H. Anouar, S. Yousuf, W. Jamil, K. Awang, N. Ahmat, K.M. Khan, S.M. KashifSynthesis, crystal structure, DFT studies and evaluation of the antioxidant activity of 3,4-dimethoxybenzenamine schiff bases, Molecules, 2014; 19:8414-8433
7. S. Imran, M. Taha, N.H. Ismail, K.M. Khan, F. Naz, M. Hussain, S. Tauseef, Synthesis of novel bisindolylmethane schiff bases and their antibacterial activity Molecules, 2014; 19:11722-11740
8.W. Jamil, S. Perveen, S.A.A. Shah, M. Taha, N.H. Ismail, S. Perveen, N. Ambreen, K.M. Khan, M.I. Choudhary, Phenoxyacetohydrazide schiff bases: β-glucuronidase inhibitors, Molecules, 2014; 19:8788-8802
9. Jamil, W., Solangi, S., Ali, M., Khan, K.M., Taha, M., Khuhawar, M.Y., 2015 Syntheses, Characterization, In Vitro Antiglycation and DPPH Radical Scavenging Activities of Isatin Salicylhydrazidehydrazone and its Mn (II), Co (II), Ni (II), Cu (II), and Zn (II) Metal Complexes. Arabian J. Chem. (http://dx.doi.org/10.1016/j.arabjc.2015.02.015) (in press).
10.K.M. Khan, M. Taha, F. Naz, S. Siddiqui, S. Ali, F. Rahim, S. Perveen, M.I. ChoudharyAcylhydrazide Schiff bases: DPPH radical and superoxide anion scavengers, Med. Chem., 2012; 8:705-710
11.K.M. Khan, M. Taha, F. Rahim, M.I. Fakhri, S. Rasheed, F. Rahim, W. Jamil, M. Khan, A. Karim, S. Perveen, M.I. choudharyAcylhydrazide schiff bases: synthesis and antiglycation activity, J. Chem. Soc. Pak., 2013; 35:930-938
12.K.M. Khan, F. Rahim, N. Ambreen, M. Taha, M. Khan., H. Jahan, Najeebullah, A. Shaikh, S. Iqbal, S. Perveen, M.I. Choudhary, Synthesis of benzophenonehydrazone Schiff bases and their in vitro antiglycating activities, Med. Chem., 2013; 9:588-595
13.K.M. Khan, M. Irfan, M. Ashraf, M. Taha, S.M. Saad, S. Perveen, M.I. Choudhary, Synthesis of phenyl thiazole hydrazones and their activity against glycation of proteins, Med. Chem. Res., 2015; 24:3077-3085
14.M. Taha, N.H. Ismail, M. Ali, K.M. Khan, W. Jamil, S.M. Kashif, M. Asraf, Synthesis of indole-2-hydrazones in search of potential leishmanicidal agents, Med. Chem. Res., 2014; 23:5282-5293
15.M. Taha, N.H. Ismail, A. Khan, A.A.S. Syed, A. Anwar, S.A. Halim, M.Q. Fatmi, S. Imran, F. Rahim, K.M. Khan, Synthesis of novel derivatives of oxindole, their urease inhibition and molecular docking studies, Bioorg. Med. Chem. Lett., 2015; 25:3285-3289
16.M. Taha, N.H. Ismail, M.S. Baharudin, S. Lalani, S. Mehboob, K.M. Khan, S. yousuf, S. Siddiqui, F. Rahim, M.I. Choudhary, Synthesis crystal structure of 2-methoxybenzoylhydrazones and evaluation of their a-glucosidase and urease inhibition potential, Med. Chem. Res., 2015; 24:1310-1324
17. M. Taha, N.H. Ismail, S. Imran, M.Q.B. Rokei, S.M. Saad, K.M. KhanSynthesis of new oxadiazole derivatives as α-glucosidase inhibitors, Bioorg. Med. Chem., 2015; 23:4155-4162
18. Kohno T, Ohtaka H, Tsukamoto G, Yoshino K: Synthesis and anti-inflammatory activity of some 2- (substituted-pyridinyl) benzimidazoles. Journal of Medicinal Chemistry 1980, 23:734-738.
19. Bhise UN, Kumar SBV, Ramanatham V, Vaidya SD: Synthesis, antibacterial, anti-asthmatic and antidiabetic activities of novel N-substituted benzimidazoles. European Journal of Medicinal Chemistry 2008, 43(5):986-995.
20. Francisco AC, Gabriel NV, Hermenegilda MD: Design, microwave-assisted synthesis and spasmolytic activity of 2-(alkyloxyaryl)-1H-benzimidazole derivatives as constrained stilbene bioisosteres. Bioorganic and Medicinal Chemistry Letters 2006, 16(16):4169-4173.
21. Pashinski VG, Romanova TV, Mukhina NA, Shkrabova LV: Diuretic activity of benzimidazole urea derivatives. Farmakol Toksikol 1978, 41(2):196-9.
22. Durmaz R, Gunal S, Kucukbay H: Synthesis, antibacterial and antifungal activities of electron-rich olefins derived benzimidazole compounds. Science Direct: II Farmaco 2003, 58:431-437.
23. Solominova PS, Pilyugin VS, Pyurin AA: Targated search for new anthelmentic among 5 (6- Aminophenylthio (oxy)-2-amino benzimidazole derivatives. Journal of Pharmaceutical Chemistry 2004, 38:425-430.
24. Gardiner JM, Loyns CR, Burke A, Khan A: Synthesis and HIV -1 inhibition of novel benzimidazole derivatives. Bioorganic and Medicinal Chemistry Letters 1995, 5(12):1251-1254.
25. Bariwal JB, Shah AK, Kathiravan MK, Somani RS, Jagtap JR: Synthesis and antiulcer activity of novel pyrimidylthiomethyl and Pyrimidylsulfinylmethyl benzimidazoles as potential reversible proton pump inhibitors. Indian Journal of Pharmaceutical Education and Research 2008, 42(3):225-231.
26. Durmaz R, Gunal S, Kucukbay H: Synthesis, antibacterial and antifungal activities of electron-rich olefins derived benzimidazole compounds. Science Direct: II Farmaco 2003, 58:431-437.
27. Chimrri A, Sarro AD, Sarro GD, Giho G, Zappala M: Synthesis and anticonvulsant properties of 2, 3, 3a-4-tetrahydro-1-H pyrrolo (1,2-a) benzimidazol-1-one derivatives. Science Direct: II Farmaco 2001, 56(11):821-826.
28. Zawawi et al. Benzimidazole derivatives as new α-glucosidase inhibitors and in silico studies. Bioorganic Chemistry J. 2016; 64: 29–36.
29. Taha M. Synthesis crystal structure of 2-methoxybenzoylhydrazones and evaluation of their α-glucosidase and urease inhibition potential. Medicinal chemistry research J. 2015, 24; 3:1310-1324.
30. Taha M. Synthesis of novel derivatives of 4-methylbenzimidazole and evaluation of their biological activities. European Journal of Medicinal Chemistry. 2014; 84:731-738.
31. Matthew Clark, Richard D. Cramer III , Nicole Van Opdenbosch, Validation of the general purpose tripos 5.2 force field, 2004, 10; 8: 982-1012.
32. Agarwal A, Taylor EW. 3-D QSAR for intrinsic activity of 5-HT1 A receptor ligands by the method of comparative molecular field analysis. J Comput Chem. 1993; 14(2):237–245.
33. Baurin N, Vangrevelinghe E, Morin-Allory L, Me´rour JY, Renard P, Payard M, Guillaumet G, Marot C. 3D-QSAR CoMFA study on imidazolinergic I2 ligands: a significant model through a combined exploration of structural diversity and methodology. J Med Chem. 2000; 43:1109–1122.
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