Synthesis of novel drug-like small molecules library based on 1H-benzo[d]imidazole
Tejasvi H. Parmar
A , Chetan B. Sangani A * and Mahesh Kulkarni B
A Department of Chemistry, Shri Maneklal M. Patel Institute of Sciences and Research, Kadi Sarva Vishwavidyalaya, Gandhinagar – 382023, India.
B Department of Chemistry, Organic Chemistry Research Centre, K. R. T. Arts, B. H. Commerce and A. M. Science College, Gangapur Road, Nashik 422 002, Maharashtra, India.
Australian Journal of Chemistry 75(4) 276-284 https://doi.org/10.1071/CH21238
Submitted: 17 September 2021 Accepted: 26 November 2021 Published: 8 April 2022
© 2022 The Author(s) (or their employer(s)). Published by CSIRO Publishing.
Abstract
A series of novel ‘drug-like’ small molecules based on 1H-benzo[d]imidazole derivatives bearing furan-2-yl, 4-piperidine and 5-aryl/aminoaryl substitutions were designed and synthesised. The key intermediate tert-butyl-4-(5-bromo-2-(furan-2-yl)-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (5) was synthesised via sequential reaction starting from 4-bromo-1-fluoro-2-nitrobenzene (1). The 5-aryl-substituted molecular library was generated via Suzuki–Miyura coupling of tert-butyl-4-(5-bromo-2-(furan-2-yl)-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (5) with various boronic acids while Buchwald coupling of 5 with various anilines generated the second molecular library of tert-butyl-4-(2-(furan-2-yl)-5-(arylamino)-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylates. The structures of all the newly synthesised compounds were confirmed by spectral analysis. The optimised procedure gives easy access to two new molecular libraries of 1H-benzo[d]imidazoles with operational simplicity and good yield.
Keywords: 1H-benzo[d]imidazole, BINAP, C–C coupling, C–N coupling, drug-like small molecules, hydrogen bond acceptors, hydrogen bond donors.
References
[1] LB Akella, D DeCaprio, Curr Opin Chem Biol 2010, 14, 325.| Crossref | GoogleScholarGoogle Scholar | 20457001PubMed |
[2] W Walters, AA Murcko, MA Murcko, Curr Opin Chem Biol 1999, 3, 384.
| Crossref | GoogleScholarGoogle Scholar | 10419858PubMed |
[3] SL Schreiber, PNAs 2001, 17, 6699.
[4] RE Dolle, Discovery of enzyme inhibitor through combinatorial chemistry. Mol Divers 1997, 2, 223.
| 9249758PubMed |
[5] D Brown, Future pathways for combinatorial chemistry. Mol Divers 1997, 2, 217.
| Future pathways for combinatorial chemistry.Crossref | GoogleScholarGoogle Scholar | 9249757PubMed |
[6] E Lenci, A Trabocchi, Chem Bio Chem 2019, 9, 1115.
[7] Stocks M. The small molecule drug discovery process – from target selection to candidate selection. In: Ganellin CR, Jefferis R, Roberts S, editors. Introduction to Biological and Small Molecule Drug Research and Development. Elsevier; 2013. pp. 81–126.
[8] G Schneider, U Fechner, Nat Rev Drug Dis 2005, 4, 649.
| Crossref | GoogleScholarGoogle Scholar |
[9] O’Connell KMG, Galloway WRJD, Spring DR. The Basics of Diversity-Oriented Synthesis. In: Trabocchi A, Schreiber SL, editors. Diversity-Oriented Synthesis: Basics and Applications in Organic Synthesis, Drug Discovery, and Chemical Biology. John Wiley and Sons; 2013. pp. 1–24.
[10] WRDJ Galloway, A Isidro-Llobet, DR Spring, Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules. Nat Commun 2010, 1, 80.
| Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules.Crossref | GoogleScholarGoogle Scholar |
[11] FS Macchi, K Pissinate, AD Villela, BL Abbadi, V Rodrigues-Junior, DD Nabinger, S Altenhofen, N Sperotto, A da Silva Dadda, FT Subtil, TF deFreitas, AP Erhart Rauber, AF Borsoi, CD Bonan, CV Bizarro, LA Basso, DS Santos, P Machado, Eur J Med Chem 2018, 155, 153.
| Crossref | GoogleScholarGoogle Scholar | 29885576PubMed |
[12] B Shankar, P Jalapathi, B Saikrishna, et al. Synthesis, antimicrobial activity, cytotoxicity of some novel substituted (5-(3-(1H-benzo[d]imidazol-2-yl)-4-hydroxybenzyl)benzofuran-2-yl)(phenyl)methanone analogs. Chem Cent J 2018, 12, 1.
| Synthesis, antimicrobial activity, cytotoxicity of some novel substituted (5-(3-(1H-benzo[d]imidazol-2-yl)-4-hydroxybenzyl)benzofuran-2-yl)(phenyl)methanone analogs.Crossref | GoogleScholarGoogle Scholar | 29318401PubMed |
[13] Iwahi T, Satoh H. U.S. Patent 1991, 5013, 743.
[14] Masaki M, Yamakawa T, Nomura Y, Matsukura H. U.S. Patent 1996, 5576, 341.
[15] KG Desai, KR Desai, Bioorg Med Chem 2006, 14, 8271.
| Crossref | GoogleScholarGoogle Scholar | 17035035PubMed |
[16] H Göker, C Kus, DW Boykin, S Yıldız, Bioorg Med Chem 2002, 10, 2589.
| Crossref | GoogleScholarGoogle Scholar | 12057648PubMed |
[17] B SivaKumar, S Vaidya, R Kumar, S Bhiryd, R Manr, Eur J Med Chem 2006, 41, 599.
| Crossref | GoogleScholarGoogle Scholar |
[18] K Ansari, C Lal, Chem Sci 2009, 121, 1017.
| Crossref | GoogleScholarGoogle Scholar |
[19] K Ansari, C Lal, Eur J Med Chem 2009, 44, 4028.
| Crossref | GoogleScholarGoogle Scholar | 19482384PubMed |
[20] K Ansari, C Lal, Eur J Med Chem 2009, 44, 2294.
| Crossref | GoogleScholarGoogle Scholar | 18316140PubMed |
[21] C Gill, G Jadhav, M Shaikh, R Kale, A Shawalkar, D Nagargoje, M Shiradkar, Bioorg Med Chem Lett 2008, 18, 6244.
| Crossref | GoogleScholarGoogle Scholar | 18930654PubMed |
[22] M Hranjec, K Starčević, SK Pavelić, et al. Eur J Med Chem 2011, 46, 2274.
| Crossref | GoogleScholarGoogle Scholar | 21439689PubMed |
[23] A Chen, C Yu, B Gatto, LF Liu, Proc Natl Acad Sci USA 1993, 90, 8131.
| Crossref | GoogleScholarGoogle Scholar | 7690143PubMed |
[24] AY Chen, C Yu, AL Bodley, LF Peng, LF Liu, Cancer Res 1993, 53, 1332.
| 8383008PubMed |
[25] E Kraut, T Fleming, M Segal, J Neidhart, B Behrens, J MacDonald, Invest New Drugs 1991, 9, 95.
| Crossref | GoogleScholarGoogle Scholar | 1709154PubMed |
[26] B Tolner, J Hartly, D Hochhauser, Mol Pharamcol 2001, 59, 699.
| Crossref | GoogleScholarGoogle Scholar |
[27] TA Beerman, MM McHugh, R Sigmund, JW Lown, KE Rao, Y Bathini, Biochim Biophys Acta 1992, 1131, 53.
| Crossref | GoogleScholarGoogle Scholar | 1374646PubMed |
[28] M Hranjec, G Pavlovi, M Marjanovi_c, M Kralj, G Karminski-Zamola, Eur J Med Chem 2010, 45, 2417.
| Crossref | GoogleScholarGoogle Scholar |
[29] (a) M Batista, P Susana, M Costa, M Belsley, MM Raposo, Tetrahedron 2007, 63, 9842.
| Crossref | GoogleScholarGoogle Scholar |
(b) I Nurulla, A Tanimoto, K Shiraishi, S Sasaki, T Yamamoto, Polymer 2002, 43.
[30] Y Bansal, O Silakari, Bioorg Med Chem 2012, 20, 6208.
| Crossref | GoogleScholarGoogle Scholar | 23031649PubMed |
