We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Published Online:https://doi.org/10.4155/ppa-2023-0021

Morita–Baylis–Hillman adducts are polyfunctionalized compounds that result from a three-component reaction involving an electrophilic sp2 carbon (aldehyde, ketone or imine) and the α-position of an activated alkene, catalyzed by a tertiary amine. These adducts exhibit a wide range of biological activities and act as valuable starting materials for developing drug candidates, pesticides, polymers, and other applications. In this regard, the present review aimed to explore the biological potential of Morita–Baylis–Hillman adducts and their derivatives as documented in patent literature. Additionally, the review delves into the synthetic methodologies employed in their preparation.

Graphical abstract

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

  • 1. Basavaiah D, Naganaboina RT. The Baylis–Hillman reaction: a new continent in organic chemistry – our philosophy, vision and over three decades of research. New J. Chem. 42(17), 14036–14066 (2017). •• Provide a concise summary of the philosophical perspective on the history and development of the MBH reaction by one of the foremost authorities in the field.
  • 2. Basavaiah D, Reddy GC. Intramolecular Baylis-Hillman reaction: synthesis of heterocyclic molecules. ARKIVOC: Online Journal of Organic Chemistry ii, 172–205 (2016).
  • 3. Correia PRS, Freitas JD, Zeoly LA, Porto RS, Lima DJP. Discovery and structure-activity relationship of Morita–Baylis–Hillman adducts as larvicides against dengue mosquito vector, Aedes aegypti (Diptera: culicidae). Bioorg. Med. Chem. 117315 (2023).
  • 4. Coelho F, Almeida WP. The Baylis-Hillman reaction: a strategy for the preparation of multifunctionalised intermediates for organic synthesis. Química nova 23, 98–101 (2000).
  • 5. Zhong W, Liu Y, Wang G et al. Recent advances in construction of nitrogen-containing heterocycles from Baylis-Hillman adducts. Org. Prep. Proc. Int. 43(1), 1–66 (2011).
  • 6. Zhu H, Shao N, Chen T, Zou H. Functionalized heterocyclic scaffolds derived from Morita–Baylis–Hillman acetates. Chem. Commun. 49(70), 7738–7740 (2013).
  • 7. Selig P, Turočkin A, Raven W. Guanidine-Catalyzed γ-Selective Morita–Baylis–Hillman Reactions on α, γ- Dialkyl-Allenoates: Access to Densely Substituted Heterocycles. Synlett 24(19), 2535–2539 (2013).
  • 8. Reddy YS, Kadigachalam P, Basak RK, Pal AJ, Vankar YD. Total synthesis of (+)-pericosine B and (+)-pericosine C and their enantiomers by using the Baylis–Hillman reaction and ring-closing metathesis as key steps. Tetrahedron Lett. 53(2), 132–136 (2012).
  • 9. Yuan P, Gaich T. Enantioselective total synthesis of (+)-Pepluanol A. Org. Lett. 24(26), 4717–4721 (2022).
  • 10. Bhowmik S, Batra S. Morita–Baylis–Hillman approach toward formal total synthesis of Tamiflu and total synthesis of gabaculine. Eur. J. Org. Chem. 2013(31), 7145–7151 (2013).
  • 11. Dunn PJ, Hughes ML, Searle PM, Wood AS. The chemical development and scale-up of sampatrilat1. Org. Process Res. Dev. 7(3), 244–253 (2003). • Reports the process of scaling up the production of a significant MBH-derived ACE inhibitor, showcasing its immense potential for industrial applications.
  • 12. Wani MM, Dar AA, Bhat BA. Micelle-guided Morita–Baylis–Hillman reaction of ketones in water. Org. Biomol. Chem. 20(24), 4888–4893 (2022).
  • 13. Pereira MP, de Souza Martins R, de Oliveira MAL, Bombonato FI. Amino acid ionic liquids as catalysts in a solvent-free Morita–Baylis–Hillman reaction. RSC Advances 8(42), 23903–23913 (2018).
  • 14. Bharadwaj KC. Intramolecular Morita–Baylis–Hillman and Rauhut–Currier reactions. A catalytic and atom economic route for carbocycles and heterocycles. RSC Advances 5(93), 75923–75946 (2015).
  • 15. Lima–Junior CG, Vasconcellos ML. Morita–Baylis–Hillman adducts: biological activities and potentialities to the discovery of new cheaper drugs. Bioorg. Med. Chem. 20(13), 3954–3971 (2012).
  • 16. Bhowmik S, Batra S. Applications of Morita–Baylis–Hillman reaction to the synthesis of natural products and drug molecules. Curr. Org. Chem. 18(24), 3078–3119 (2014).
  • 17. Elleuch H, Mihoubi W, Mihoubi M, Ketata E, Gargouri A, Rezgui F. Potential antioxidant activity of Morita- Baylis-Hillman adducts. Bioorg. Chem. 78, 24–28 (2018).
  • 18. Chang L, Thorimbert S, Dechoux L. The bio-based methyl coumalate involved Morita–Baylis–Hillman reaction. Org. Biomol. Chem. 17(10), 2784–2791 (2019).
  • 19. Haleem A, Ullah H, Samiullah Akbar A, Ahmad N, Ellahi M, Nawaz M. Synthesis and biological activity of morita baylis hillman adducts and their oximes. Pharm. Chem. J. 56(2), 185–190 (2022).
  • 20. Ferreira LAMP, de Lima LM, Ferreira LKDP et al. Biological activities of Morita–Baylis–Hillman adducts (MBHA). Mini-Rev. Med. Chem. 23(17), 1691–1710 (2023). •• Describing a recent and comprehensive review, this article highlights the biological activities of MBH adducts documented in the literature.
  • 21. Mattiuzzi C, Lippi G. Current cancer epidemiology. J. Epidemiol. Glob. Health 9(4), 217 (2019). • Provides a succinct summary of the current cancer epidemiology and furnishes up-to-date data on the incidence, mortality and survival rates for the top 15 types of cancers globally
  • 22. Sung H, Ferlay J, Siegel RL et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71(3), 209–249 (2021).
  • 23. Habib SH, Saha S. Burden of non-communicable disease: global overview. Diabetes & metabolic syndrome. Clin Res Rev. 4(1), 41–47 (2010).
  • 24. Alzahrani SM, Al Doghaither HA, Al Ghafari AB. General insight into cancer: an overview of colorectal cancer. Mol Clin Oncol. 15(6), 1–8 (2021).
  • 25. Zhu H, Swami U, Preet R, Zhang J. Harnessing DNA replication stress for novel cancer therapy. Genes 11(9), 990 (2020).
  • 26. Lee CH, Jung HJ, Kim SG et al. KR20060035091 A (2006).
  • 27. Furdas SD, Kannan S, Sippl W, Jung M. Small molecule inhibitors of histone acetyltransferases as epigenetic tools and drug candidates. Archiv der Pharmazie 345(1), 7–21 (2012).
  • 28. Adimulam T, Arumugam T, Foolchand A, Ghazi T, Chuturgoon AA. The effect of organoselenium compounds on histone deacetylase inhibition and their potential for cancer therapy. International Journal of Molecular Sciences 22(23), 12952 (2021).
  • 29. Ma L, Bian X, Lin W. The dual HDAC-PI3 K inhibitor CUDC-907 displays single-agent activity and synergizes with PARP inhibitor olaparib in small cell lung cancer. J. Exp. Clin. Cancer Res. 39(1), 1–14 (2020).
  • 30. Ganai SA, Sheikh FA, Baba ZA. Plant flavone Chrysin as an emerging histone deacetylase inhibitor for prosperous epigenetic‐based anticancer therapy. Phytotherapy Research 35(2), 823–834 (2021).
  • 31. Lee CH, Jung HJ, Kim JH et al. KR100711944B1 (2007).
  • 32. Price RN. Artemisinin drugs: novel antimalarial agents. Expert Opin. Investig. Drugs 9(8), 1815–1827 (2000).
  • 33. Slezáková S, Ruda-Kucerova J. Anticancer activity of artemisinin and its derivatives. Anticancer Res. 37(11), 5995–6003 (2017).
  • 34. Baisha G, Barua NC, Goswami A et al. WO2011089507A1 (2011).
  • 35. Krishna PR, Reddy PN, Sreeshailam A, Kiran MU, Jagdeesh B. The Baylis–Hillman reaction: a strategic tool for the synthesis of higher-carbon sugars. Tetrahedron Letters 48(37), 6466–6470 (2007).
  • 36. Zhang L, Huo X, Liao Y, Yang F, Gao L, Cao L. Zeylenone, a naturally occurring cyclohexene oxide, inhibits proliferation and induces apoptosis in cervical carcinoma cells via PI3K/AKT/mTOR and MAPK/ERK pathways. Sci. Rep. 7(1), 1–13 (2017).
  • 37. Zhang L, Jin J, Zhang L et al. Quantitative analysis of differential protein expression in cervical carcinoma cells after zeylenone treatment by stable isotope labeling with amino acids in cell culture. J. Proteom. 126, 279–287 (2015).
  • 38. Huo X, Liao Y, Tian Y, Gao L, Cao L. Zeylenone promotes apoptosis in chronic myelogenous leukemia-derived K562 cells by a mechanism involving Jak2 and Src kinase. RSC Adv. 6(115), 114096–114108 (2016).
  • 39. Xu X, Sun Z, Cao L, Tian Y, Yang S. CN112409183 B (2022).
  • 40. Zhong W, Shao B, Xiao X, Ling F. CN112939999 B (2022).
  • 41. Mou J, Li L, Zhou T, Yang R, Xiang R, Pei D. CN112300106 B (2023).
  • 42. Sabatino A, Regolisti G, Cosola C, Gesualdo L, Fiaccadori E. Intestinal microbiota in type 2 diabetes and chronic kidney disease. Current Diabetes Reports 17, 1–9 (2017).
  • 43. Farooqui AA, Farooqui T, Panza F, Frisardi V. Metabolic syndrome as a risk factor for neurological disorders. Cell. Mol. Life Sci. 69, 741–762 (2012).
  • 44. Grygiel-Górniak B. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications-a review. Nutrition Journal 13, 1–10 (2014).
  • 45. Jung JH, Zhiran J. KR102072378B1 (2020).
  • 46. Chavez-Dominguez R, Perez-Medina M, Aguilar-Cazares D et al. Old and new players of inflammation and their relationship with cancer development. Front. Oncol. 11, 722999 (2021).
  • 47. Robinson MW, Harmon C, O'Farrelly C. Liver immunology and its role in inflammation and homeostasis. Cell. Mol. Immunol. 13(3), 267–276 (2016).
  • 48. Oguntibeju OO. Medicinal plants with anti-inflammatory activities from selected countries and regions of Africa. J. Inflamm. Res. 307–317 (2018).
  • 49. Baj T, Seth R. Role of curcumin in regulation of TNF-α mediated brain inflammatory responses. Recent Pat Inflamm Allergy Drug Discov. 12(1), 69–77 (2018).
  • 50. Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: a current perspective. Biochem. Pharmacol. 180, 114147 (2020).
  • 51. Mascarenhas SR, Silva JSF, Lima EA et al. BR102021015691-0A2 (2023).
  • 52. Chen SL, Morgan TR. The natural history of hepatitis C virus (HCV) infection. Int. J. Med. Sci. 3(2), 47 (2006).
  • 53. Feeney ER, Chung RT. Antiviral treatment of hepatitis C. BMJ 348, g3308 (2014).
  • 54. Zheng ZB, D'Andrea S. US8716275B2 (2014).
  • 55. Doron S, Gorbach SL. Bacterial infections: overview. Int. Enc. Publ. Health 2008, 273–282 (2008).
  • 56. Porto VA, dos Santos Correia PR, Porto RS. Synthesis and antibacterial activity of 2-mercaptobenzimidazole derivatives: a literature review. Rev. Virtual Quim. 13(6), 1457–1466 (2021).
  • 57. Wei W, Cheng P, Bo H et al. CN104774155 A (2015).
  • 58. Doehlemann G, Ökmen B, Zhu W, Sharon A. Plant pathogenic fungi. Microbiol. Spectr. 5(1), 5–1 (2017).
  • 59. Denning DW, Hope WW. Therapy for fungal diseases: opportunities and priorities. Trends Microbiol. 18(5), 195–204 (2010). •• Offers an overview of the present state of drug therapy for invasive fungal diseases, along with key areas of focus for future advancements in the development of new compounds.
  • 60. Anderson R, Lee SF, Du V, Hokama T, Oey R, Arakaki P. WO2005115148A1 (2005).
  • 61. Kim JM, Kim KH, Kim TH, Kim JN. The first successful intermolecular Heck reaction of Baylis–Hillman adducts: synthesis of β-aryl substituted Baylis–Hillman adducts. Tetrahedron Lett. 49(20), 3248–3251 (2008).
  • 62. Xie JW, Li D, Wei PS. CN105777773 A (2015).
  • 63. Wei PS, Wang MX, Xu DC, Xie JW. Synthesis of 2, 3-Dihydrothieno (2, 3-b) quinolines and Thieno (2, 3-b)- quinolines via an Unexpected Domino Aza-MBH/Alkylation/Aldol Reaction. J. Org. Chem. 81(3), 1216–1222 (2016).
  • 64. Dos Santos MS, Coelho FAS, Schreiber AZ, Fernandes LL, De Carvalho JA, Ruiz ALT. BR102017018013-1 A2 (2017).
  • 65. Moye-Rowley WS. Linkage between genes involved in azole resistance and ergosterol biosynthesis. PLoS Pathog 16(9), e1008819 (2020). • Examines in detail the mechanism of action associated with resistance to azole antifungals
  • 66. Sobel JD, Sobel R. Current treatment options for vulvovaginal candidiasis caused by azole-resistant Candida species. Expert Opin. Pharmacother. 19(9), 971–977 (2018).
  • 67. White NJ. Antimalarial drug resistance. J. Clin. Invest. 113(8), 1084–1092 (2004).
  • 68. Puli N, Banda G, Uppalanchi S et al. WO2007032016A1 (2007).
  • 69. Eustache J, Boiteau JG, Tarnus C, Rodeschini V, Van de Weghe P. WO03040119A1 (2003).
  • 70. Lee S-F, Hokama T, Anderson R. WO2005123727A1 (2005).
  • 71. Neamati N, Kabalka G, Venkataiah B, Dayam R. WO2007081966A2 (2007).
  • 72. Yu CX. CN1315778 C (2007).
  • 73. Wurtz NR, Priestley ES, Cheney DL, Zhang X, Parkhurst B, Ladziata V. WO2008079759A1 (2008).
  • 74. Lee CH, Jung HJ, Kim JH et al. WO2008054154A1 (2008).
  • 75. Chattopadhyaya J, Upadhyaya RS. WO2009091324A1 (2009).
  • 76. Ryu DH, Hwang GS, Kim KH, Park JH, Kim HJ. WO2009110655A1 (2009).
  • 77. Mcguire H, Bist S, Bifulco N et al. WO2013150296A1 (2013).
  • 78. Chen L, Jones ED, Ma D et al. CN101990536 B (2014).
  • 79. Vishwakarma RA, Bharate SB, Bhushan S et al. WO2014170914A1 (2014).
  • 80. Ramesh V, Rani PU, Rao VJ, Ramesh V, Rani PU, Rao VJ. WO2017109795A1 (2017).
  • 81. Kumar J, Mahendar B, Saidulu M, Banerjee SK, Rao VJ. WO2017072796A1 (2017).
  • 82. Fuentefria AM, Braga AL, Batista BG et al. BR102017015184A2 (2019).
  • 83. Zajdel P, Drop M, Canale V et al. WO2020117075A1 (2020).
  • 84. Ramachandran PV, Seleen M. WO2022204231A2 (2022).
  • 85. Pelegrini C, Fornai M, Antonioli L et al. WO2022234447A1 (2022).
  • 86. Hou W, Lan J, Huang H, Xu X, Huang L. CN115721652 A (2023).