Review
Morita–Baylis–Hillman adducts: Biological activities and potentialities to the discovery of new cheaper drugs

https://doi.org/10.1016/j.bmc.2012.04.061Get rights and content

Abstract

This review aims to present by the first time the Morita–Baylis–Hillman adducts (MBHA) as a new class of bioactive compounds and highlight its potentialities to the discovery of new cheaper and efficient drugs. Now, most these compounds can be prepared fast and on a single synthetic step (one-pot reaction) in high yields and using ecofriendly synthetic protocols. We highlight here the aromatic MBHA, which have shown diverse biological activities as anti-Leishmania chagasi and Leishmania amazonensis (parasites that cause cutaneous and visceral leishmaniasis), anti-Trypanosoma cruzi (parasite that cause Chagas disease), anti-Plasmodium falciparum and Plasmodium berghei (parasites that cause malaria), lethal against Biomphalaria glabrata (the snail transmitter of schistosomiasis), antibacterial, antifungal, herbicide and actives against some human tumor cell lines. Understanding of the biological mechanisms of action of this new class of molecules is still in the infancy stage. However, we report here which has been described to date on the possibilities of biological mechanisms of action, and we present new analyzes based on literature in this area. The academic and industrial interest in selecting green and cheaper experiments to the drugs development has been the prime mover of the growth on the subject.

Graphical abstract

This review aims to present by the first time the Morita–Baylis–Hillman adducts (MBHA) as a new class of bioactive compounds and highlight its potentialities to the discovery of new green efficient drugs.

  1. Download : Download full-size image

Introduction

The Morita–Baylis–Hillman reaction (MBHR) is a relatively recent form to the C–C bond formation.1, 2 This reaction occurs between an sp2 electrophilic carbon (e.g., aldehydes, ketones or imines) and the α position of an alkene (or alkyne) connected to an electron-attractors groups (EAG), under tertiary amines as nucleophilic catalysis, being 1,4-diazabicyclo [2.2.2]octane (DABCO) widely used catalyst (Scheme 1).3 This reaction generates compounds called Morita–Baylis–Hillman adducts (MBHA). The MBHA have been widely used as the starting material in the natural and unnatural products synthesis.4 When the group X is N (typically NTs) this reaction is classified as Aza-MBHR and products of this reaction are the Aza-MBHA.4

This reaction has important features such as the complete atom economy, the possibility of being performed in an aqueous medium or in absence of solvents and on free-metal condition (organocatalysis). These characteristics are today receiving great attention of the synthetic organic chemists which work into academic and industries laboratories on searching on the more ecological, efficient and cheap synthetic protocols to new drug discovery.

A pivotal limitation described in several articles about this reaction is the long reaction time, for example, there are reactions that were performed in more than 65 days.3 However, due to the synthetic utility of these MBHA adducts, several protocols have been described an improvement in reaction time and yields, such as the use of ultrasound, high pressures, use of ionic liquids, change of catalyst, change of solvents, microwaves irradiation, and several other experimental protocols.4

Section snippets

Mechanistic aspects

The first mechanistic proposal for the MBHR was published by Hoffman and Rabe in 1983 following 7 years after by Hill and Isaacs. In these propositions the first step is a Michael addition of the catalyst (tertiary amine 1) to an activated alkene 2, generating a zwitterionic enolate 3 (Fig. 1). The next stage consists of an aldol addition of the aldehydes 4 and the intermediate 3 generating the new intermediate 5, which was proposed as the low step. The subsequent step involves an intramolecular

The growth and the present status

The last general review about MBHR was recently published by Basavaiah et al. in 2010 where the 1028 references cited therein shows the importance of this reaction for synthetic organic chemistry, in addition to the progress on the search for new asymmetric catalysts, intramolecular version, heterocyclic synthesis and advances in mechanistic understanding.4 A recent book published last year by Shi et al. entitled ‘The Chemistry of the Morita–Baylis–Hillman Reaction’ also demonstrates the great

The use of MBHA as starting material on the chemical synthesis

Since the work of Drewes and Emslie11 and Hoffman and Rabe,12 the MBHA have been used by chemists as synthetic intermediates on total synthesis. Various natural products and molecules of biological interest were synthesized from MBHA or using the MBH reaction as the key step for the preparation of compounds with biological interest.4 For example, in Figure 3 below we show some compounds prepared from MBHA and its biological activities.13, 14, 15, 16, 17, 18 However, it is important to detach

Conclusion

The simple MBHA have become an important class of bioactive compounds already presenting diversified biological activities as antimalarial, molluscicide, leishmanicidal, antichagasic, antitumoral, antifungal, antibacterial and herbicide. Recent applications of medicinal chemistry strategies in the design of new drug candidates for the MBHA are gaining space in literature. Now the preparation of MBHA can be performed in a single synthetic step, efficiently, with several challenges in these

Acknowledgments

This work has been supported by CNPq, CAPES and FAPESQ-PB. We are grateful for all members of the LASOM-PB’family, without which much of these presented results could not be obtained.

References and notes (72)

  • A. Patra et al.

    Bioorg. Med. Chem.

    (2003)
  • P. Narender et al.

    Bioorg. Med. Chem.

    (2006)
  • M.K. Kundu et al.

    Bioorg. Med. Chem. Lett.

    (1999)
  • P. Narender et al.

    Bioorg. Med. Chem. Lett.

    (2005)
  • L.K. Kohn et al.

    Eur. J. Med. Chem.

    (2006)
  • T.J. Ritchie et al.

    Drug Discovery Today

    (2009)
  • R. Mohan et al.

    Bioorg. Med. Chem.

    (2006)
  • L.R. Berube et al.

    Int. J. Radiat. Oncol. Biol. Phys.

    (1992)
  • O.W. Griffith et al.

    J. Biol. Chem.

    (1979)
  • C.R. Yu et al.

    J. Fluorine Chem.

    (2006)
  • R.O.M.A. de Souza et al.

    Eur. J. Med. Chem.

    (2007)
  • T.C. Barbosa et al.

    Eur. J. Med. Chem.

    (2009)
  • J.M. Sandes et al.

    Bioorg. Chem.

    (2010)
  • A.L. Edinger et al.

    Curr. Opin. Cell Biol.

    (2004)
  • J.A. Urbina et al.

    Mol. Biochem. Parasitol.

    (2002)
  • M.A. La-Scalea et al.

    J. Pharm. Biomed. Anal.

    (2002)
  • C.G.L. Junior et al.

    Bioorg. Chem.

    (2010)
  • F.P.L. Silva et al.

    Eur. J. Med. Chem.

    (2011)
  • T.P. Barbosa et al.

    Bioorg. Med. Chem.

    (2011)
  • J.H. Tocher et al.

    Biochem. Pharmacol.

    (1995)
  • M.J. Almela et al.

    Toxicol. In vitro

    (2009)
  • N. Hayashi et al.

    Tetrahedron: Asymmetry

    (1998)
  • K. Morita et al.

    Bull. Chem. Soc. Jpn.

    (1968)
  • Baylis, A. B.; Hillman, M. E. D. U.S. Patent 3,743,669, 1973; Chem. Abstr. 1972, 77,...
  • D. Basavaiah et al.

    Chem. Rev.

    (2003)
  • D. Basavaiah et al.

    Chem. Rev.

    (2010)
  • K.E. Price et al.

    Org. Lett.

    (2005)
  • R. Robiette et al.

    J. Am. Chem. Soc.

    (2007)
  • G.W. Amarante et al.

    J. Org. Chem.

    (2009)
  • D. Cantillo et al.

    J. Org. Chem.

    (2010)
  • C.G.L. Junior et al.

    J. Braz. Chem Soc.

    (2011)
  • M. Shi et al.

    Chemistry of the Morita–Baylis–Hillman Reaction

    (2011)
  • S.E. Drewes et al.

    J. Chem. Soc., Perkin Trans. 1

    (1982)
  • H.M.R. Hoffmann et al.

    Angew. Chem., Int. Edit.

    (1983)
  • R. Sreevani et al.

    J. Heterocycl. Chem.

    (2011)
  • Ryu, D. H.; Hwang, G. S.; Kim, K. H.; Park, J. H.; Kim, H. J. Int. Patent 110655 A1,...
  • Cited by (0)

    View full text