Plenary Lecture 13

Title: Discovery of multitarget prototypes for treatment of multifactorial diseases:
N-acylhydrazone framework as privileged structure

Professor Carlos Alberto Manssour Fraga

Federal University of Rio de Janeiro, Brazil


Lecture Summary: The growing impact of the network pharmacology in the discovery of new drugs useful for treatment of multifactorial diseases changed the classical idea originally supported by Ehrlich's philosophy of magic bullets, which states that an efficient biologically active compound should act selectively on some specific disease-related biomacromolecule. The combination of two or more clinically validated therapeutic targets with mutual participation in specific multifactorial diseases can represent an interesting strategy to increase the available pharmacological space for the discovery of new drug candidates.1 Emerging from this new Medicinal Chemistry approach, the concept of multitarget drugs appears as an interesting therapeutic innovation in the search for more efficient and safe drugs for treating chronic diseases, by combining in a single molecular architecture structural requirements able to assure it molecular recognition by two or more distinct biological targets, involved in the same disease. In our research group, i.e. LASSBio-UFRJ, we have successfully exploited the N-acylhydrazone (NAH) framework as a privileged structure2 to the identification of compounds able to be selectively recognized by different biotargets, such as adenosine A2A receptors,3 PDE-4 inhibitors4 and selective inhibitors of HDAC6 and HDAC8,5 among others. This peptidomimetic framework, which is resultant from the fusion between amide and imine subunits, is able to provide points of interaction with a wide range of amino acid residues, comprising both H-bond acceptor and donor sites.6,7 Among these compounds, deserves attention the NAH derivatives LASSBio-1359 and LASSBio-1911 (Figure 1), which showed to be powerful multitarget prototypes able to treat pulmonary hypertension8 and cancer, respectively. So, this lecture describes the structural design of these two NAH compounds, the full characterization of their structural9,10 and physicochemical properties and also the evaluation of their ability to modulate multiple targets associated with the respective chronic disease.  


Figure 1: Chemical structure of multitarget NAH prototypes
LASSBio1359 and LASSBio-1911.


Acknowledgments: Thanks are due to National Institute of Drugs and Medicines (INCT-INOFAR, BR), to National Council of Research and Development (CNPq, BR) and also to Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro (FAPERJ) for the financial support and fellowships.


References: 1 Barreiro, E.J.; Fraga, C. A. M. Curr. Drug Ther. 2008, 1.

2 Duarte, C. D.; Barreiro, E. J..; Fraga, C. A. M. Mini-Rev. Med. Chem. 2007, 1108.

3 Alencar, A. K. N.; Pereira, S. L.; Montagnoli, T. L.; Maia, R. C.; Kümmerle, A. E.; Landgraf, S. S.; Caruso-Neves, C.; Ferraz, E. B.; Tesch, R.; Nascimento, J. H. M.; Santanna, C. M. R.; Fraga, C. A. M.; Barreiro, E. J.; Sudo, R. T.; Zapata-Sudo, G. Brit. J. Pharmacol. 2013169, 953.

4 Kümmerle, A. E.; Schmitt, M.; Cardozo, S. V. S.; Lugnier, C.; Villa, P.; Lopes, A. B.; Romeiro, N. C.; Justiniano, H.; Martins, M. A.; Fraga, C. A. M.; Bourguignon, J. J.; Barreiro, E. J.  J. Med. Chem. 2012, 55, 7525.

5 Rodrigues, D. A.;, Ferreira-Silva, G. A.; Ferreira, A. C. S.; M. A.; Fernandes, R. A.; Kwee, J. K.; Sant'anna, C. M. R.; Ionta, M.; Fraga, C. A. M.  J. Med. Chem. 2016, 59, 655.

6 Maia, R. C.; Tesch, R.; Fraga, C. A. M. Expert Opin. Ther. Pat. 2014, 24, 1161.

7 Senger, M. R.; Fraga, C. A. M.; Dantas, R. F.; Silva-Jr, F. P. Drug Discov. Today 2016, 21, 868. 

8 Alencar, A. K. N.; Pereira, S. L.; Silva, F. E.; Mendes, L. V. P.; Cunha, V. M. N.; Lima, L. M.; Montagnoli, T. L.; Caruso-Neves, C.; Ferraz, E. B.; Tesch, R.; Nascimento, J. H. M.; Santanna, C. M. R.; Fraga, C. A. M.; Barreiro, E. J.; Sudo, R. T.; Zapata-Sudo, G. Int. J. Cardiol. 2014173, 154.

9 Kummerle, A. E.; Raimundo, J. M.; Leal, C. M.; Silva, G. S.; Balliano, T. L.; Pereira, M. A.; Simone, C. A.; Sudo, R. T.; Zapata-Sudo, G.; Fraga, C. A. M.; Barreiro, E. J. Eur. J. Med. Chem. 2009, 44, 4004.

10 Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011111, 5215.