Hybrid Molecules with a Dual Mode of Action: Dream or Reality?^†

Bernard Meunier was born in 1947 and educated at the Universities of Montpellier (R. J. P. Corriu) and Paris-Orsay (H. Felkin). After a postdoc at Oxford University, he joined the “Laboratoire de Chimie de Coordination du CNRS” in Toulouse in 1979. He has been Director of Research at the CNRS, Associate Professor at the Ecole Polytechnique (1993–2006), and President of the CNRS (2004–2006). He is currently CEO of Palumed, a small company that he founded in 2000. He is the author of 339 publications and 29 patents. He is a member of the French Academy of Sciences (1999) and the Polish Academy of Sciences (2005).

The drug market is still dominated by small molecules, and more than 80% of the clinical development of drug candidates in the top 20 pharmaceutical firms is still based on small molecules. The high cost of developing and manufacturing “biological drugs” will contribute to leaving an open space for drugs based on cheap small molecules.

Four main routes can be explored to design affordable and efficient drugs: (i) a drastic reduction of the production costs of biological drugs, (ii) a real improvement of drug discovery via “computer-assisted combinatorial methods”, (iii) going back to an extensive exploration of natural products as drug sources, and (iv) drug discovery by rational drug design and bio-inspired design that hopefully includes serendipity and human inspiration.

At the border between bio-inspired design and rational design, one can imagine preparation of hybrid molecules with a dual mode of action to create efficient new drugs. In this Account, hybrid molecules are defined as chemical entities with two or more structural domains having different biological functions and dual activity, indicating that a hybrid molecule acts as two distinct pharmacophores.

In order to obtain new antimalarial drugs that are affordable and able to avoid the emergence of resistant strains, we developed hybrid molecules with a dual mode of action (a “double-edged sword”) able to kill multiresistant strains by oral administration. These hybrid molecules, named trioxaquines, with two pharmacophores able to interact with the heme target are made with a trioxane motif covalently linked to an aminoquinoline entity.

More than 100 trioxaquines have been prepared by Palumed over a period of 4 years, and in collaboration with Sanofi-Aventis, the trioxaquine PA1103-SAR116242 has been selected in January 2007 as candidate for preclinical development.