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

Abstract

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.

Cinnamic Acid/Chloroquinoline Conjugates as Potent Agents against Chloroquine‐Resistant Plasmodium falciparum

“…[3] A recent rational approach of antimalarial drug design characterized as "covalent bitherapy" involves linking two molecules with individual intrinsic activity to create a single agent, thus packaging dual activity into a single hybrid molecule. [4,5] In this regard, we have synthesized twelve novel compounds (7) with the heteroaromatic core of 1, 4-amino-7-chloroquinoline, linked to differently substituted cinnamoyl groups (CIN) through a flexible aminobutyl spacer (Scheme 1 a). Compound design rationale was based on 1) relevance of 6 for inhibition of heme biocrystallization, and consequently, of the development of erythrocytic malaria parasites; [3] and 2) previous reports on cinnamic acid derivatives with promising antimalarial properties.…”

Selection of a trioxaquine as an antimalarial drug candidate

“…In addition, the presence of a second cyclohexyl ring within the linker enhanced the metabolic stability of this molecule compared with other trioxaquines with a linear aliphatic tether. The synthesis of PA1103/SAR116242 is outlined in Based on our previous studies (17)(18)(19)(20)(21), the dual mode of action of PA1103/SAR116242 has also been shown (heme alkylation via the reductive activation the trioxane entity, heme stacking with the aminoquinoline moiety, and inhibition of hemozoin formation). The alkylating capacity of PA1103/SAR116242 toward iron(II)-heme was evaluated in vitro, and several heme drug adducts have been observed (m/z peaks at 917, 858, and 818).…”

“…5 and references therein), we designed original hybrid molecules, named trioxaquines, containing 2 pharmacophores (a 1,2,4-trioxane and a 4-aminoquinoline) to create molecules with a dual mode of action (heme alkylation with the trioxane entity, heme stacking with the aminoquinoline moiety and inhibition of hemozoin formation) (15)(16)(17)(18)(19)(20)(21). One trioxaquine prototype DU1302 shows very good activity in vitro and in vivo (mice model) but has too many centers of chirality to be considered for development (16,(18)(19)(20)(21). Here, we report the preparation and the pharmacological properties and the antimalarial activities of PA1103/ SAR116242 that we selected for full preclinical development as a drug candidate that is active by the oral route.…”

Azide-alkyne cycloaddition en route to 1 H -1,2,3-triazole-tethered 7-chloroquinoline-isatin chimeras: Synthesis and antimalarial evaluation

“…This strategy has resulted in the development of trioxane-aminoquinoline [10], artemisininquinine [11] and ferrocene-CQ chimeras [12] with improved antimalarial activity compared to the parent drugs.…”