Next-Generation Antimalarial Drugs: Hybrid Molecules as a New Strategy in Drug Design

Abstract

Malaria is a disease that affects nearly 40% of the global population, and chemotherapy remains the mainstay of its control strategy. The global malaria situation is increasingly being exacerbated by the emergence of drug resistance to most of the available antimalarials, necessitating search for novel drugs. A recent rational approach of antimalarial drug design characterized as "covalent bitherapy" involves linking two molecules with individual intrinsic activity into a single agent, thus packaging dual-activity into a single hybrid molecule. Current research in this field seems to endorse hybrid molecules as the next-generation antimalarial drugs. If the selective toxicity of hybrid prodrugs can be demonstrated in vivo with good bioavailability at the target site in the parasite, it would offer various advantages including dosage compliance, minimized toxicity, ability to design better drug combinations, and cheaper preclinical evaluation while achieving the ultimate object of delaying or circumventing the development of resistance. This review is focused on several hybrid molecules that have been developed, with particular emphasis on those deemed to have high potential for development for clinical use. Drug Dev Res 71: 20-32, 2010. © 2009 Wiley-Liss, Inc.

Fig. 1

OZ277 (RBx-11160), a fully synthetic trioxolane and a potent peroxidic antimalarial.

Fig. 2

A 1,2,4-trioxolaquine, a potent hybrid antimalarial drug.

Fig. 3

PA1103/SAR116242. The trioxaquine linker's cyclohexyl ring enhances its metabolic stability.

Fig. 4

Artemisinin-dipeptidyl vinyl sulfone conjugates.

Fig. 5

A generalized chemical structure of dual-function acridone derivatives. For compound T3.5: n,m = 2 and R₁,R₂,R₃,R₄ = CH₂CH₃.The rigid tricyclic acridone core promotes π-π stacking for haem binding. The side chain attachment at the central nitrogen atom provides a hydrogen bond acceptor needed for the chemosensitization function, and in conjunction with the side chain at position 6, facilitates accumulation in the digestive vacuole (DV) via acid trapping. [Color figures can be viewed in the online issue, which is available at http://www.interscience.wiley.com]

Fig. 6

An aminoquinoline-imipramine hybrid molecule.

Fig. 7

A 4-aminoquinoline-based isatin derivative. [Color figures can be viewed in the online issue, which is available at http://www.interscience.wiley.com]

Fig. 8

Aminoquinoline-glutathione reductase inhibitor conjugate molecules.