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.
Highlights
Chloroquine (CQ), a 4-aminoquinoline, has been the mainstay of malarial chemotherapy for much of the past five decades
Hybrid molecules of this type had in vitro antiplasmodial activity against both CQ-sensitive and -resistant P. falciparum isolates, activity that was independent of parasite CQ-susceptibility [Biot et al, 2007]
Hybrid molecules with dual functionality development and/or multitherapeutic strategies, which utilize new chemical entities with two different heterocyclic skeletons, represent a valid and rational approach in design and development of novel antimalarials. These drugs have the potential to surmount the rapid development of resistance, enhance patient compliance, and reduce both the cost and the risk of drug–drug interactions
Summary
Chloroquine (CQ), a 4-aminoquinoline, has been the mainstay of malarial chemotherapy for much of the past five decades. Biot et al [2007] synthesized chimeras of thiosemicarbazones and the new drug candidate, ferroquine, a new 4-aminoquinoline in which a ferrocenyl group is associated with CQ [Barends et al, 2007] Hybrid molecules of this type had in vitro antiplasmodial activity against both CQ-sensitive and -resistant P. falciparum isolates, activity that was independent of parasite CQ-susceptibility [Biot et al, 2007]. The bis-quinoline 7-chloro-4-[4(7-chloro-4-quinolyl)-7-ferrocenylmethyl-1,4,7-triazacyclononan-1-yl]quinoline, showed potent antimalarial activity in vitro against the CQ-resistant P. falciparum isolate Dd2 This relatively new strategy involved incorportation of organometallocenic moiety of ferroquine, which has cytotoxic properties into CQ pharmacophore, which enables vectorizing the drug to the selected target [Biot et al, 2004]. It will be interesting to evaluate whether the principle of ‘‘covalent bitherapy’’ can be exploited to develop modular hybrid molecules that restore activity of other dug class such as antifolates (e.g., sulfadoxine/pyrimethamine), which become ineffective due to resistance
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