engleski

Design and synthesis of sahaquines, potential dual-acting antimalarials

Malaria is a deadly mosquito-borne parasitic tropical and subtropical disease, caused by 4 species of Plasmodium, P. falciparum, P. vivax, P. ovale and P. malarie. Due to the development of resistance, monotherapy is not recommended. The current standard of care includes artemisinin-based drugs combined with blood shizontocides having independent modes of action (1). P. vivax and P. ovale merozoites in the liver can progress to hypnozoites (latent stage). In that case primaquine, as the only available hypnozoitocide, must be included in the therapy (2). Recently, the emergence of the multi-drug resistant Plasmodium strains has rendered the exiting therapy ineffective and urged discovery of new compounds with novel mechanisms of action (1). One of the methods for finding new chemical entities is to combine two pharmacophores in one molecule, i.e. to prepare hybrid drugs, which should have two independent modes of action (1, 3). That strategy has already been employed by our group, leading to primaquine-cinnamic acid conjugates (4). Human hystone deacethylases (HDACs) play crucial roles in modulating mammalian cell chromatin structure, transcription and gene expression. HDACs are also identified as regulators of transcription in P. falciparum. Out of five P. falciparum HDACs, three are Zn-dependent enzymes, prone to inhibition with SAHA (suberoilanilide hydroxamic acid, vorinostat), the known inhibitor of human HDACs, and registered anticancer drug. Inhibition of P. falciparum HDACs has been reported to effectively kill the parasites (5). Such finding prompted us to design sahaquines, SAHA- primaquine conjugates, in which both modes of action are expected to be retained: HDAC inhibition which leads to blood shizontocidal activity, and liver hypnozoitocidal activity. To fully test our hypothesis, the following features were varied: the length and nature of the linker between primaquine and hydroxamic acid moiety (saturated or unsaturated alkyl, or aryl linker), as well as the substitution of the hydroxamic acid moiety, leading to 4 different types of derivatives: O-benzyl hydroxamic acids 4, unsubstituted hydroxamic acids 5, O-methyl hydroxamic acids 6 and N-methyl hydroxamic acids 7. The synthetic path leading to the products was straightforward and the yields were high. Evaluation of HDAC inhibition and antimalarial activity is in progress.

vorinostat, primaquine, hybrid drugs, malaria, hystone deacethylase

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