Abstract Malaria is a tropical disease caused by several species of the Plasmodium genus with P. falciparum being the most prevalent and dangerous specie. Despite the plethora of antimalarial drugs available, there is still the pressing need to develop new agents to treat the disease; this is due to problems with existing medications such as toxicity and parasite resistance to previously effective drugs. Histone deacetylase enzyme catalyzes the removal of the acetyl group from histone lysine residues and has been shown to play a key role in the regulation of gene expression in the plasmodium parasite. In the present study, the concept of covalent bitherapy was employed to synthesize a compound in which the Artemisinin pharmacophore is chemically conjugated to a histone deacetylase inhibitor via an ester linkage. The antiplasmodial activity of the compound was evaluated against a standard sensitive strain of Plasmodium falciparum. They cytotoxicity of the compound was also evaluated using the Brine Shrimp lethality assay. The conjugate showed good activity against the parasite with IC50: value of 5.369 nM as compared to the standard drugs Chloroquine (IC50: 13.003 nM) and Dihydroartemisinin alone (IC50: 9.968 nM). The conjugate showed good activity and provides a good starting point for the development of a new class of antimalarial agents.
Keywords Histone deacetylase inhibitor, Dihydroartemisinin, Phenylbutyric acid, Malaria, Hybrid.