Synthesis of 5-phenoxyprimaquine derivatives and their tetraoxane conjugates as anti-malarial agents

Abstract

Currently, the development of the new anti-malarial drug for the treatment of the increasing drug-resistant strains of malaria was necessary. Therefore, this research was performed by synthesis and evaluation of their antimalarial activity for the development of primaquine which currently was used for anti-malarial drug. The substituents group on 5-phenoxyprimaquine derivatives which had the highest therapeutic index and less toxicity than primaquine were emphasized. The effect of substituted group at para position was studied. Three new derivatives with CN (7e), CF3 (7g), CONH2 (7h) substituents, and five known derivatives with OMe (7b), Br (7c), Cl (7d), F (7f) substituents and the unsubstituted derivative (7a) of primaquine were synthesized. Their structures were characterized by 1H, 13C, 19F NMR and HRMS techniques. In addition, all synthesized compounds were evaluated for their anti-malarial activity using Malaria SYBR Green I-base fluorescence (MSF) assay against P. falciparum 3D7 in the blood-stage. 7a exhibited the greatest inhibitory effects with the IC50 value of 3.65 ± 0.39 µM comparing with primaquine (IC50 = 11.33 ± 0.79 µM) and another derivative with IC50 values ranging from 4.62 to 13.5 µM. Subsequently, 7a conjugated with tetraoxane 14 using a linker of four carbon to afford new 5-phenoxy primaquine-tetraoxane conjugated (15). Pleasingly, 15 exhibited inhibitory effects with IC50 values of 0.38 ± 0.11 µM, which was 30-fold more potent than that of the primaquine. Moreover, new compound 7e and 15 with high antimalarial activity had selectivity index (SI) values of more than 25 and 45.61, respectively.