The rapid emergence of drug resistance to the current antimalarial agents has led to the urgent need for the discovery of new and effective compounds. In this work, a series of 5-phenoxy primaquine analogs with 8-aminoquinoline core (7a–7h) was synthesized and investigated for their antimalarial activity against Plasmodium falciparum. Most analogs showed improved blood antimalarial activity compared to the original primaquine. To further explore a drug hybrid strategy, a conjugate compound between tetraoxane and the representative 5-phenoxy-primaquine analog 7a was synthesized. In our work, the hybrid compound 12 exhibited almost a 30-fold increase in the blood antimalarial activity (IC50 = 0.38 ± 0.11 μM) compared to that of primaquine, with relatively low toxicity against mammalian cells (SI = 45.61). Furthermore, we found that these 5-phenoxy primaquine analogs and the hybrid exhibit significant heme polymerization inhibition, an activity similar to that of chloroquine, which could contribute to their improved antimalarial activity. The 5-phenoxy primaquine analogs and the tetraoxane hybrid could serve as promising candidates for the further development of antimalarial agents.

A flavonoid is a versatile core structure with various cellular, immunological, and pharmacological effects. Recently, flavones have shown anti-dengue activities by interfering with viral translation and replication. However, the molecular target is still elusive. Here we chemically modified apigenin by adding an alkyne moiety into the B-ring hydroxyl group. The alkyne serves as a chemical tag for the alkyne-azide cycloaddition reaction for subcellular visualization. The compound located at the perinuclear region at 1 and 6 h after infection. Interestingly, the compound signal started shifting to vesicle-like structures at 6 h and accumulated at 24 and 48 h after infection. Moreover, the compound treatment in dengue-infected cells showed that the compound restricted the viral protein inside the vesicles, especially at 48 h. As a result, the dengue envelope proteins spread throughout the cells. The alkyne-tagged apigenin showed a more potent efficacy at the EC50 of 2.36 ± 0.22, and 10.55 ± 3.37 µM, respectively, while the cytotoxicities were similar to the original apigenin at the CC50 of 70.34 ± 11.79, and 82.82 ± 11.68 µM, respectively. Molecular docking confirmed the apigenin binding to the previously reported target, ribosomal protein S9, at two binding sites. The network analysis, homopharma, and molecular docking revealed that the estrogen receptor 1 and viral NS1 were potential targets at the late infection stage. The interactions could attenuate dengue productivity by interfering with viral translation and suppressing the viral proteins from trafficking to the cell surface.

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.