5-Phenoxy Primaquine Analogs and the Tetraoxane Hybrid as Antimalarial Agents

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.     

Alkyne-Tagged Apigenin,a Chemical Tool to Navigate Potential Targets of Flavonoid Anti-Dengue Leads

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.     

Diverted total synthesis of melodorinol analogues and evaluation of their cytotoxicity

A series of melodorinol analogues were synthesized via a diverted total synthesis approach, leading to structural modifications on several regions of the molecule. Their cytotoxicity was evaluated against five human cancer cell lines (KB, HeLa-S3, MCF-7, HT-29 and A549). Structure-activity relationship studies revealed key parameters that affect the cytotoxicity. In particular, the novel 4-bromo-furanone analogues exhibited greater cytotoxicity compared to the corresponding non-brominated analogues. The stereochemistry at C-6 and the nature of acyl substituents on the C-6 and C-7 hydroxyl groups also play an important role. The most potent analogues exhibit approximately 15-fold higher cytotoxicity towards KB and HeLa-S3 than melodorinol and also show exceptionally high potency against MCF-7, HT-29 and A549 cell lines.     

18F‐Labeling of Aryl‐SCF3, ‐OCF3 and ‐OCHF2 with [18F]Fluoride

We report that halogenophilic silver(I) triflate permits halogen exchange (halex) nucleophilic ¹⁸F‐fluorination of aryl‐OCHFCl, ‐OCF₂Br and ‐SCF₂Br precursors under mild conditions. This Ag^I‐mediated process allows for the first time access to a range of ¹⁸F‐labeled aryl‐OCHF₂, ‐OCF₃ and ‐SCF₃ derivatives, inclusive of [¹⁸F]riluzole. The ¹⁸F‐labeling of these medicinally important motifs expands the radiochemical space available for PET applications.     

Synthesis of Flavones through NaI-Mediated Electrochemical Cyclization of Chalcones

A mild electrochemical oxidative cyclization for the synthesis of flavones from easy-access 2’-hydroxychalcones was developed using an inexpensive NaI as mediator and electrolyte under ambient temperature in a mixture of EtOH and H₂O as solvent. This method was successfully applied to synthesize 26 examples of flavones from a variety of functionalized 2’-hydroxychalcones. A gram-scale formal synthesis of bioactive scutellarein was successfully demonstrated. Control experiments were conducted to disclose a possible indirect oxidation via in situ generation of iodine. The main advantages of this reaction include its broad substrate scope, scalability, ability to operate with benign solvent, and no requirement for strong oxidizing agents and external additives.