NaI-Mediated Electrochemical Cyclization-Desulfurization for the Synthesis of N-Substituted 2-Aminobenzimidazoles.

An electrochemical method for the synthesis of N-substituted 2-aminobenzimidazoles through a NaI-mediated desulfurization-cyclization process is reported. This electrosynthesis method utilizes cost-effective NaI as both a mediator and an electrolyte in a catalytic amount (0.2 equiv), replacing traditional oxidizing reagents. N-Substituted o-phenylenediamines and isothiocyanates undergo a thiourea formation/cyclization/desulfurization process to provide N-substituted 2-aminobenzimidazoles (55 examples, up to 98% yield) in a single reaction vessel. Importantly, this electrochemical methodology is applicable to gram-scale synthesis, maintaining reaction efficiency.

Electrochemical NaI-mediated one-pot synthesis of guanidines from isothiocyanates via tandem addition-guanylation.

In this study, we present an electrochemical approach for the synthesis of guanidines from isothiocyanates and amines in a single reaction vessel. This one-pot operation takes place in aqueous media, utilizing an undivided cell setup with NaI serving as both the electrolyte and mediator. The process involves the in situ generation of thiourea, followed by electrolytic guanylation with amines. Under ambient temperature conditions, we successfully demonstrated the formation of 30 different guanidine compounds, achieving yields ranging from fair to excellent. Furthermore, the synthesis method could be carried out on a gram scale with a good yield. This protocol stands out for its cost-effectiveness, step-economical design, high tolerance towards various functional groups, and environmentally friendly reaction conditions.

Dibromopinocembrin and Dibromopinostrobin Are Potential Anti-Dengue Leads with Mild Animal Toxicity.

Dengue infection is one of the most deleterious public health concerns for two-billion world population being at risk. Plasma leakage, hemorrhage, and shock in severe cases were caused by immunological derangement from secondary heterotypic infection. Flavanone, commonly found in medicinal plants, previously showed potential as anti-dengue inhibitors for its direct antiviral effects and suppressing the pro-inflammatory cytokine from dengue immunopathogenesis. Here, we chemically modified flavanones, pinocembrin and pinostrobin, by halogenation and characterized them as potential dengue 2 inhibitors and performed toxicity tests in human-derived cells and in vivo animal model. Dibromopinocembrin and dibromopinostrobin inhibited dengue serotype 2 at the EC50s of 2.0640 ± 0.7537 and 5.8567 ± 0.5074 µM with at the CC50s of 67.2082 ± 0.9731 and >100 µM, respectively. Both of the compounds also showed minimal toxicity against adult C57BL/6 mice assessed by ALT and Cr levels in day one, three, and eight post-intravenous administration. Computational studies suggested the potential target be likely the NS5 methyltransferase at SAM-binding pocket. Taken together, these two brominated flavanones are potential leads for further drug discovery investigation.

The 8-bromobaicalein inhibited the replication of dengue, and Zika viruses and targeted the dengue polymerase.

Dengue and Zika viruses are mosquito-borne flaviviruses burdening millions every year with hemorrhagic fever and neurological symptoms. Baicalein was previously reported as a potential anti-flaviviral candidate and halogenation of flavones and flavanones potentiated their antiviral efficacies. Here, we reported that a chemically modified 8-bromobaicalein effectively inhibited all dengue serotypes and Zika viruses at 0.66-0.88 micromolar in cell-based system. The compound bound to dengue serotype 2 conserved pocket and inhibited the dengue RdRp activity with 6.93 fold more than the original baicalein. Moreover, the compound was mildly toxic against infant and adult C57BL/6 mice despite administering continuously for 7 days. Therefore, the 8-bromobaicalein should be investigated further in pharmacokinetics and efficacy in an animal model.