Tocainide Hydrochloride

Three analogues of To042, a tocainide‐related lead compound recently reported for the treatment of myotonia, were synthesized and evaluated in vitro as skeletal muscle sodium channel blockers possibly endowed with enhanced use‐dependent behavior. Patch‐clamp experiments on hNav1.4 expressed in HEK293 cells showed that N‐[(naphthalen‐1‐yl)methyl]‐4‐[(2,6‐dimethyl)phenoxy]butan‐2‐amine, the aryloxyalkyl bioisostere of To042, exerted a higher use‐dependent block than To042 thus being able to preferentially block the channels in over‐excited membranes while preserving healthy tissue function. It also showed the lowest active transport across BBB according to the results of P‐glycoprotein (P‐gp) interacting activity evaluation and the highest cytoprotective effect on HeLa cells. Quantum mechanical calculations and dockings gave insights on the most probable conformation of the aryloxyalkyl bioisostere of To042 in solution and the target residues involved in the binding, respectively. Both approaches indicated the conformations that might be adopted in both the unbound and bound state of the ligand. Overall, N‐[(naphthalen‐1‐yl)methyl]‐4‐[(2,6‐dimethyl)phenoxy]butan‐2‐amine exhibits an interesting toxico‐pharmacological profile and deserves further investigation.

The large-scale production and usage of tetrabromobisphenol A (TBBPA) and its analogues have caused widespread contamination, raising concern about their potential endocrine disruption effects on both humans and ecosystems. In the present study, debromination and unknown mixed bromine/chlorine transformation products of TBBPA (X-BBPA) were screened in dust samples from an e-waste dismantling site. Five monochloro products (2-chloro-2',6,6'-TriBBPA, 2-chloro-2',6-DiBBPA, 2-chloro-2',6'-DiBBPA, 2-chloro-2'-MoBBPA, and 2-chloro-6-MoBBPA) and two dichloro products (2,2'-dichloro-6,6'-DiBBPA and 2,2'-dichloro-6-MoBBPA) were successfully synthesized and structurally identified. TBBPA and its transformation products were detected by comparison of their mass spectra and retention times with those of synthetic standards. The mean concentration of X-BBPA was 1.63 × 10⁴ ng/g in e-waste dismantling workshop dust samples based on dry weight, which was at a similar level to TBBPA. However, it was 1 order of magnitude lower than the concentrations of the debromination congeners. Thus, both debromination and chlorine-bromine exchange may be important reactions during the thermal processing of e-waste. The results on mixed chlorinated/brominated TBBPA transformation products provided new insights into TBBPA transformation. The elevated levels of the transformation products of TBBPA suggested that these products should be targeted to avoid underestimation of possible health risks.