Design, Synthesis, and Activity Evaluation of Fluorine-Containing Scopolamine Analogues as Potential Antidepressants

Abstract

This study aimed to develop novel rapid-acting antidepressants with sustained efficacy and favorable safety profiles. We designed and synthesized a series of fluorine-containing scopolamine analogues and evaluated their antidepressant potential. In vitro cytotoxicity assays showed that most of these compounds exhibited minimal toxicity against neuronal and non-neuronal mammalian cell lines (IC 50 > 100 μM). The antidepressant activities of the compounds were evaluated using the tail suspension test, and S-3a was identified as a lead compound with potent and sustained antidepressant effects. Behaviorally, S-3a alleviated depressive symptoms in mice and displayed a higher cognitive safety margin than scopolamine. Toxicological assessments confirmed S-3a's safety, while pharmacokinetics showed a rapid clearance (half-life: 16.6 min). Mechanistically, S-3a antagonized M 1 receptors and elevated BDNF levels, suggesting its potential as an antidepressant for further exploration.

Iodine(III)-Mediated Trifluoroacetylation of a C(sp2)–H or C(sp)–H Bond with Masked Trifluoroacyl Reagents

“…Fluorine-containing compounds have attracted a significant amount of attention from medicinal and synthetic chemists, due to their enhanced physicochemical and biological properties . In particular, trifluoromethyl ketone represents one of the most important fluorine-containing scaffolds, widely present in biologically active molecules (Scheme a) .…”