Hydride Abstraction as the Rate-Limiting Step of the Irreversible Inhibition of Monoamine Oxidase B by Rasagiline and Selegiline: A Computational Empirical Valence Bond Study

Monoamine oxidases (MAOs) catalyze the degradation of a very broad range of biogenic and dietary amines including many neurotransmitters in the brain, whose imbalance is extensively linked with the biochemical pathology of various neurological disorders, and are, accordingly, used as primary pharmacological targets to treat these debilitating cognitive diseases. Still, despite this practical significance, the precise molecular mechanism underlying the irreversible MAO inhibition with clinically used propargylamine inhibitors rasagiline and selegiline is still not unambiguously determined, which hinders the rational design of improved inhibitors devoid of side effects current drugs are experiencing. To address this challenge, we present empirical valence bond QM/MM simulations of the rate-limiting step of the MAO inhibition involving the hydride anion transfer from the inhibitor α-carbon onto the N5 atom of the flavin adenin dinucleotide (FAD) cofactor. The proposed mechanism is strongly supported by the obtained free energy profiles, which confirm a higher reactivity of selegiline over rasagiline, while the calculated difference in the activation Gibbs energies of ΔΔG‡ = 3.1 kcal mol−1 is found to be in very good agreement with that from the measured literature kinact values that predict a 1.7 kcal mol−1 higher selegiline reactivity. Given the similarity with the hydride transfer mechanism during the MAO catalytic activity, these results verify that both rasagiline and selegiline are mechanism-based irreversible inhibitors and offer guidelines in designing new and improved inhibitors, which are all clinically employed in treating a variety of neuropsychiatric and neurodegenerative conditions.

Charge Storage Properties of Nanostructured Poly (3,4–ethylenedioxythiophene) Electrodes Revealed by Advanced Electrogravimetry

PEDOT nanowires (NWs) directly grown on the conducting electrode of quartz resonators enable an advanced electrogravimetric analysis of their charge storage behavior. Electrochemical quartz crystal microbalance (EQCM) and its coupling with electrochemical impedance spectroscopy (ac–electrogravimetry or AC–EG) were used complementarily and reveal that TBA+, BF4− and ACN participate in the charge compensation process with different kinetics and quantity. BF4− anions were dominant in terms of concentration over TBA+ cations and the anion transfer results in the exclusion of the solvent molecules. TBA+ concentration variation in the electrode was small compared to that of the BF4− counterpart. However, Mw of TBA+ is much higher than BF4− (242.3 vs. 86.6 g·mol−1). Thus, TBA+ cations’ gravimetric contribution to the EQCM response was more significant than that of BF4−. Additional contribution of ACN with an opposite flux direction compared with BF4−, led to a net mass gain/lost during a negative/positive potential scan, masking partially the anion response. Such subtleties of the interfacial ion transfer processes were disentangled due to the complementarity of the EQCM and AC–EG methodologies, which were applied here for the characterization of electrochemical processes at the PEDOT NW electrode/organic electrolyte interface.

Cyanomethyl anion transfer reagents for diastereoselective Corey–Chaykovsky cyclopropanation reactions

A readily available sulfonium salt opens up new synthetic pathways to access nitrile cyclopropanes in a highly diastereoselective fashion.

Benzyl anion transfer in the fragmentation of N-(phenylsulfonyl)-benzeneacetamides: a gas-phase intramolecular SNAr reaction

This work is the first example reporting the gas-phase benzyl anion transfer to conduct the intramolecular SNAr reactions.

Anion transfer across “anion channels” at the liquid/liquid interface modified by anion-exchange membrane

A novel strategy is proposed to mimic anion channels and study anion transfer reactions at the water/1,2-dichloroethane (W/DCE) interface modified by a homogeneous anion-exchange membrane (AEM).