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 k_inact 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.

Harmicines represent hybrid compounds composed of β-carboline alkaloid harmine and cinnamic acid derivatives (CADs). In this paper we report the synthesis of amide-type harmicines and the evaluation of their biological activity. N-harmicines 5a–f and O-harmicines 6a–h were prepared by a straightforward synthetic procedure, from harmine-based amines and CADs using standard coupling conditions, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIEA). Amide-type harmicines exerted remarkable activity against the erythrocytic stage of P. falciparum, in low submicromolar concentrations, which was significantly more pronounced compared to their antiplasmodial activity against the hepatic stages of P. berghei. Furthermore, a cytotoxicity assay against the human liver hepatocellular carcinoma cell line (HepG2) revealed favorable selectivity indices of the most active harmicines. Molecular dynamics simulations demonstrated the binding of ligands within the ATP binding site of PfHsp90, while the calculated binding free energies confirmed higher activity of N-harmicines 5 over their O-substituted analogues 6. Amino acids predominantly affecting the binding were identified, which provided guidelines for the further derivatization of the harmine framework towards more efficient agents.

Seven bis(2-picolyl)amine (bpa) and five iminodiacetamide (imda) ligands were prepared with different modifications in their side chain structure. The coordination properties of the ligands (L) were influenced by changes in the aliphatic linker length (C1, C2, or C3), amide group isomers and type of chiral terminal group. Complexation with Cu(II) afforded two polymorphs of a ML complex which features tetradentate coordination of a ligand with C2 linkers, while crystal structures of three trans–fac ML₂ complexes with Cu(II) and Ni(II) show tridentate coordination of ligands with a C3 linker. The stoichiometry and stereochemistry of Zn(II) and Cu(II) complexes was further studied in solution by NMR and UV-Vis spectroscopy. DFT calculations gave an insight into the relative stability of isomers, as well as potential hydrogen bonding between two ligands in a ML₂ complex. Furthermore, ML complexes of Cu(II) exhibited DNA cleavage activity.

The antiepileptic drug carbamazepine (CBZ) is one of the most persistent pharmaceuticals in the environment. Its chemical fate is influenced by the type of wastewater treatment. This study sets out to determine the degradation mechanism and products in the reaction between CBZ and hypochlorous acid (HOCl), which is the main chlorinating species in water. In the search for the most feasible pathways of HOCl-induced transformations of CBZ, a quantum chemical approach was employed. Chlorination and epoxidation of CBZ are two initial, competitive processes that result in two key intermediates: N-chloramide and 10,11-epoxide. The calculated free energy barriers (ΔG^‡ ₂₉₃) for these reactions are 105.7 and 95.7 kJ mol⁻¹ resp., which is in agreement with the experimental energy barrier of 98.2 kJ mol⁻¹. All transformation products detected in chlorination experiments were located by computational models, and the reaction mechanism underlying their formation was described in detail. Different computational methods (density functional and ab initio theory) were applied, and the double hybrid B2-PLYPD functional was found to be superior in terms of efficiency and accuracy. Of special interest are oxoiminostilbene and formylacridine, which are the final products in the degradation cascade. Their exceptional thermodynamic stability, as predicted by quantum chemical methods, suggests that these structures should be considered as recalcitrants in chlorinated waters. Fruitful interplay between computational models and experimental data proves that the quantum chemical approach can be used as a predictive tool in environmental degradation studies.