Topiroxostat

Dinuclear complex [Ir₂(μ-L1)(η⁵-Cp*)₂Cl₂](PF₆)₂ (1) exhibits low micromolar cytotoxic activity in vitro in various human cancer cells (GI₅₀ = 1.7-3.0 μM) and outperformed its mononuclear analogue [Ir(η⁵-Cp*)Cl(L2)]PF₆ (2; GI₅₀ > 40.0 μM); Cp* = pentamethylcyclopentadienyl, L1 = 4-chloro-2,6-bis[5-(pyridin-2-yl)-1,3,4-thiadiazol-2-yl]pyridine, L2 = 5-(pyridin-2-yl)-1,3,4-thiadiazol-2-amine. Compound 1 upregulated the Keap1/Nrf2 oxidative stress-protective pathway in the treated MV4-11 acute myeloid leukemia cells. In connection with the redox-mediated mode of action of 1, its NADH-oxidizing activity was detected in solution (¹H NMR), while NAD⁺ remained intact (with formate as a hydride source). Surprisingly, only negligible NADH oxidation was detected in the presence of the reduced glutathione and ascorbate. Following the results of in-solution experiments, NAD(H) concentration was assessed in 1-treated MV4-11 cancer cells. Besides the intracellular NADH oxidation in the presence of 1, the induced oxidative stress also led to a decrease of NAD⁺, resulting in depletion of both NAD⁺/NADH coenzymes. The discussed findings provide new insight into the biochemical effects of catalytic anticancer compounds that induce cell death via a redox-mediated mode of action.

The article explores the polypharmacological profiling of 4-((5-(decylthio)-4-methyl-4H-1,2,4-triazole-3-yl)methyl)morpholine as a potential antimicrobial agent. The study utilized 15148 electronic pharmacophore models of organisms, ranked by the Tversky index. Detailed analysis revealed classical bonding patterns with selected enzymes, identifying key amino acid residues involved in complex formation. Protein target prediction was conducted through various stages using the Galaxy web service, including ligand structure creation, pharmacophore alignment, and target ranking. The activities of the molecules against 1G6C, 2W6O, 3G7F, 3OWU, 4IVR, and 4TZT proteins were compared. Docking studies with PyMOL and Discovery Studio Visualizer revealed binding to thymidine kinase, thiamine phosphate synthase, and biotin carboxylase with promising binding affinities. These interactions suggest potential antibacterial and antiviral effects, warranting further virtual screening and in-depth studies for the development of effective antimicrobial drugs. Calculations of the molecules were made with the gaussian package program. Calculations were made on the 6-31++g** basis set at B3LYP, HF, and M062X levels with Gaussian software. Afterwards, the 0-100 ns interaction of the molecule with the highest activity was examined.