Bojan P. Bondzic

A visible-light-driven photoredox protocol for the α-amino C(sp ³ )–H heteroarylation of N -aryl pyrrolidines and piperidines with 2-chlorobenzothiazole derivatives in batch and in flow conditions is developed.

Quercetin, a well-known flavonoid with significant medicinal potential, was derivatized at the C8 position with a tetrahydroisoquinoline (THIQ) moiety, and physicochemical and pharmacological properties, inhibition potential, antioxidant activity, and cytotoxicity of new compounds were evaluated. Physicochemical and pharmacological properties, including lipophilicity, membrane permeability, and P-glycoprotein substrate affinity, were assessed theoretically using the SwissADME software. The metal-chelating ability of the new compounds was evaluated on metal ions Fe²⁺, Zn²⁺, and Cu²⁺, whose homeostasis disruption is linked to the development of Alzheimer’s disease. Inhibition potential was tested on the cholinergic enzymes acetylcholinesterase and butyrylcholinesterase, as well as Na⁺, K⁺-ATPase, an enzyme commonly overexpressed in tumours. Antioxidant potential was assessed using the DPPH assay. Cytotoxicity studies were conducted on healthy MRC-5 cells and three cancer cell lines: HeLa, MDA-231, and MDA-468. The results indicated that derivatization of quercetin with THIQ yielded compounds with lower toxicity, preserved chelating ability, improved antioxidant potential, increased selectivity toward the cholinergic enzyme butyrylcholinesterase, and enhanced inhibition potential toward Na⁺, K⁺-ATPase and butyrylcholinesterase compared to quercetin alone. Therefore, the synthesized derivatives represent compounds with an improved profile and could be promising candidates for further optimization in developing drugs for neurodegenerative and cancer diseases.

We have synthesized 22 C-1 functionalized-N-aryl-1,2,3,4-tetrahydroisoquinoline derivatives showing biological activities towards cholinergic enzymes. Synthesis was performed using visible-light-promoted photo-redox chemistry, starting from a common intermediate, and the application of this synthetic methodology drastically simplified synthetic routes and purification of desired compounds. All synthesized derivates were divided into four groups based on the substituents in the C-1 position, and their inhibition potencies towards two cholinergic enzymes, acetyl- and butyrylcholinesterase were evaluated. Most potent derivatives were selected, and kinetic analysis was further carried out to obtain insights into the mechanisms of inhibition of these two enzymes. Further validation of the mode of inhibition of cholinergic enzymes by the two most potent THIQ compounds, 3c and 3i, was performed using fluorescence-quenching titration studies. Molecular docking studies further confirmed the proposed mechanism of enzymes’ inhibition. In silico predictions of physicochemical properties, pharmacokinetics, drug-likeness, and medicinal chemistry friendliness of the selected most potent derivatives were performed using Swiss ADME tool. This was followed by UPLC-assisted log P determination and in vitro BBB permeability studies performed in order to assess the potential of the synthesized compounds to pass the BBB.

Lipophilicity expressed by the n-octanol/water partition coefficient, logPo/w, is one of the physicochemical properties of the drug that determines its solubility, the ability to penetrate through cell barriers, and the probability of transport to the molecular target. It also affects pharmacokinetic processes such as adsorption, distribution, metabolism and excretion of a drug. The aim of this study was to evaluate the influence of substitution with different functional groups of biologically active N-aryl-tetrahydroisoquinoline derivatives (THIQs) on the logPo/w. The logPo/w for a set of six N-aryl-tetrahydroisoquinoline derivatives was estimated using reversed-phase ultra performance liquid chromatography (RP-UPLC) technique using a C18 column as a stationary phase and water/acetonitrile mixtures as mobile phases.

Functionalization of biologically important tetrahydroisoquinolines (THIQs) is achieved under visible light irradiation in the presence of Ir photocatalyst under microflow conditions. N– Benzoxazol and N-Benzthiazol substituted THIQs were alkylated at C1 position through Ir promoted C-H oxidation/organocatalyzed Mannich reaction sequence. Reactions were optimized in batch conditions regarding photo- and organocatalyst, temperature and light source and subsequently transferred to the custom-made polymeric type microreactor (polydimethylsiloxane polymer, PDMS). Application of the oxygen porous PDMS microreactor proved crucial regarding Ir catalyzed C-H oxidation step and overall reaction performance.

The potential therapeutic applications of metal chelation in the treatment of Alzheimer’s disease have attracted significant attention due to the involvement of metal ion dysregulation in the pathology of the disease. This study investigates the chelation properties of a novel compound, tetrahydroisoquinoline-derivatized quercetin, THIQ-Q, with Cu²⁺, Zn²⁺, and Fe²⁺ ions, aiming to evaluate its efficacy as a potential treatment for Alzheimer’s disease. Using UV/Vis spectroscopy we analysed the binding interactions and stoichiometry of the compound with these metal ions. Obtained results indicate that the newly synthesized compound, THIQ-Q, forms 2:1 complex with Cu²⁺ and Zn²⁺ while 1:1 complex is formed with Fe2+, which indicate its potential as a therapeutic agent in managing metal ion dysregulation in Alzheimer’s disease.

The aim of this study was to test the potential of Cu-based MOF for removing chlorpyrifos. The effect of ethanol concentration on removal potential was evaluated by testing the MOF’s performance in 100% and 25% ethanolic solutions. Additionally, the effects of MOF concentration and chlorpyrifos concentration were assessed. The results indicated that the selected MOF, [{Cu4(μ3-Hbes)4(μ-hba)}K(H2O)3]n, shows promising potential for application in water remediation.

Visible light promoted photoredox catalyzed formation of α-amino radicals from cyclic tertiary amine compounds and their subsequent addition to Michael acceptors performed in flow conditions allowed access to a wide range of functionalized N-aryl-substituted tetrahydroisoquinolines (THIQs) and N-aryl-substituted tetrahydro-β-carbolines (THBCs). Visible light in conjunction with Ru(bpy)₃Cl₂ photocatalyst allowed the formation and high reactivities of α-amino radicals in flow conditions at room temperature. These reactions gave valuable products with high efficiencies; some previously unavailable reaction pathways photo or thermal reaction conditions; i.e. direct synthesis of 1-substituted (THBCs) via α-amino radical path were successfully realized in flow. The use of custom-made FEP tube microreactor proved to be the key to succesfull α-amino-radical formation and overall reaction performance in flow. Three types of light transparent custom-made microfluidic devices were tested, among them glass/silicon and FEP type reactor showed very good results in the conversion of tested compounds. Plausible reaction mechanism is proposed in accordance with known principles of photo activation of tertiary amines. Graphical abstract Visible light promoted C(sp3)-H functionalization of N-aryl-protected tetrahydroisoquinolines and N-aryl-protected tetrahydro-β-carbolines in microflow conditions via a-amino radical pathway with various coupling partners in excellent yields and efficiencies.

A catalytic, asymmetric Diels-Alder reaction of α-fluoro α,β-unsaturated aldehydes and cyclopentadiene was developed using diarylprolinol silyl ether as an organocatalyst. The reaction proceeds in toluene with trifluoroacetic acid as an additive (condition A). Perchloric acid salt of diarylprolinol silyl ether also promotes the reaction using water as a reaction medium (condition B). In both cases, excellent exo-selectivity and enantioselectivity were obtained with generation of a fluorinated quaternary chiral center.