Ferhan Tümer

The development of multifunctional small molecules capable of simultaneously modulating multiple pathological pathways represents a rational strategy in medicinal chemistry for complex disorders such as Alzheimer's disease (AD) and cancer. Herein, a novel series of methoxyphenol‐based 1,2,3‐triazole hybrids ( 5a–h ) was designed and synthesized via Cu(I)‐catalyzed azide–alkyne cycloaddition (CuAAC). All derivatives were fully characterized by FT‐IR, ¹ H/ ¹³ C NMR spectroscopy, and elemental analysis. Biological evaluation encompassed in vitro antioxidant screening (DPPH•, ABTS• ⁺ , and CUPRAC), acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition (modified Ellman method), and antiproliferative activity against the PC3 prostate cancer cell line using HDF‐1 healthy fibroblasts as a selectivity control. Compound 5c proved the most potent AChE inhibitor (IC ₅₀ = 1.44 ± 0.33 μM; SI = 16.77), while 5h exhibited preferential BuChE inhibition (IC ₅₀ = 11.40 ± 1.25 μM). Enzyme kinetic studies confirmed a mixed‐type inhibition mechanism for both lead compounds, suggesting dual‐site engagement within the cholinesterase gorge. In the antiproliferative assay, 5e and 5c surpassed the reference drug methotrexate (IC ₅₀ = 4.42 ± 0.15 μM) with IC ₅₀ values of 3.57 ± 0.11 μM and 3.89 ± 0.20 μM, respectively, alongside favorable selectivity over healthy fibroblasts. In silico ADMET profiling confirmed drug‐likeness for all derivatives, and DFT calculations at the B3LYP/6‐311++G(d,p) level provided electronic rationale for observed reactivity trends. Molecular docking against human AChE (PDB: 4EY7) and BuChE (PDB: 4BDS) rationalized key stabilizing interactions including π–π stacking with Trp86/Trp286 and hydrogen bonding with active‐site residues. Collectively, these findings identify the methoxyphenol–triazole scaffold as a promising lead platform warranting further optimization for multitarget therapeutic applications in neurodegenerative and oncological disorders.

Novel hybrid compounds, incorporating 4‐iodosulfonamide and 1,2,3‐triazole units, were synthesized and characterized using FT‐IR, NMR, and elemental analysis. Their antioxidant (ABTS, DPPH, Cuprac), cholinesterase inhibition (AChE, BuChE), and anticancer (Caco‐2, PC3) activities were evaluated. In DPPH assays, compounds 13, 6, and 11 showed superior antioxidant activity compared to α‐tocopherol and BHT. Compound 6 exhibited the highest ABTS activity, while compound 9 excelled in Cuprac assays. For cholinesterase inhibition, compounds 8 and 13 outperformed Galantamine against AChE, and compound 9 showed the strongest BuChE inhibition. Antiproliferative studies revealed compound 13's effectiveness against PC3 and compound 9 against Caco‐2. Comprehensive ADMET analysis indicated favorable pharmaceutical properties, including oral absorption via the BBB and GI tract. In silico molecular docking supported these findings, confirming the therapeutic potential of these hybrid structures.

This study aimed to synthesize novel nitrophenol-triazole hybrid molecules, investigate their biological activities (cholinesterase inhibition, antioxidant, and anticancer effects), and profile them using computational methods (molecular docking, ADMET). Eight new hybrid compounds were successfully synthesized, and the crystal structures of compounds 10a and 10g were determined by single-crystal X-ray diffraction analysis. Among the obtained compounds, derivative 10e exhibited notable cholinesterase inhibitory activity with high potency and selectivity against acetylcholinesterase (AChE), demonstrating an IC₅₀ value of 1.56 µM. The compounds displayed promising antioxidant capacity, especially in terms of ABTS radical scavenging activity, with IC₅₀ values ranging narrowly from 8.01 µg/mL (10a) to 8.52 µg/mL (10d). In anticancer activity evaluations, compound 10a showed noteworthy cytotoxicity against the Caco-2 cell line with an IC₅₀ value of 1.77 µM. In silico ADMET analyses predicted that most compounds adhere to Lipinski's Rule of Five and possess a favorable profile. Molecular docking studies elucidated the binding interactions, revealing binding energies of - 10.9 kcal/mol for compound 10e with AChE and - 9.1 kcal/mol for compound 10h with BuChE.

Eight new hybrid constructs containing a series of sulfonamide and 1,2,3-triazole units were designed and synthesized. Anticancer, antioxidant and cholinesterase activities of these hybrid structures were investigated. In our design, the Cu(I)-catalyzed click reaction between N,4-dimethyl-N-(prop-2-yn-1-yl)benzenesulfonamide (6) and aryl azides 8a-h was used. Antioxidant activity values of 9f (IC₅₀: 229.46 ± 0.001 μg/mL) and 9h (IC₅₀: 254.32 ± 0.002 μg/mL) hybrid structures were higher than BHT (IC₅₀: 286.04 ± 0.003 μg/mL) and lower than Ascorbic acid (IC₅₀: 63.53 ± 0.001 μg/mL) and α-Tocopherol (IC₅₀: 203.21 ± 0.002 μg/mL). We determined that the cytotoxic effects of hybrid constructs 9d (IC₅₀: 3.81 ± 0.1084 µM) and 9g (IC₅₀: 4.317 ± 0.0367 µM) against A549 and healthy cell line (HDF) are much better than standard cisplatin (IC₅₀: 6.202 ± 0.0705 µM). It was determined that the AChE inhibitory activities of all synthesized compounds were much better than Galantamine used as a standard. In particular, 9c (IC₅₀: 13.81 ± 0.0026 mM) had ten times better activity than the standard Galantamine (IC₅₀: 136 ± 0.008 mM). The ADMET properties of the molecules have been thoroughly examined and met the criteria for drug-like substances. They also have a high oral absorption rate, as they can effectively cross the blood-brain barrier and are easily absorbed in the gastrointestinal tract. In vitro experiments were confirmed by in silico molecular docking studies.Communicated by Ramaswamy H. Sarma.

New hybrid compounds belonging to the class of 1,4-disubstituted 1,2,3-triazoles were synthesized. The structural characterization of the synthesized compounds was performed using IR, ¹H-NMR, ¹³C NMR and elemental analysis techniques. Diarylketones 1a and 1b were used as starting compounds for the synthesis of triazoles. The corresponding diarylmethanol derivatives (2a,b) were obtained from reduction of ketone units with NaBH₄. Oxyalkynes (3a,b) were obtained by treating the hydroxyl group with NaH in anhydrous THF and then with propargylbromide. The target hybrid structures 6a-n were obtained from the metal-catalyzed "click reaction" of the arylazide and alkyne units. The newly synthesized compounds were structurally analysed using ¹H-NMR, ¹³C-NMR, elemental analysis, LC-MS and FT-IR. The antioxidant and anticancer activities of all compounds were investigated. It has been determined that the new hybrid structures have very good antioxidant and anticancer activities according to the standards. In particular, compounds 6b, 6h, 6i and 6j (IC₅₀: 1.87, 12.5, 7.22, 8.04 µM) showed excellent activity compared to standard 5-Fu (IC₅₀: 40.89 µM). According to the results of molecular docking of compounds 6b and 6i with the highest cancer activity, MetAP-2 was found to have a high affinity through exposed polar and apolar contacts with fundemental residues in the binding pocket. Communicated by Ramaswamy H. Sarma