Kalay, Erbay; Demir, Yeliz; Türkeş, Cüneyt; Aslan, Osman Nuri; Pezik, Esra; Şahin, Engin

Aldose reductase (ALR2), a key enzyme in the polyol pathway, plays a significant role in the onset and progression of diabetic complications, rendering it a critical pharmacological target. In this study, a novel series of twenty-four sulfonate ester-functionalized rhodanine derivatives (compounds 1–24) were rationally designed, synthesized via Knoevenagel condensation, and comprehensively evaluated for their inhibitory activity against ALR2. Spectroscopic and spectrometric methods confirmed the structural integrity of the synthesized compounds. In vitro enzyme inhibition assays revealed that all compounds acted as competitive inhibitors, with several analogues, particularly compounds 6 and 8, exhibiting stronger ALR2 inhibition (Ki = 0.43 µM and 0.48 µM, respectively) than the reference drug epalrestat (Ki = 0.98 µM). Structure–activity relationship (SAR) analysis highlighted the critical influence of para-substituted electron-donating (e.g., methyl) and electron-withdrawing (e.g., nitro, halogen) groups on binding potency. Molecular docking of the most potent inhibitor (compound 6) demonstrated a stable binding pose supported by key interactions, including hydrogen bonding with His110 and π–π stacking with Phe122. In silico ADME profiling confirmed favorable drug-likeness properties for all derivatives. Cytotoxicity studies on L929, A549, and RG-2 cell lines revealed that most compounds were less toxic than the reference drug at lower concentrations, with compound 8 showing a promising cytotoxic profile. These findings position rhodanine–sulfonate hybrids as promising scaffolds for the development of next-generation ALR2 inhibitors for the treatment of diabetic complications.

Kuzu, Burak; Alagoz, M. Abdullah; Demir, Yeliz; Gulcin, Ilhami; Burmaoglu, Serdar; Algul, Oztekin

An important research topic is the discovery of multifunctional compounds targeting different disease-causing components. This research aimed to design and synthesize a series of 2-aryl-6-carboxamide benzoxazole derivatives that inhibit cholinesterases on both the peripheral anionic and catalytic anionic sides. Compounds (7–48) were prepared from 4-amino-3-hydroxybenzoic acid in three steps. The Ellman test, molecular docking with Maestro, and molecular dynamics simulation studies with Desmond were done (Schrodinger, 12.8.117). Compound 36, the most potent compound among the 42 new compounds synthesized, had an inhibitory concentration of IC50 12.62 nM for AChE and IC50 25.45 nM for BChE (whereas donepezil was 69.3 nM and 63.0 nM, respectively). Additionally, compound 36 had docking values ​​of − 7.29 kcal/mol for AChE and − 6.71 kcal/mol for BChE (whereas donepezil was − 6.49 kcal/mol and − 5.057 kcal/mol, respectively). Furthermore, molecular dynamics simulations revealed that compound 36 is stable in the active gorges of both AChE (average RMSD: 1.98 Å) and BChE (average RMSD: 2.2 Å) (donepezil had average RMSD: 1.65 Å and 2.7 Å, respectively). The results show that compound 36 is a potent, selective, mixed-type dual inhibitor of both acetylcholinesterase and butyrylcholinesterase. It does this by binding to both the catalytically active and peripheral anionic sites of cholinesterases at the same time. These findings show that target compounds may be useful for establishing the structural basis for new anti-Alzheimer agents.

Kızılcan, Dilek Şeyma; Güzel, Yahya; Türkmenoğlu, Burçin

The behavior of a molecule within its environment is governed by chemical fields present in 3D space. However, beyond local descriptors in 3D, the conformations a molecule assumes, and the resulting clusters also play a role in influencing structure–activity models. This study focuses on the clustering of atoms according to the vector space of four atoms aligned in the Z-Matrix Reference system for molecular similarity. Using 3D-QSAR analysis, it was aimed to determine the pharmacophore groups as interaction points in the binding region of the β2-adrenoceptor target of fenoterol stereoisomers. Different types of local reactive descriptors of ligands have been used to elucidate points of interaction with the target. Activity values for ligand-receptor interaction energy were determined using the Levenberg–Marquardt algorithm. Using the Molecular Comparative Electron Topology method, the 3D pharmacophore model (3D-PhaM) was obtained after aligning and superimposing the molecules and was further validated by the molecular docking method. Best guesses were calculated with a non-output validation (LOO-CV) method. Finally, the data were calculated using the ‘graphic fingerprint’ technique. Based on the eLKlopman (Electrostatic LUMO Klopman) descriptor, the Q2 value of this derivative set was calculated as 0.981 and the R2ext value is calculated as 0.998.

Demir, Yeliz; Tokalı, Feyzi Sinan; Kalay, Erbay; Türkeş, Cüneyt; Tokalı, Pelin; Aslan, Osman Nuri; Şendil, Kıvılcım; Beydemir, Şükrü

In the polyol pathway, aldose reductase (AR) catalyzes the formation of sorbitol from glucose. In order to detoxify some dangerous aldehydes, AR is essential. However, due to the effects of the active polyol pathway, AR overexpression in the hyperglycemic state leads to microvascular and macrovascular diabetic problems. As a result, AR inhibition has been recognized as a potential treatment for issues linked to diabetes and has been studied by numerous researchers worldwide. In the present study, a series of acyl hydrazones were obtained from the reaction of vanillin derivatized with acyl groups and phenolic Mannich bases with hydrazides containing pharmacological groups such as morpholine, piperazine, and tetrahydroisoquinoline. The resulting 21 novel acyl hydrazone compounds were investigated as an inhibitor of the AR enzyme. All the novel acyl hydrazones derived from vanillin demonstrated activity in nanomolar levels as AR inhibitors with IC 50 and K I values in the range of 94.21 ± 2.33 to 430.00 ± 2.33 nM and 49.22 ± 3.64 to 897.20 ± 43.63 nM, respectively. Compounds 11c and 10b against AR enzyme activity were identified as highly potent inhibitors and showed 17.38 and 10.78-fold more effectiveness than standard drug epalrestat. The synthesized molecules’ absorption, distribution, metabolism, and excretion (ADME) effects were also assessed. The probable-binding mechanisms of these inhibitors against AR were investigated using molecular-docking simulations. Graphical abstract: [Figure not available: see fulltext.]

Lolak, Nebih; Akocak, Süleyman; Durgun, Mustafa; Duran, Hatice Esra; Necip, Adem; Türkeş, Cüneyt; Işık, Mesut; Beydemir, Şükrü

Abstract: To discover alternative substances to compounds used to treat many diseases, especially treating Alzheimer’s disease (AD) and Parkinson’s disease targeting carbonic anhydrase (hCA) and acetylcholinesterase (AChE) enzymes, is important. For this purpose, a series of novel bis-ureido-substituted sulfaguanidine (SG1–4) and sulfisoxazole (SO1–4) derivatives were synthesized, and their inhibitory capacities were screened against hCA isoenzymes (hCA I and II) and AChE. Possible binding mechanisms of inhibitors to the active site were elucidated by in silico studies, and the results were supported by in vitro results. Moreover, the percent radical scavenging capacities of the derivatives were also evaluated. The derivatives (SG1–4 and SO1–4) were more effective against hCAs compared to standard drug acetazolamide (KI values of 98.28–439.17 nM for hCA I and II, respectively) and exhibited the highest inhibition with the KIs in the ranges of 2.54 ± 0.50–41.02 ± 7.52 nM for hCA I, 11.20 ± 2.97–67.14 ± 13.58 nM for hCA II, and 257.60 ± 27.84–442.60 ± 52.13 nM for AChE. Also, compounds SG1 and SO1 also showed ABTS radical scavenging activity at the rate of 70% and 78%, respectively. These results will contribute to the literature for the rational design and synthesis of new potent and selective inhibitors targeting hCAs and AChE with multifunctional effects such as radical scavenging as well as inhibition. Graphical abstract: This study focused on the synthesis and inhibitory effects of bis-ureido-substituted sulfaguanidine (SG1–4) andsulfisoxazole (SO1–4) derivatives against human hCA I and II isoforms and AChE. In order to test synthesizedderivatives’ free radical scavenging potentials were the DPPH and ABTS assays. In silico studies elucidatedpossible binding mechanisms of inhibitors to the active site.[Figure not available: see fulltext.].

Güleç, Özcan; Türkeş, Cüneyt; Arslan, Mustafa; Demir, Yeliz; Yeni, Yeşim; Hacımüftüoğlu, Ahmet; Ereminsoy, Ergün; Küfrevioğlu, Ömer İrfan; Beydemir, Şükrü

Abstract: The acetylcholinesterase and carbonic anhydrase inhibitors (AChEIs and hCAIs) remain key therapeutic agents for many bioactivities such as anti-Alzheimer and antiobesity antiepileptic, anticancer, antiinfective, antiglaucoma, and diuretic effects. Here, it has been attempted to discover novel multi-target AChEIs and hCAIs that are highly potent, orally bioavailable, may be brain penetrant, and have higher effectiveness at lower doses than tacrine and acetazolamide. After detailed investigations both in vitro and in silico, novel N-substituted sulfonyl amide derivatives (6a–j) were determined to be highly potent inhibitors for AChE and hCAs (KIs are in the range of 23.11–52.49 nM, 18.66–59.62 nM, and 9.33–120.80 nM for AChE, hCA I, and hCA II, respectively). Moreover, according to the cytotoxic effect studies, such as the ADME-Tox, cortex neuron cells, and neuroblastoma SH-SY5Y cell line, compounds 6a, 6d, and 6h, which are the most potent representative versus the target enzymes, were identified as orally bioavailable, highly selective, and brain preferentially distributed AChEIs and hCAIs. The docking studies revealed precise binding modes between 6a, 6d, and 6h and hCA II, hCA I, and AChE, respectively. The results presented here might provide a solid basis for further investigation into more potent AChEIs and hCAIs. Graphical abstract: [Figure not available: see fulltext.]