Türkeş, Cüneyt; Lolak, Nebih; Duran, Hatice Esra; Yapar, Gönül; Akocak, Suleyman

The conformational and kinetic intricacies of enzyme-ligand interactions are critical for understanding molecular mechanisms underlying metabolic and neurodegenerative pathologies. Herein, we report a rationally designed series of ureido-benzenesulfonamides as dual-acting nanomolar inhibitors targeting aldose reductase (ALR2) and cholinesterases (AChE and BChE). Spectrophotometric inhibition assays revealed that compound 3SA-a displayed exceptional ALR2 affinity (KI = 7.00 ± 0.68 nM), surpassing epalrestat by over 30-fold. Likewise, 3SA-f selectively inhibited BChE with a KI of 24.20 ± 2.26 nM, outperforming tacrine by a factor of 7.8. Molecular docking simulations highlighted distinct dynamic binding modes: 3SA-a engaged ALR2's catalytic cleft through a hydrogen bond with Tyr48 and water-bridged interactions, whereas 3SA-f leveraged π-π stacking and halogen bonding within BChE's extended acyl pocket. These binding orientations were consistent with SAR findings, where meta-sulfonamide placement and halogen substitution optimized selectivity and conformational complementarity. Complementary in silico ADME-Tox predictions confirmed the drug-like nature of all compounds (0 Lipinski/PAINS violations), moderate oral permeability (QPPCaco: 79–85 nm/s), and low CNS exposure (CNS score = −2), aligning with a peripheral mechanism of action. Collectively, this study provides a detailed structural and dynamic framework for dual-target enzyme inhibition, offering a tunable scaffold for future therapeutics targeting the ALR2-ChE axis.

Efeoglu, Cagla; Demir, Yeliz; Türkeş, Cüneyt; Yabalak, Erdal; Seferoglu, Zeynel; Nural, Yahya

In this study, a series of new 1,2,3-triazole derivatives were synthesized in 84–93 % yield using copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry and characterized by 1H/13C NMR, FT-IR, and HRMS analyses. The synthesized compounds (4a–h) were evaluated for their inhibitory activities against human carbonic anhydrase isoforms I and II (hCA I and hCA II) and acetylcholinesterase (AChE), which are clinically relevant targets in neurological and metabolic disorders. Among them, compounds 4f and 4g exhibited the most potent dual inhibitory activities. Compound 4f showed KI values of 144.30 nM for hCA II and 205.10 nM for AChE, while compound 4g exhibited KI values of 239.10 nM for hCA II and 125.90 nM for AChE. These values demonstrate that 4f and 4g are more effective than the reference drugs acetazolamide (hCA II, KI = 381.44 nM) and tacrine (AChE, KI = 255.44 nM). Structure-activity relationship (SAR) analysis revealed that hydrophobicity, steric bulk, and aromaticity significantly influenced enzyme affinity. In silico docking confirmed strong interactions with key active site residues. Furthermore, ethanol solubility profiling revealed that polar and hydrogen-bonding groups significantly improved solubility, while bulky or aromatic hydrophobic substituents reduced it. The combined biological activity and solubility data emphasize the potential of these triazole derivatives particularly 4f and 4g as promising candidates for multitarget drug design and further preclinical development.

Yakan, Hasan; Muğlu, Halit; Erdoğan, Musa; Türkeş, Cüneyt; Demir, Yeliz

New naphthyl-thiosemicarbazone derivatives (1–9) were obtained from 1-naphthaldehyde and numerous thiosemicarbazides. New naphthyl-thio/carbohydrazones (10–12) were prepared from 1-naphthaldehyde and various thio/carbohydrazides. FT-IR, 1H NMR, 13C NMR, and elemental analysis were used to elucidate the structures of the newly obtained compounds. The inhibitory effects of these compounds against human carbonic anhydrase isoforms I and II (hCA I and hCA II) and acetylcholinesterase (AChE) were systematically evaluated. Several compounds exhibited potent inhibition, particularly derivatives bearing halogenated and electron-donating aromatic substituents. Among them, compound 11 demonstrated the strongest inhibition for all three enzymes, with KI values of 52.42 nM (hCA I), 59.23 nM (hCA II), and 40.16 nM (AChE), surpassing the reference standards acetazolamide and tacrine. Structure–activity relationship (SAR) analysis highlighted the critical influence of substituent type and position on enzymatic activity. In addition, molecular docking simulations were conducted to elucidate the binding interactions of the most potent compound with hCA I, hCA II, and AChE enzymes. The docking results supported the in vitro findings, revealing favorable binding energies and key interactions such as π–π stacking and hydrogen bonding, especially for compound 11.

Biçer, Abdullah; Çağlayan, Cüneyt; Demir, Yeliz; Türkeş, Cüneyt; Altundaş, Ramazan; Akyıldız, Hasan; Beydemir, Şükrü

In this study, thiazole derivatives containing sulphonamide, amide, and phenyl amino groups were synthesized to protect the free amino groups of 5-methyl-4-phenyl-2-aminothiazole and 4-phenyl-2-aminothiazole. Halogenated reactions of N-protected thiazole derivatives have been investigated. LCMS, FT-IR, 1H NMR, and 13C NMR spectroscopy techniques were used to elucidate the structures of the synthesized compounds. Inhibition effects of the N-protected thiazole derivatives against human carbonic anhydrase I, II (hCA I, hCA II), and acetylcholinesterase (AChE) were investigated. The best results among the synthesized N-protected thiazole derivatives showed Ki values in the range of 46.85–587.53 nM against hCA I, 35.01–578.06 nM against hCA II, and in the range of 19.58–226.18 nM against AChE. Furthermore, in silico studies with the target enzyme of the thiazole derivatives (9 and 11), which showed the best results experimentally, have examined the binding interactions of the related compounds at the enzyme active site.

Lolak, Nabih; Türkeş, Cüneyt; Akocak, Suleyman; Duran, Hatice Esra; Işık, Mesut; Durgun, Mustafa; Beydemir, Şükrü

Sulfonamides, recognized as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, are crucial in treating diverse diseases, including epilepsy, glaucoma, bacterial infections, and various pathological processes, e.g., high blood pressure, rheumatoid arthritis, ulcerative colitis, pain, and inflammation. Additionally, therapeutically, 1,3-diaryl-substituted triazenes and sulphamethazines (SM) are integral components in various drug structures, and the synthesis of novel compounds within these two categories holds substantial significance. Herein, ten 1,3-diaryltriazene-substituted sulphamethazine derivatives SM(1–10), which were created by reacting the diazonium salt of sulphamethazine with substituted aromatic amines, were synthesized and the physiologically and pharmacologically relevant human (h) isoforms hCA I and II, cytosolic isozymes, were included in the study. The synthesized compounds showed excellent inhibition versus hCAs; the 4-butoxy (SM7, KI of 5.69 ± 0.59 nM) compound exhibited a potent inhibitory effect against the hCA I compared with the reference drug acetazolamide (AAZ, KI of 116.00 ± 8.48 nM). The 4-cyano (SM4, KI of 5.87 ± 0.57 nM) compound displayed higher potency than AAZ (KI of 57.25 ± 4.15 nM) towards hCA II. Meanwhile, among the synthesized molecules, the 3,4-dimethoxy (SM9, KI of 74.98 ± 10.49 nM, SI of 9.94) compound (over hCA I) displayed a noticeable selectivity for hCA isoform II. The target compounds in the molecular docking investigation were determined to take part in various hydrophilic and hydrophobic interactions with nearby amino acids and fit nicely into the active sites of the hCAs. This research has yielded compounds displaying varying affinity toward hCA isoenzymes, ultimately serving as potent and selective hCA inhibitors. Given its substantial biological inhibitory potency, this particular derivative series is determined to hold the potential to serve as a promising lead compound against these hCAs.

Türkeş, Cüneyt

Aldose reductase (AR, EC1.1.1.21), a member of the aldo-keto reductase family, is critically implicated in the pathogenesis of chronic complications associated with diabetes mellitus, including neuropathy, nephropathy, and retinopathy. Hyperglycemia-induced AR overactivity results in intracellular sorbitol accumulation, NADPH depletion, and oxidative stress. Consequently, AR is recognized as a key mediator of oxidative and inflammatory signaling pathways involved in diverse human pathologies such as cardiovascular diseases, inflammatory disorders, and cancer. This has sparked renewed interest in developing novel AR inhibitors (ARIs) with enhanced therapeutic profiles. In this study, we evaluated the inhibitory potential of five quinolone antibiotics-gatifloxacin, lomefloxacin, nalidixic acid, norfloxacin, and sparfloxacin-as ARIs relevant to various physiological and pathological conditions. Through comprehensive in vitro and in silico analyses, we explored these antibiotics' binding interactions and affinities within the AR active site. Our findings reveal that these quinolones moderately inhibit AR at micromolar concentrations, with inhibition constants (KIs) ranging from 1.03 ± 0.13 μM to 4.12 ± 0.51 μM, compared to the reference drug epalrestat (KI of 0.85 ± 0.06 μM). The combined in vitro and in silico results underscore significant interactions between these drugs and AR, suggesting their potential as therapeutic agents against the aforementioned pathological conditions. Furthermore, these insights will aid in optimizing clinical dosing regimens and mitigating unexpected drug-drug interactions when these antibiotics are co-administered with other treatments.

Türkeş, Cüneyt

The authors regret that we did not include Acknowledgement on the original submission. The corrected acknowledgement is updated as below.

Güleç, Özcan; Türkeş, Cüneyt; Arslan, Mustafa; Işık, Mesut; Demir, Yeliz; Duran, Hatice Esra; Fırat, Muhammet; Küfrevioğlu, Ömer İrfan; Beydemir, Şükrü

In contemporary medicinal chemistry, employing a singular small molecule to concurrently multi-target disparate molecular entities is emerging as a potent strategy in the ongoing battle against metabolic disease. In this study, we present the meticulous design, synthesis, and comprehensive biological evaluation of a novel series of 1,2,3-triazolylmethylthio-1,3,4-oxadiazolylbenzenesulfonamide derivatives (8a-m) as potential multi-target inhibitors against human carbonic anhydrase (EC.4.2.1.1, hCA I/II), α-glycosidase (EC.3.2.1.20, α-GLY), and α-amylase (EC.3.2.1.1, α-AMY). Each synthesized sulfonamide underwent rigorous assessment for inhibitory effects against four distinct enzymes, revealing varying degrees of hCA I/II, a-GLY, and a-AMY inhibition across the tested compounds. hCA I was notably susceptible to inhibition by all compounds, demonstrating remarkably low inhibition constants (KI) ranging from 42.20 ± 3.90 nM to 217.90 ± 11.81 nM compared to the reference standard AAZ (KI of 439.17 ± 9.30 nM). The evaluation against hCA II showed that most of the synthesized compounds exhibited potent inhibition effects with KI values spanning the nanomolar range 16.44 ± 1.53–70.82 ± 4.51 nM, while three specific compounds, namely 8a-b and 8d, showcased lower inhibitory potency than other derivatives that did not exceed that of the reference drug AAZ (with a KI of 98.28 ± 1.69 nM). Moreover, across the spectrum of synthesized compounds, potent inhibition profiles were observed against diabetes mellitus-associated α-GLY (KI values spanning from 0.54 ± 0.06 μM to 5.48 ± 0.50 μM), while significant inhibition effects were noted against α-AMY, with IC50 values ranging between 0.16 ± 0.04 μM and 7.81 ± 0.51 μM) compared to reference standard ACR (KI of 23.53 ± 2.72 μM and IC50 of 48.17 ± 2.34 μM, respectively). Subsequently, these inhibitors were evaluated for their DPPH· and ABTS+· radical scavenging activity. Moreover, molecular docking investigations were meticulously conducted within the active sites of hCA I/II, α-GLY, and α-AMY to provide comprehensive elucidation and rationale for the observed inhibitory outcomes.