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Abstract: The synthesis, structure, spectroscopic and electro-spectrochemical properties of steric hindered Schiff-base ligand [N,N′-(3,4-benzophenon)-3,5-Bu t 2-salicylaldimine (LH2)] and its mononuclear Cu(II), Co(II), Ni(II), Mn(II) and Fe(II) complexes are described in this work. The new dissymmetric steric hindered Schiff-base ligand containing a donor set of NONO was prepared through reaction of 3,4-diaminobenzophenon with 3,5-Bu t 2-salicylaldehyde. Certain metal complexes of this ligand were synthesized by treating an ethanolic solution of the ligand with an equimolar amount of metal salts. The ligand and its complexes were characterized by FT-IR, UV–vis, 1H NMR, elemental analysis, molar conductivity and thermal analysis methods in addition to magnetic susceptibility, electrochemistry and spectroelectrochemistry techniques. The tetradentate and mononuclear metal complexes were obtained by reacting N,N′-(3,4-benzophenon)-3,5-Bu t 2-salicylaldimine (LH2) with some metal acetate in a 1:1 mole ratio. The molar conductance data suggest metal complexes to be non-electrolytes. [Copyright &y& Elsevier]

This study examines efficiency of a newly synthesized sulfonamide derivative 2-bromo-N-(4-sulfamoylphenyl)propanamide (MMH-1) on the inhibition of Carbonic Anhydrase IX (CA IX), which is overexpressed in many solid tumors including breast cancer. The inhibitory potential of MMH-1 compound against its four major isoforms, including cytosolic isoforms hCA I and II, as well as tumor-associated membrane-bound isoforms hCA IX and XII, was evaluated. To this context, the cytotoxic effect of MMH-1 on cancer and normal cells was tested and found to selectively affect MDA-MB-231 cells. MMH-1 reduced cell proliferation by holding cells in the G0/G1 phase (72 %) and slowed the cells' wound healing capacity. MMH-1 inhibited CA IX under both hypoxic and normoxic conditions and altered the morphology of triple negative breast cancer cells. In MDA-MB-231 cells, inhibition of CA IX was accompanied by a decrease in extracellular pH acidity (7.2), disruption of mitochondrial membrane integrity (80 %), an increase in reactive oxygen levels (25 %), and the triggering of apoptosis (40 %). In addition, the caspase cascade (CASP-3, -8, -9) was activated in MDA-MB-231 cells, triggering both the extrinsic and intrinsic apoptotic pathways. The expression of pro-apoptotic regulatory proteins (Bad, Bax, Bid, Bim, Cyt-c, Fas, FasL, TNF-a, TNF-R1, HTRA, SMAC, Casp-3, -8, P21, P27, and P53) was increased, while the expression of anti-apoptotic proteins, apoptosis inhibitor proteins (IAPs), and heat shock proteins (HSPs) (Bcl-2, Bcl-w, cIAP-2, HSP27, HSP60, HSP70, Survivin, Livin, and XIAP) was decreased. These results propose that the MMH-1 compound could triggers apoptosis in MDA-MB-231 cells via the pH/MMP/ROS pathway through the inhibition of CA IX. This compound is thought to have high potential and promising anticancer properties in the treatment of aggressive tumors., (© 2024 Wiley-VCH GmbH.)

The present study focused on the synthesis and characterization of novel pyrazole carboxamide derivatives (SA1-12). The inhibitory effect of the compounds on cholinesterases (ChEs; AChE and BChE) and carbonic anhydrases (hCAs; hCA I and hCA II) isoenzymes were screened as in vitro. These series compounds have been identified as potential inhibitors with a K I values in the range of 10.69±1.27-70.87±8.11 nM for hCA I, 20.01±3.48-56.63±6.41 nM for hCA II, 6.60±0.62-14.15±1.09 nM for acetylcholinesterase (AChE) and 54.87±7.76-137.20 ±9.61 nM for butyrylcholinesterase (BChE). These compounds have a more effective inhibition effect when compared to the reference compounds. In addition, the potential binding positions of the compounds with high affinity for ChE and hCAs were demonstrated by in silico methods. The results of in silico and in vitro studies support each other. As a result of the present study, the compounds with high inhibitory activity for metabolic enzymes, such as ChE and hCA were designed. The compounds may be potential alternative agents used as selective ChE and hCA inhibitors in the treatment of Alzheimer's disease and glaucoma., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Sulfonamide compounds known as human carbonic anhydrase (hCA) inhibitors are used in the treatment of many diseases such as epilepsy, antibacterial, glaucoma, various diseases. 1,3-diaryl-substituted triazenes and sulfaguanidine are used for therapeutic purposes in many drug structures. Based on these two groups, the synthesis of new compounds is important. In the present study, the novel 1,3-diaryltriazene-substituted sulfaguanidine derivatives (SG1-13) were synthesized and fully characterized by spectroscopic and analytic methods. Inhibitory effect of these compounds on the hCA I and hCA II was screened as in vitro. All the series of synthesized compounds have been identified as potential hCA isoenzymes inhibitory with K I values in the range of 6.44±0.74-86.85±7.01 nM for hCA I and with K I values in the range of 8.16±0.40-77.29±9.56 nM for hCA II. Moreover, the new series of compounds showed a more effective inhibition effect than the acetazolamide used as a reference. The possible binding positions of the compounds with a binding affinity to the hCA I and hCA II was demonstrated by in silico studies. In conclusion, compounds with varying degrees of affinity for hCA isoenzymes have been designed and as selective hCA inhibitors. These compounds may be potential alternative agents that can be used to treat or prevent diseases associated with glaucoma and hCA inhibition., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

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 (K I values of 98.28-439.17 nM for hCA I and II, respectively) and exhibited the highest inhibition with the K I s 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. This study focused on the synthesis and inhibitory effects of bis-ureido-substituted sulfaguanidine (SG1-4) and sulfisoxazole (SO1-4) derivatives against human hCA I and II isoforms and AChE. In order to test synthesized derivatives' free radical scavenging potentials were the DPPH and ABTS assays. In silico studies elucidated possible binding mechanisms of inhibitors to the active site., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background SARS-CoV-2 infects cells via angiotensin-converting enzyme 2 (ACE2). ACE2 levels are high in the thyroid gland. Although the thyroid gland can be directly infected in COVID-19 patients, the hypothalamic-pituitary-thyroid axis is also affected. Therefore, changes in thyroid function occur in COVID-19 patients. This study aimed to examine the effect of thyroid function tests on the prognosis of COVID-19. Methodology A total of 146 patients who were diagnosed with COVID-19 and treated in the intensive care unit between August and November 2021 and who had no previous history of thyroid disease were included in the study. Demographic information, laboratory tests, and thyroid hormone levels during hospitalization and discharge patterns were evaluated. The patients were divided into two groups: group I included those who were discharged after recovery, and group II included those who did not respond to treatment and died. Results When the fT3 and fT4 levels of the patients were compared, the hormone levels decreased as the clinical severity of the disease increased. The amount of decrease in hormone levels was mostly seen in group II. In the recovered patient group, the amount of hormone decreased was less. The difference between fT3 and ft4 values between the groups was found to be statistically significant ( P  = 0.015 and P  = 0.004). In addition, the difference between the groups' C-reactive protein (CRP), D-dimer, and ferritin values was statistically significant ( P  = 0.036, P  = 0.022, and P  < 0.000, respectively). There was no statistically significant difference between the groups in terms of demographic characteristics ( P  > 0.05). Conclusions Thyroid hormone changes were found to be an important prognostic parameter affecting disease severity and mortality in COVID-19 patients and can be used to predict mortality., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Durgun et al.)

Backgrounds: The positive effects of reduction mammoplasty on metabolic profile have been shown in a limited number of studies. This study objective to reveal the effects of reduction mammoplasty on metabolic profile and anthropometric measurements., Subjects and Method: The study was prospectively conducted on 42 patients who were operated between April 2019 and March 2020. Fasting plasma glucose, fasting plasma insulin, total cholesterol, triglyceride, high-density lipoprotein and low-density lipoprotein cholesterol, HgA1c, homeostasis model assessment scores, adiponectin, leptin, and resistin levels were evaluated. In addition, age, height, weight, body mass index; breast, chest, waist, hip circumference; waist-hip ratio, and bilateral breast resection tissue weights were recorded. Data and blood samples were collected one hour before the operation, 6 and 12 weeks after the operation., Result: The patients' mean age was 43.14±10.24, and their average height was 159.42±4.96 cm. The excised bilateral dermo fatty tissue weight was 1435.85±721.16 g. At the postoperative 40th day a decrease in leptin (p = 0.001), resistin (p =0.008), glucose (p = 0.021) and insulin resistance values (p=0.013) stated. There was an increase in adiponectin (p < 0.001) and HDL (p = 0.013) levels at the postoperative 40th day. In the postoperative third month, these data returned to the previous levels that were measured before operations. However, an increase in hip circumference (p = 0.034) and a decrease in waist-hip ratio (p < 0.001) was detected in third month. Also, there was no difference in body mass index and weight compared to pre-operation., Conclusion: After reduction mammoplasty, compensatory fat growth in the hip area, an increase in the hip circumference, and a decrease in the waist-hip ratio were observed in the postoperative third month., Level of Evidence: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Objective: The frontal QRS-T angle (fQRS-T) is associated with myocardial ischemia and ventricular arrhythmias. On the other hand, acute pulmonary embolism (APE) is a major risk factor for cardiac adverse events. This research aimed to determine whether the fQRS-T, a marker of ventricular heterogeneity, can be used to predict successful thrombolytic therapy in patients with APE., Methods: This was a retrospective observational study. Patients diagnosed with APE and hospitalized in the intensive care unit between 2020 and 2022 were included in the research. A total of 136 individuals with APEs were enrolled in this research. The patients were divided into two groups: thrombolytic-treated (n=64) and non-treated (moderate to severe risk, n=72). An ECG was conducted for each patient, and echocardiography was performed., Results: The mean age of the thrombolytic group was 58.2±17.6 years, with 35 females (55.1% of the group) and 29 males (44.9%). The non-thrombolytic group had a mean age of 63.1±16.2, with 41 females (56.5%) and 31 males (43.5%). Respiratory rate, heart rate, and fQRS-T were higher in the thrombolytic group, and oxygen saturation ratio and systolic and diastolic blood pressure were higher in the non-thrombolytic group (p=0.006, p<0.001, p=0.021; p<0.001, p=0.015, p<0.001, respectively). In the thrombolytic therapy group, comparing pre- and post-treatment ECG data revealed a statistically significant change in the fQRS-T value (p=0.019)., Conclusion: The fQRS-T may provide important clues for the successful treatment of APEs., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Durgun et al.)

Background: Cervical cancer is one of the most common types of cancer among women. Therefore, cancer studies are underway for a new chemo-agent with more effect on cancer cells and fewer side effects on normal human healthy cells. The currently studied novel ligand L 2 b as a reduced salicylaldimine derivative was examined in seven cell lines, HeLa, DU-145, PC3, DLD-1, ECC, HT-29, and PNT1-A as a control., Aim: Because of the antiproliferative ability of L 2 b, this study intends to look at the apoptotic, cytotoxic, and genotoxic activity of L 2 b on HeLa., Methods: For this purpose, MTT assay is for screening cytotoxic effects, comet assay for looking for DNA damaging or genotoxicity levels, ELISA and DNA fragmentation for apoptotic measuring, AO/EB stain test for checking the rates of live, apoptotic and necrotic cells were performed. To reveal the oxidative state, OSI was assessed by total oxidant and antioxidant status ratios. FRAP assay was calculated for ferric-reducing antioxidant power, using total thiol and GSH assays to measure the antioxidant values of HeLa cells., Results: Of this result, we have found a tremendous effect of L 2 b on HeLa cells, especially in raising the ROS rate, damaging their DNA, and causing a range of reactions leading to apoptosis., Conclusion: In conclusion, the data predict which ligand L 2 b is capable of rising apoptosis in vitro cervical cancer cell line studied. Further cancer studies are needed to reveal the apoptosis pathways of the ligand L 2 b in the HeLa cell line and its anticancer drug potency in vivo work., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Developing new anticancer agents are crucial for cancer treatment. Antiproliferative activity of L1H as a bis-structured Schiff base was subjected to preliminary research in eight different kinds of cell lines by the cell viability method using different concentrations to determine their inhibitory concentration. L1H demonstrated the highest cytotoxicity in human breast cancer cell line MCF-7. In this perspective, the MCF-7 cell line was cultured for the examination of different molecular techniques, including MTT, apoptosis analysis by enzyme-linked immunosorbent assay (ELISA), and comet assay. Moreover, the DNA ladder, acridine orange/ethidium bromide as another apoptotic cell analysis, markers of oxidative stress, and total antioxidant status, total thiol, and GSH as nonenzymatic antioxidants assay were conducted. The above techniques have proven that L1H is a growth inhibitor effect when compared to cisplatin as a positive control in human breast cancer cells, especially those affected by L1H. The findings clearly show that L1H evaluated in MCF-7 cell lines causes rising or induced apoptosis, DNA damage, diminished antioxidant status against the increase of oxidized protein, and prevents cell proliferation. Manifold evidence supported our hypothesis that L1H has a potential therapeutically improved effect against the MCF-7 cell line, and then without a doubt is a suitable candidate drug for investigating cancers next., (© 2022 Wiley Periodicals LLC.)

Objective: The purpose of this study was to compare the effect of body posture and apnea severity on the tone, stiffness, and elasticity of upper airway muscles in awake patients with obstructive sleep apnea syndrome (OSAS)., Methods: Eighty adult patients with OSAS from the Sleep Laboratory of the Bitlis State Hospital between April and December 2021 were included in the study. The tone, stiffness, and elasticity of the genioglossus and accessory muscles (sternocleidomastoid, masseter) were measured while the patients were awake, sitting upright, and in supine posture. According to polysomnography results and the Apnea-Hypopnea Index, patients were classified as mild, moderate, or severe OSAS., Results: There were 56 male (70%) and 24 female (30%) patients (age 45.0 ± 11.0 years). Tone of genioglossus, masseter, and sternocleidomastoid muscles were higher in supine than in sitting posture (all P < .05). There was no difference in elasticity scores of the bilateral genioglossus muscle in sitting and supine posture (P > .05). The elasticity scores of the sternocleidomastoid and masseter muscles were higher in sitting (all P < .05). An interaction effect of postural change and apnea severity was observed on stiffness scores of the genioglossus muscle (P < .05)., Conclusion: Results showed that the genioglossus muscle and accessory muscles take on the inspiratory load that develops with postural strain, regardless of the severity of apnea, in awake patients with OSAS. For participants measured in this study, accessory muscles supported respiration by increasing their elasticity., (Copyright © 2022. Published by Elsevier Inc.)

Background: Prostate-specific membrane antigen (PSMA) expression is encountered in tumor-associated neovascularization., Methods: PSMA-antibody was applied to the paraffin blocks of 51 patients who were diagnosed with squamous cell carcinoma of the larynx and underwent laryngectomy and one who underwent lymph node dissection. The percentage of vascular expression in tumoral and extratumoral stroma and lymph nodes and intensity score in tumoral epithelium were evaluated and divided into groups according to the level of PSMA expression. Final PSMA expression was determined by multiplying intensity and percentage scores., Results: The mean age was 61±10 years. Patients with perineural invasion, cartilage invasion, and local invasion exhibited higher PSMA expression scores. Age, tumor differentiation, tumor diameter, perineural invasion, tumor localization, capsular invasion, depth of invasion, surgical margin status, local invasion, nodal metastasis, TNM classification, and stage were similar in high and low PSMA expression groups. There was no PSMA expression in extratumoral vascular stroma. Significantly higher PSMA expression was observed in the vascular endothelium of metastatic lymph nodes compared with reactive lymph nodes. Patients with advanced-stage disease exhibited higher PSMA vascular expression scores compared to those with earlier stages (p<.001). PSMA expression was not correlated with overall survival, disease-specific survival, or disease-free survival (p>.05)., Conclusions: Our study suggests that higher PSMA expression is associated with cartilage invasion, local invasion, and advanced-stage of disease. PSMA expression can be utilized for detection of lymph node metastasis and has some predictive role in cases of neck metastasis.

Carbonic anhydrase IX (CAIX) is a hypoxia-associated transmembrane protein that is critical in the survival of cells. Because CAIX has a key role in pH regulation, its therapeutic effects have been heavily studied by different research laboratories. This study aims to investigate how a synthetic CAIX inhibitor triggers apoptosis in a cancer cell line, HeLa. In this regard, we investigated the effects of the compound I, synthesized as a CAIX inhibitor, on the survival of cancer cells. The compound I inhibited the proliferation of the CAIX+ HeLa cells, kept the cells in G0/G1 phase (74.7%) and altered the cells morphologies (AO/EtBr staining) and the nuclear structure (γ-H2AX staining). CAIX inhibition triggered apoptosis in HeLa cells with a rate of 47.4%. According to the expression of mediator genes (CASP-3, -8, -9, BAX, BCL-2, BECLIN, LC3), the both death pathways were activated in HeLa cells with the inhibition of CAIX with the compound I. The compound I was also determined to affect the genes and proteins that have a critical role in the regulation of apoptotic pathways (pro casp-3, cleaved casp-3, -8, -9, cleaved PARP and CAIX). Furthermore, CAIX inhibition caused changes in pH balance, disruption in organelle integrity of mitochondria, and increase intracellular reactive oxygen level of HeLa cells. Taken together, our findings suggest that CAIX inhibition has a potential in cancer treatment, and the compound I, a CAIX inhibitor, could be a promising therapeutic strategy in the treatment of aggressive tumours., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The underlying cause of many metabolic diseases is abnormal changes in enzyme activity in metabolism. Inhibition of metabolic enzymes such as cholinesterases (ChEs; acetylcholinesterase, AChE and butyrylcholinesterase, BChE) and α-glucosidase (α-GLY) is one of the accepted approaches in the treatment of Alzheimer's disease (AD) and diabetes mellitus (DM). Here we reported an investigation of a new series of novel ureido-substituted derivatives with sulfamethazine backbone ( 2a-f ) for the inhibition of AChE, BChE, and α-GLY. All the derivatives demonstrated activity in nanomolar levels as AChE, BChE, and α-GLY inhibitors with K I values in the range of 56.07-204.95 nM, 38.05-147.04 nM, and 12.80-79.22 nM, respectively. Among the many strong N -(4,6-dimethylpyrimidin-2-yl)-4-(3-substitutedphenylureido) benzenesulfonamide derivatives ( 2a-f ) detected against ChEs, compound 2c , the 4-fluorophenylureido derivative, demonstrated the most potent inhibition profile towards AChE and BChE. A comprehensive ligand/receptor interaction prediction was performed in silico for the three metabolic enzymes providing molecular docking investigation using Glide XP, MM-GBSA, and ADME-Tox modules. The present research reinforces the rationale behind utilizing inhibitors with sulfamethazine backbone as innovative anticholinergic and antidiabetic agents with a new mechanism of action, submitting propositions for the rational design and synthesis of novel strong inhibitors targeting ChEs and α-GLY.Communicated by Ramaswamy H. Sarma.

Aldose reductase (ALR2), one of the metabolically important enzymes, catalyzes the formation of sorbitol from glucose in the polyol pathway. ALR2 inhibition is required to prevent diabetic complications. In the present study, the novel bis-hydrazone compounds bearing isovanillin moiety (GY1-12) were synthesized, and various chromatographic methods were applied to purify the ALR2 enzyme. Afterward, the inhibitory effect of the synthesized compounds on the ALR2 was screened in vitro. All the novel bis-hydrazones demonstrated activity in nanomolar levels as AR inhibitors with IC 50 and K I values in the range of 12.55-35.04 nM, and 13.38-88.21 nM, respectively. Compounds GY-11, GY-7, and GY-5 against ALR2 were identified as the highly potent inhibitors, respectively, and were superior to the standard drug, epalrestat. Moreover, a comprehensive ligand-receptor interactions prediction was performed using ADME-Tox, Glide XP, and MM-GBSA modules of Schrödinger Small-Molecule Drug Discovery Suite to elucidate the novel bis-hydrazone derivatives, potential binding modes versus the ALR2. As a result, these compounds with ALR2 inhibitory effects may be potential alternative agents that can be used to treat or prevent diabetic complications., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Natural products from plants, such as flavonoids, arouse immense interest in medicine because of the therapeutic and many other bioactive properties. The molecular docking is a very useful method to screen the molecules based on their free binding energies and give important structural suggestions about how molecules might activate or inhibit the target receptor by comparing reference molecules. Alliin and Allicin differ from many other flavonoids because of containing no benzene rings and having nitrogen and sulfur atoms in their structure. In this study Alliin and Allicin affinity on AMPA, NMDA and GABA-A receptors were evaluated in the central nervous system by using the molecular docking method. Both Alliin and Allicin indicated no inhibitory effects. However Alliin showed significant selectivity to human AMPA receptor (3RN8) as an excitatory. The binding energy of glutamate to 3RN8 was -6.61 kcal mol -1 , while the binding energy of Allin was -8.08 kcal mol -1 . Furthermore Alliin's affinity to the other AMPA and NMDA receptors is quite satisfactory compared to the reference molecule glutamate. In conclusion based on the molecular docking study, Alliin can be useful for synaptic plasticity studies whereas might be enhance seizure activity because of the increased permeability to cations. It also can be beneficial to improve learning and memory and can be used as a supportive product to the hypofunction of NMDA associated problems., (© 2021 IOP Publishing Ltd.)

Sulfonamide derivatives exhibit a wide biological activity and can function as potential medical molecules in the development of a drug. Studies have reported that the compounds have an effect on many enzymes. In this study, the derivatives of amine sulfonamide ( 1i - 11i ) were prepared with reduced imine compounds ( 1 - 11 ) with NaBH 4 in methanol. The synthesized compounds were fully characterized by spectral data and analytical. The effect of the synthesized derivatives on acetylcholinesterase (AChE), glutathione S-transferase (GST) and α-glycosidase (α-GLY) enzymes were determined. For the AChE and α-GLY, the most powerful inhibition was observed on 10 and 10i series with K I value in the range 2.26 ± 0.45-3.57 ± 0.97 and 95.73 ± 13.67-102.45 ± 11.72 µM, respectively. K I values of the series for GST were found in the range of 22.76 ± 1.23-49.29 ± 4.49. Finally, the compounds have a stronger inhibitor in lower concentrations by the attachment of functional electronegative groups such as two halogens (-Br and -CI), -OH to the benzene ring and -SO 2 NH 2 . The crystal structures of AChE, α-GLY, and GST in complex with selected derivatives 4 and 10 show the importance of the functional moieties in the binding modes within the receptors.Communicated by Ramaswamy H. Sarma.

Carbonic anhydrase IX (CAIX) is a hypoxia-related protein that plays a role in proliferation in solid tumours. However, how CAIX increases proliferation and metastasis in solid tumours is unclear. The objective of this study was to investigate how a synthetic CAIX inhibitor triggers apoptosis in the HeLa cell line. The intracellular effects of CAIX inhibition were determined with AO/EB, AnnexinV-PI, and γ-H2AX staining; measurements of intracellular pH (pHi), reactive oxygen species (ROS), and mitochondrial membrane potential (MMP); and analyses of cell cycle, apoptotic, and autophagic modulator gene expression (Bax, Bcl-2, caspase-3, caspase-8, caspase-9, caspase-12, Beclin, and LC3), caspase protein level (pro-caspase 3 and cleaved caspase-3, -8, -9), cleaved PARP activation, and CAIX protein level. Sulphonamide CAIX inhibitor E showed the lowest IC 50 and the highest selectivity index in CAIX-positive HeLa cells. CAIX inhibition changed the morphology of HeLa cells and increased the ratio of apoptotic cells, dramatically disturbing the homeostasis of intracellular pHi, MMP and ROS levels. All these phenomena consequent to CA IX inhibition triggered apoptosis and autophagy in HeLa cells. Taken together, these results further endorse the previous findings that CAIX inhibitors represent an important therapeutic strategy, which is worth pursuing in different cancer types, considering that presently only one sulphonamide inhibitor, SLC-0111, has arrived in Phase Ib/II clinical trials as an antitumour/antimetastatic drug.

A series of six N-carbamimidoyl-4-(3-substituted phenylureido)benzenesulfonamide derivatives were synthesized by reaction of sulfaguanidine with aromatic isocyanates. In vitro and in silico inhibitory effects of the novel ureido-substituted sulfaguanidine derivatives were investigated by spectrophotometric methods for α-glycosidase (α-GLY), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzymes associated with diabetes mellitus (DM) and Alzheimer's disease (AD). N-Carbamimidoyl-4-{[(3,4-dichlorophenyl)carbamoyl]amino}benzene-1-sulfonamide (2f) showed AChE and BChE inhibitory effects, with K I values of 515.98±45.03 nM and 598.47±59.18 nM, respectively, while N-carbamimidoyl-4-{[(3-chlorophenyl)carbamoyl]amino}benzene-1-sulfonamide (2e) showed strong α-GLY inhibitory effect, with K I values of 103.94±13.06 nM. The antidiabetic effects of the novel synthesized compounds are higher than their anti-Alzheimer's effects, because the inhibition effect of the compounds on the α-GLY with diabetic enzyme is greater than the effect on esterase enzymes. Indeed, inhibition of the metabolic enzymes is important for the treatment of DM and AD., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

Sulphonamides are biologically important compounds with low toxicity, many bioactivities and cost-effectiveness. Eight sulphonamide derivatives were synthesised and characterised by FT-IR, 13 C NMR, 1 H NMR, LC-MS and elemental analysis. Their inhibitory effect on AChE, and carbonic anhydrase I and II enzyme activities was investigated. Their antioxidant activity was determined using different bioanalytical assays such as radical scavenging tests with ABTS •+ , and DPPH •+ as well as metal-reducing abilities with CUPRAC, and FRAP assays. All compounds showed satisfactory enzyme inhibitory potency in nanomolar concentrations against AChE and CA isoforms with K I values ranging from 10.14 ± 0.03 to 100.58 ± 1.90 nM. Amine group containing derivatives showed high metal reduction activity and about 70% ABTS radical scavenging activity. Due to their antioxidant activity and AChE inhibition, these novel compounds may be considered as leads for investigations in neurodegenerative diseases.

In the present study, a series of eleven novel 1,3-diaryltriazene-substituted sulfathiazole moieties (ST1-11) was synthesized by the reaction of diazonium salt of sulfathiazole with substituted aromatic amines and their chemical structures were characterized by Fourier transform infrared, 1 H-NMR (nuclear magnetic resonance), 13 C-NMR, and high-resolution mass spectroscopy methods. These synthesized novel derivatives were found to be effective inhibitor molecules for α-glycosidase (α-GLY), human carbonic anhydrase (hCA), and acetylcholinesterase (AChE), with K I values in the range of 426.84 ± 58.42-708.61 ± 122.67 nM for α-GLY, 450.37 ± 50.35-1,094.34 ± 111.37 nM for hCA I, 504.37 ± 57.22-1,205.36 ± 195.47 nM for hCA II, and 68.28 ± 10.26-193.74 ± 19.75 nM for AChE. Among the synthesized novel compounds, several lead compounds were investigated against the tested metabolic enzymes. More specifically, ST11 (4-[3-(perfluorophenyl)triaz-1-en-1-yl]-N-(thiazol-2-yl)benzenesulfonamide) showed a highly efficient inhibition profile against hCA I, hCA II, and AChE, with K I values of 450.37 ± 50.35, 504.37 ± 57.22, and 68.28 ± 10.26 nM, respectively. Due to its significant biological inhibitory potency, this derivative may be considered as an interesting lead compound against these enzymes., (© 2020 Deutsche Pharmazeutische Gesellschaft.)

Some metabolic enzyme inhibitors can be used in the treatment of many diseases. Therefore, synthesis and determination of alternative inhibitors are essential. In this study, the inhibition effect of newly synthesized compounds on carbonic anhydrase (cytosolic isoforms, hCA I and hCA II), α-glycosidase (α-GLY), and acetylcholinesterase (AChE) were investigated. The possible binding mechanism of the compounds with a high inhibitory effect on the active site of the enzyme was demonstrated by molecular docking method. We investigated the inhibition effects of novel synthesized compounds (MZ1-MZ11) on metabolic enzymes such as α-GLY, AChE, and hCA I and II. The compound MZ6 for AChE, MZ8 for CA I and CA II and MZ7 for α-GLY showed a very active inhibition profile (K I s 51.67 ± 4.76 for hCA I, 40.35 ± 5.74 nM for hCA II, 41.74 ± 8.08 nM for α-GLY and 335.76 ± 46.91 nM for AChE). The novel synthesized compounds (MZ1-MZ11) have a higher enzyme (α-GLY, AChE, hCA I, and II) inhibitory potential than ACR, TAC, and AZA, respectively. The compounds may have the potential to be used as alternative medicines after further research in the treatment of many diseases such as diabetes, Alzheimer's disease, heart failure, ulcer, and epilepsy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Sulfonamides known as inhibitors of many metabolic enzymes have been widely used as antimicrobial drugs for a long time. In the present study, we investigated in vitro inhibitory activities of benzenesulfonamide derivatives on human paraoxonase-I (hPON1). For this aim, PON1 was purified from human serum with a specific activity of 2603.57 EU/mg and 8.34% yield using simple chromatographic methods. The various concentrations of early-synthesized sixteen sulfonamide derivatives were tested on the paraoxonase activity. K i values of compounds were found in the range of 0.28-357.70 µM. Compound H4 had the highest inhibitory activity on hPON1 as competitive. Estimated structure-activity relationship (SAR) for compounds was done based on different substituents and their positions in the compounds. Besides, the molecular docking analysis of compound H4 was performed to understand the binding interactions on the active site of the enzyme. According to these experimental results, compound H4 was a potential inhibitor of PON1., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Cervical cancer is a common type of cancer. Carbonic anhydrase IX (CA IX) is an attractive target for tumour therapy, being overexpressed in many cancers. We investigated the anticancer properties of the aromatic sulphonamide S-1 as a CA IX inhibitor on cervical cancer cells (HeLa) positive for CA IX expression and normal prostate epithelial cell line (PNT1-A) negative for CA IX. We examined the cytotoxic, apoptosis, genotoxic, and oxidative stress activity of S-1 on HeLa and PNT1-A cell lines. S-1 induced significant reduction of cell viability, caused apoptosis, and up-regulated ROS production. This decrease in cell survival rate can be attributed to the high level of ROS and apoptosis, which has also been shown to arrest the cell cycle. Our findings indicated that S-1 is more effective on HeLa than PNT1-A. S-1 was able to induce apoptosis of cervical cancer cells and is a possible candidate for future anticancer studies.