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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, K I of 5.69 ± 0.59 nM) compound exhibited a potent inhibitory effect against the hCA I compared with the reference drug acetazolamide (AAZ, K I of 116.00 ± 8.48 nM). The 4-cyano (SM4, K I of 5.87 ± 0.57 nM) compound displayed higher potency than AAZ (K I of 57.25 ± 4.15 nM) towards hCA II. Meanwhile, among the synthesized molecules, the 3,4-dimethoxy (SM9, K I of 74.98 ± 10.49 nM, S I 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., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study introduces a series of ten hybrid molecules DK(1-10), which combine diazo and coumarin moieties along with diverse aromatic substitutions. The primary objective was to evaluate the inhibitory capabilities of these compounds against four prominent isoforms: the cytosolic hCA I and II, as well as the tumor-associated membrane-bound hCA IX and XII. Impressively, the majority of the tested compounds exhibited significant inhibition activity against the tumor-associated isoforms hCA IX and XII, with K I values ranging from 29.2 to 293.3 nM. Notably, compound DK-8 displayed particularly robust inhibitory activity against the tumor-associated membrane-bound isoforms, hCA IX and XII, yielding K I values of 32.5 and 29.2 nM, respectively. Additionally, another derivative, DK-9, containing a primary sulfonamide, exhibited notable inhibition against hCA XII with a K I value of 36.4 nM. This investigation aimed to explore the structure-activity relationships within these compounds, shedding light on how various substitutions and structural components influence their inhibitory potential. As a result, these compounds present promising candidates for further exploration in medicinal and pharmacological research. Their ability to selectively inhibit specific isoforms, particularly those associated with hypoxic tumors, suggests their potential as foundational compounds for the development of novel therapeutic agents., (© 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.)

Tyrosinase is a crucial copper-containing enzyme involved in the production of melanin. Melasma, age spots, and freckles are examples of hyperpigmentation diseases caused by excess production of melanin. Inhibiting tyrosinase activity is a crucial method for treating these disorders along with various applications such as cosmetics, food technology, and medicine. Natural products have proven a rich source of tyrosinase inhibitors, with several molecules from plant, marine, and microbial sources showing potential inhibitory action. This chapter provides a complete overview of natural compounds that have been found as tyrosinase inhibitors, with emphasis on their structures, modes of action, and prospective applications., (Copyright © 2024. Published by Elsevier Inc.)

Aim: The aim of this study was to synthesize a library of novel di-sulfa drugs containing 1,3- diaryltriazene derivatives TS (1-13) by conjugation of diazonium salts of primary sulfonamides with sulfa drugs to investigate the cytotoxic effect of these new compounds in different cancer types and to determine their inhibitory activity against tumor-associated carbonic anhydrases IX and XII., Materials and Methods: A carbonic anhydrase inhibitory activity of the obtained compounds was evaluated against four selected human carbonic anhydrase isoforms (hCA I, hCA II, hCA IX and hCA XII) by a stoppedflow CO 2 hydrase assay. In addition, in vitro , cytotoxicity studies were applied by using A549 (lung cancer), BEAS-2B (normal lung), MCF-7 (breast cancer), MDA-MB-231 (breast cancer), CRL-4010 (normal breast epithelium), HT-29 (colon cancer), and HCT -116 (colon cancer) cell lines., Results: As a result of the inhibition data, the 4-aminobenzenesulfonamide derivatives were more active than their 3-aminobenzenesulfonamide counterparts. More specifically, compounds TS-1 and TS-2, both of which have primary sulfonamides on both sides of the triazene linker, showed the best inhibitory activity against hCA IX with K i values of 19.5 and 13.7 nM and also against hCA XII with K i values of 6.6 and 8.3 nM, respectively. In addition, in vitro cytotoxic activity on the human breast cancer cell line MCF-7 showed that some derivatives of di-sulfa triazenes, such as TS-5 and TS-13, were more active than SLC-0111., Conclusion: With the aim of developing more potent and isoform-selective CA inhibitors, these novel hybrid molecules containing sulfa drugs, triazene linkers, and the classical primary sulfonamide chemotype may be considered an interesting example of effective enzyme inhibitors and important anticancer agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

A novel series of twelve aromatic bis-ureido-substituted benzenesulfonamides was synthesised by conjugation of aromatic aminobenzenesulfonamides with aromatic bis-isocyanates. The obtained bis-ureido-substituted derivatives were tested against four selected human carbonic anhydrase isoforms (hCA I, hCA II, hCA IX and hCA XII). Most of the new compounds showed an effective inhibitory profile against isoforms hCA IX and hCA XII, also having some selectivity with respect to hCA I and hCA II. The inhibition constants of these compounds against isoforms hCA IX and XII were in the range of 6.73-835 and 5.02-429 nM, respectively. Since hCA IX and hCA XII are important drug targets for anti-cancer/anti-metastatic drugs, these effective inhibitors reported here may be considered of interest for cancer related studies in which these enzymes are involved.

This research introduces a series of fourteen 4-aryl-hydrazonopyrazolone sulfonamide derivatives, denoted as 3(a-g) and 4(a-g), which encompass various aromatic substitutions. The aim was to assess the inhibitory potential of these compounds against four significant isoforms, including the cytosolic isoforms hCA I and II, as well as the tumor-associated membrane-bound isoforms hCA IX and XII. Most of the tested compounds exhibited substantial inhibition against the tumor-associated isoform hCA IX, with K i values spanning from 1.1 to 158.2 nM. Notably, compounds 3e and 3g showed particularly strong inhibitory activity against the tumor-associated membrane-bound isoforms, hCA IX and XII, while maintaining a high selectivity ratio over cytosolic off-target isoforms hCA I and II. This selectivity is vital due to the potential of hCA IX and hCA XII as drug targets for hypoxic tumors. In an effort to create novel analogs that exhibit enhanced carbonic anhydrase inhibitory activity and specificity, we investigated the structure-activity relationships of these compounds and provided a concise interpretation of our findings. Consequently, these compounds merit consideration for subsequent medicinal and pharmacological research, holding potential for developing novel therapeutic agents targeting specific isoforms in hypoxic tumors., 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 © 2023 Elsevier Ltd. All rights reserved.)

Multidrug resistance (MDR) causes difficulties in the treatment of infections and cancer. Research and development studies have become increasingly important for the strategy of preventing MDR. There is a need for new multitarget drug research and advancement to reduce the development of drug resistance in drug-drug interactions and reduce cost and toxic effects. This study aimed to determine the effects of multi-target triazene compounds on antibacterial, antifungal, antiviral, cytotoxic, and larvicidal activities were investigated in vitro. A series of 12 novel of 1,3-diaryltriazene-substituted sulfadiazine (SDZ) derivatives were synthesized, and the obtained pure products characterized in detail by spectroscopic and analytic methods (FT-IR, 1 H-NMR, 13 C-NMR, and melting points). The antibacterial and antifungal activities of these derivatives (AH1-12) were determined by broth microdilution method. All derivatives have been evaluated in cell-based assays for cytotoxic and antiviral activities against Modified Vaccinia Virus Ankara. The larvicidal efficacy of these chemical compounds was also investigated by using Lucilia sericata (L. sericata) larvae. Twelve 1,3-diaryltriazene-substituted SDZ derivatives (AH1-12) were designed and developed as potent multitargeted compounds. Among them, the AH1 derivative showed the most antibacterial and antifungal activity. Besides, synthesized derivatives AH2, AH3, AH5, and AH7 showed higher antiviral activity than SDZ. All synthesized derivatives showed higher cytotoxic activity than SDZ. Also, they showed larvicidal activity at 72 h of the experiment. As a result, these compounds might be great leads for the development of next-generation multitargeted agents., (© 2023 The Authors. Journal of Biochemical and Molecular Toxicology published by Wiley Periodicals LLC.)

Schiff bases (imines or azomethines) are versatile ligands synthesized from the condensation of amino compounds with active carbonyl groups and used for many pharmaceutical and medicinal applications. In our study, we aimed to determine the cytotoxic, antifungal and larvicidal activities of biologically potent bis-sulfonamide Schiff base derivatives that were re-synthesized by us. For this aim, 16 compounds were re-synthesized and tested for their cytotoxic, antifungal and larvicidal properties. Among this series, compounds A1B2, A1B4, A4B2, A4B3, and A4B4 were shown to have cytotoxic activity against tested cancer lung cell line (A549). The most potent antifungal activity was observed in compounds A2B1 and A2B2 against all fungi. A1B1 showed the strongest larvicidal effect at all concentrations at the 72nd h (100% mortality). These obtained results demonstrate that these type of bis-substituted compounds might be used as biologically potent pharmacophores against different types of diseases., (© 2023 The Authors. Journal of Biochemical and Molecular Toxicology published by Wiley Periodicals LLC.)

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.)

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.)

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.)

A series of 16 novel benzenesulfonamides incorporating 1,3,5-triazine moieties substituted with aromatic amines, dimethylamine, morpholine and piperidine were investigated. These compounds were assayed for antioxidant properties by using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, 2,2`-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical decolarisation assay and metal chelating methods. They were also investigated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and tyrosinase, which are associated with several diseases such as Alzheimer, Parkinson and pigmentation disorders. These benzenesulfonamides showed moderate DPPH radical scavenging and metal chelating activity, and low ABTS cation radical scavenging activity. Compounds 2 b , 3d and 3 h showed inhibitory potency against AChE with % inhibition values of >90. BChE was also effectively inhibited by most of the synthesised compounds with >90% inhibition potency. Tyrosinase was less inhibited by these compounds.

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.

A series of novel calix[4]azacrown substituted sulphonamide Schiff bases was synthesised by the reaction of calix[4]azacrown aldehydes with different substituted primary and secondary sulphonamides. The obtained novel compounds were investigated as inhibitors of six human (h) isoforms of carbonic anhydrases (CA, EC 4.2.1.1). Their antioxidant profile was assayed by various bioanalytical methods. The calix[4]azacrown substituted sulphonamide Schiff bases were also investigated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and tyrosinase enzymes, associated with several diseases such as Alzheimer, Parkinson, and pigmentation disorders. The new sulphonamides showed low to moderate inhibition against hCAs, AChE, BChE, and tyrosinase enzymes. However, some of them possessed relevant antioxidant activity, comparable with standard antioxidants used in the study.

This study provides a structure-activity relationship study of a series of lipophilic carbonic anhydrase (CA) inhibitors with an acetazolamide backbone. The inhibitors were tested against the tumor-expressed CA isozyme IX (CA IX), and the cytosolic CA I, CA II, and membrane-bound CA IV. The study identified several low nanomolar potent inhibitors against CA IX, with lipophilicities spanning two log units. Very potent pan-inhibitors with nanomolar potency against CA IX and sub-nanomolar potency against CA II and CA IV, and with potency against CA I one order of magnitude better than the parent acetazolamide 1 were also identified in this study, together with compounds that displayed selectivity against membrane-bound CA IV. A comprehensive X-ray crystallographic study (12 crystal structures), involving both CA II and a soluble CA IX mimetic (CA IX-mimic), revealed the structural basis of this particular inhibition profile and laid the foundation for further developments toward more potent and selective inhibitors for the tumor-expressed CA IX.

Building on the conclusions of previous inhibition studies with pyridinium-benzenesulfonamides from our team and on the X-ray crystal structure of the lead compound identified, a series of 24 pyridinium derivatives of 3-aminobenzenesulfonamide was synthesized and investigated for carbonic anhydrase inhibition. The new pyridinium-sulfonamides were evaluated as inhibitors of four human carbonic anhydrase (CA, EC 4.2.1.1) isoforms, namely CA I, CA II (cytosolic), CA IX and XII (transmembrane, tumor-associated forms). Excellent inhibitory activity in the nanomolar range was observed against CA IX with most of these sulfonamides, and against CA XII (nanomolar/sub-nanomolar) with some of the new compounds. These sulfonamides were generally potent inhibitors of CA II and CA I too. Docking studies revealed a preference of these compounds to bind the P1 hydrophobic site of CAs, supporting the observed inhibition profile. The salt-like nature of these positively charged sulfonamides can further focus the inhibitory ability on membrane-bound CA IX and CA XII and could efficiently decrease the viability of three human carcinomas under hypoxic conditions where these isozymes are over-expressed, thus recommending the new compounds as potential diagnostic tools or therapeutic agents., 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.)

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.)

Eight genetically distinct carbonic anhydrase (EC 4.2.1.1) enzyme families (α-, β-, γ- δ-, ζ-, η-, θ- and ι-CAs) were described to date. On the other hand, 16 mammalian α-CA isoforms are known to be involved in many diseases such as glaucoma, edema, epilepsy, obesity, hypoxic tumors, neuropathic pain, arthritis, neurodegeneration, etc. Although CA inhibitors were investigated for the management of a variety of such disorders, the activators just started to be investigated in detail for their in vivo effects. This review summarizes the activation profiles of α-, β, γ-, δ-, ζ- and η- CAs from various organisms (animals, fungi, protozoan, bacteria and archaea) with the most investigated classes of activators, the amines and the amino acids.

In this study, a series of 10 novel copper (II) and silver complexes of 1,3-diaryltriazene-substituted sulfonamides was synthesised. All the synthesised ligands and their metal complexes were assessed for in vitro cytotoxicity against human colorectal adenocarcinoma (DLD-1), cervix carcinoma (HeLa), breast adenocarcinoma (MDA-MB-231), colon adenocarcinoma (HT-29), endometrial adenocarcinoma (ECC-1), prostate cancer (DU-145 and PC-3), normal embryonic kidney (HEK-293), normal prostate epithelium (PNT-1A), and normal retinal pigment epithelium (ARPE-19) cells. Most of the metal complexes from the series showed to be more active against all cancerous cells than the uncomplexed 1,3-diaryltriazene-substituted sulfonamides, and lower cytotoxic effects observed on normal cells. Most of the Cu (II) and Ag (I) metal complexes from the presented series showed high cytotoxic activity against HeLa cells with IC 50 values ranging from 2.08 to >300 µM. Specifically, compound L 3 -Ag showed one of the highest cytotoxicity against all cancer cell lines with IC 50 values between 3.30 to 16.18 µM among other tested compounds.

A series of histamine bis-Schiff bases and bis-spinaceamine derivatives were synthesised and investigated as activators of four human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic hCA I, II and VII, and the membrane-associated hCA IV. All isoforms were effectively activated by the new derivatives, with activation constants in the range of 4.73-10.2 µM for hCA I, 6.15-42.1 µM for hCA II, 2.37-32.7 µM for hCA IV and 32 nM-18.7 µM for hCA VII, respectively. The nature of the spacer between the two histamine/spinaceamine units of these molecules was the main contributor to the diverse activating efficacy, with a very different fine tuning for the diverse isoforms. As CA activators recently emerged as interesting agents for enhancing cognition, in the management of CA deficiencies, or for therapy memory and artificial tissues engineering, our compounds may be considered as candidates for such applications.

Herein, we have described uniformly dispersed palladium-nickel nanoparticles furnished on graphene oxide (GO-supported PdNi nanoparticles) as a powerful heterogeneous nanocatalyst for the promotion of Knoevenagel reaction between malononitrile and aromatic aldehydes under mild reaction conditions. The successful characterization of PdNi nanoparticles on the GO surface was shown by X-ray diffraction, X-ray photoelectron spectroscopy, high-resolution transmission electron microscopy (HR-TEM), and TEM. GO-supported PdNi nanoparticles, which are used as highly efficient, stable, and durable catalysts, were used for the first time for the Knoevenagel condensation reaction. The data obtained here showed that the GO-supported PdNi nanocatalyst had a unique catalytic activity and demonstrated that it could be reused five times without a significant decrease in the catalytic performance. The use of this nanocatalyst results in a very short reaction time under mild reaction conditions, high recyclability, excellent catalytic activity, and a straightforward work-up procedure for Knoevenagel condensation of malononitrile and aromatic aldehydes., Competing Interests: The authors declare no competing financial interest.

A series of twenty novel ureido benzenesulfonamides incorporating 1,3,5-triazine moieties substituted on one side with aromatic amines and on the other side with dimethylamine, morpholine and piperidine is reported. The compounds were synthesized from the 4-(3-(4,6-dichloro-1,3,5-triazin-2-yl)ureido)benzensulfonamide (1) by using stepwise nucleophilic substitution of the chlorine atoms of cyanuric chloride. The intermediates 2(a-e) and final compounds 3(a-o) were tested for their efficiency as carbonic anhydrase (CA) inhibitors against four selected physiologically relevant human carbonic anhydrase (CA, EC 4.2.1.1) isoforms, namely, the cytosolic ones hCA I and II, and the transmembrane, tumor associated ones hCA IX, and XII. The compounds 2a, 2e and 3m showed the highest activity for hCA IX with K i s in the range of 11.8-14.6 nM. Most of the compounds showed high hCA IX selectivity over the abundant off-target isoforms hCA I and II. Since hCA IX is a validated drug target for anticancer/antimetastatic agents, these isoform-selective and potent inhibitors may be considered of interest for further medicinal/pharmacologic studies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A series of 4-substituted-spinaceamine (4,5,6,7-tetrahydro-imidazolo[4,5-c]pyridine) were prepared from histamine and aromatic aldehydes Schiff bases, and investigated as activators of four human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic hCA I, II and VII, and the membrane-associated hCA IV. All isoforms were effectively activated by the new derivatives, and the nature of the moiety in position 4 of the bicyclic system was the factor influencing activation properties against all isoforms. For hCA I, these compounds showed K A s in the range of 2.52-21.5 µM, the most effective activator being 4-(2-hydroxyphenyl)-spinaceamine. For hCA II the activation constants ranged between 0.60 and 17.2 µM, with 4-(2,3,5,6-tetrafluorophenyl)- spinaceamine the best activator. Affinity for hCA IV was in the range of 0.52-63.8 µM, and the same compound as for hCA II was the most effective activator. The most sensitive isoform for activation was the brain-associated hCA VII, for which K A s in the range of 82 nM-4.26 µM were observed. Effective hCA VII activators were the (2-bromophenyl)-, 2,3,5,6-tetrafluorophenyl- and furyl-substituted spineaceamines (K A s of 82-95 nM). As CA activators may have pharmacologic applications in various fields, this work provides interesting derivatives for further studies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A series of novel ureido benzenesulfonamides incorporating 1,3,5-triazine moieties were obtained by reacting 4-isocyanato-benzenesulfonamide (2) with 2-amino-4,6-dicholoro-1,3,5-triazine (4). The 4-(3-(4,6-dichloro-1,3,5-triazin-2-yl)ureido) benzenesulfonamide (5) was subsequently derivatized by reaction with various nucleophiles such as, morpholine, ammonia, methyl amine, dimethyl amine, and piperidine. The ureido benzenesulfonamides incorporating triazinyl moieties were investigated as inhibitors of four selected physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, namely, hCA I, II, IX, and XII which are involved in various diseases such as glaucoma, epilepsy, obesity and cancer. The membrane-bound tumor-associated isoform hCA IX was potently inhibited with these compounds with K i s in the range of 0.91-126.2 nM. Specifically, compound 7j showed great potency against hCA IX with sub-nanomolar K i of 0.91 nM. Since hCA IX is a validated drug target for anticancer agents, these isoform-selective and potent inhibitors may be considered of interest for further medicinal/pharmacologic studies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A series of new 1,3-diaryltriazene sulfonamides was synthesised by reaction of diazonium salt of metanilamide (3-aminobenzene sulfonamide) with substituted aromatic amines. The obtained new compounds were assayed as inhibitors of four physiologically and pharmacologically relevant human (h) isoforms of carbonic anhydrases (CA, EC 4.2.1.1), specifically, hCA I, hCA II, and hCA VII (cytosolic isoforms), as well as the tumour-associated membrane-bound isoform hCA IX. All isoforms investigated here were inhibited by the newly synthesised 1,3-diaryltriazene sulfonamide derivatives from the micromolar to the nanomolar range. The cytosolic isoforms were inhibited with K i s in the range of 92.3-8371.1 nM (hCA I), 4.3-9194.0 nM (hCA II), and 15.6-9477.8 nM (hCA VII), respectively. For the membrane-bound tumour-associated isoform hCA IX, the K I-s ranged between 50.8 and 9268.5 nM. The structure-activity relationship (SAR) with these newly synthesised metanilamide derivatives are discussed in detail.

Background/aim: Chemotherapeutic treatment options are often ineffective due to the development of resistance in cancer cells. Therefore, developing new anti-cancer agents is crucial for cancer treatment. Some triazine derivatives, their complexes and Copper(II) have anti-cancer effects on cancer cells. In this study, we aimed to determine the anti-proliferative effect of the novel synthesized Cu(II) complex with 3-(3-(4-fluorophenyl)triaz-1-en-1-yl) benzene-sulfonamide compound on the common cancer cell lines HeLa, MDA-MB-231, A2780 and MCF7., Materials and Methods: Common cancers cell lines were treated with copper complexes. Cell viability and apoptotic gene expression were examined., Results: Novel synthesized copper complex led to decreased viability of all cell lines. It also induced apoptosis via increasing the expression of caspase-3, caspase-9, Bax and p53 proteins and decreasing ERK expression., Conclusion: The novel synthesized copper complex has a significant inhibitory effect on the viability of cancer cell lines and can be considered as an antitumor agent for further studies., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

A series of novel 1,3-diaryltriazene-substituted sulfonamides was synthesized by reaction of diazonium salt of 4-amino benzenesulfonamide with substituted aromatic amines. The obtained 1,3-diaryltriazene-substituted sulfonamides were investigated as inhibitors of four selected human carbonic anhydrase (CA, EC 4.2.1.1) isoforms (hCA I, hCA II, hCA VII and hCA IX) are involved in various diseases such as glaucoma, epilepsy, retinitis pigmentosa, cancer, obesity, etc. All these sulfonamides were found to be potent inhibitors of the cytosolic isoform hCA II with low nanomolar to sub-nanomolar K i s in the range of 0.2-21.5 nM, as well as a moderate selectivity against other cytosolic isoforms hCA I and hCA VII, and great selectivity against membrane-bound isoform hCA IX was observed. Since hCA II is an important drug target for antiglaucoma agents and diuretics, these isoform-selective inhibitors may be considered of interest as tools for the development of new candidates for these conditions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A series of novel N,N''-diaryl cyanoguanidines were synthesized by reacting diphenyl N-cyanocarbonimidate with sulfanilamide followed by treatment of the obtained cyano-O-phenylisourea with substituted aromatic amines. The newly prepared N,N''-diaryl cyanoguanidines showed a very interesting inhibition profile against four selected human carbonic anhydrase (CA, EC 4.2.1.1) isoforms, hCA I and hCA II (cytosolic), hCA IV (membrane-bound), and hCA IX (transmembrane). All these compounds showed a potent inhibition against isoform hCA II,with inhibition constants in the low nanomolar range, as well as a high selectivity for hCA II over hCA I, IV and IX. Since hCA II is an important drug target for antiglaucoma agents, these isoform-selective inhibitors may be considered of interest for further medicinal/pharmacologic studies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The study utilizes monodisperse platinum nanoparticles (Pt NPs) biosynthesized from Punica granatum crusts as anti-tumor agents on the human breast cancer cell line, MCF-7. The obtained Pt NPs were fully characterized using the UV-vis spectrum (UV-vis), transmission electron microscopy (TEM), X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM) and Fourier transformation infrared spectroscopy (FTIR). Effectiveness of the Pt NPs was determined by cell viability, propidium iodide staining test, flow cytometry and comet tests on the MCF-7 cancer cell line. Cell survival percentage was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The biosynthesized monodisperse platinum nanoparticles inhibited MCF-7 proliferation with an IC 50 of 17.84 μg/ml after 48 h of incubation. Propidium iodide staining demonstrated that the monodisperse Pt NPs induced apoptosis by means of molecular DNA fragmentation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A series of 20 histamine Schiff base was synthesised by reaction of histamine, a well known carbonic anhydrase (CA, E.C 4.2.2.1.) activator pharmacophore, with substituted aldehydes. The obtained histamine Schiff bases were assayed as activators of five selected human (h) CA isozymes, the cytosolic hCA I, hCA II, and hCA VII, the membrane-anchored hCA IV and transmembrane hCA IX. Some of these compounds showed efficient activity (in the nanomolar range) against the cytosolic isoform hCA VII, which is a key CA enzyme involved in brain metabolism. Moderate activity was observed against hCA I and hCA IV (in the nanomolar to low micromolar range). The structure-activity relationship for activation of these isoforms with the new histamine Schiff bases is discussed in detail based on the nature of the aliphatic, aromatic, or heterocyclic moiety present in the aldehyde fragment of the molecule, which may participate in diverse interactions with amino acid residues at the entrance of the active site, where activators bind, and which is the most variable part among the different CA isoforms.

Addressed herein, we report the synthesis and characterization of a tert-nonyl mercaptan (TNM) functionalized reduced graphene oxide (rGO) supported palladium (Pd) nanoparticles (NPs) (Pd/TNM@rGO) as electrochemical sensor. The highly monodisperse Pd/TNM@rGO nanocomposite was applied for electrochemical determination of hydrogen peroxide (H 2 O 2 ) at a potential range of -0.6 to +0.8 V. The Pd/TNM@rGO sensor demonstrated very high activity, sensitivity, reusability and durability toward H 2 O 2 sensing. The well dispersed Pd/TNM@rGO nanocomposite has been characterized by using several analytical techniques such as, X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), electron energy loss spectroscopy (EELS) and electrochemical impedance spectroscopy (EIS). The catalytic performance of prepared biosensor was also characterized by using cyclic voltammetry (CV) and chronoamperometry (CA) methods. The proposed H 2 O 2 biosensor showed a broad linear range up to 12 mM, and a very low detection limit of 0.0025 μM, with a quick response time of less than 10 s. Additionally, the biosensor exhibited great capability, reproducibility and durability for the examination of H 2 O 2 ., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A series of sixteen novel aromatic and heterocyclic bis-sulfonamide Schiff bases were prepared by conjugation of well known aromatic and heterocyclic aminosulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor pharmacophores with aromatic and heterocyclic bis-aldehydes. The obtained bis-sulfonamide Schiff bases were investigated as inhibitors of four selected human (h) CA isoforms, hCA I, hCA II, hCA VII and hCA IX. Most of the newly synthesized compounds showed a good inhibitory profile against isoforms hCA II and hCA IX, also showing moderate selectivity against hCA I and VII. Several efficient lead compounds were identified among this bis-sulfonamide Schiff bases with low nanomolar to sub-nanomolar activity against hCA II (K i s ranging between 0.4 and 861.1nM) and IX (K i s between 0.5 and 933.6nM). Since hCA II and hCA IX are important drug targets (antiglaucoma and anti-tumor agents), these isoform-selective inhibitors may be considered of interest for various biomedical applications., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

A series of aromatic/heterocyclic bis-sulfonamides were synthesized from three established aminosulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor pharmacophores, coupled with either ethylene glycol oligomeric or polymeric diamines to yield bis-sulfonamides with short or long (polymeric) linkers. Testing of novel inhibitors and their precursors against a panel of membrane-bound CA isoforms, including tumor-overexpressed CA IX and XII and cytosolic isozymes, identified nanomolar-potent inhibitors against both classes and several compounds with medium isoform selectivity in a detailed structure-activity relationship study. The ability of CA inhibitors to kill tumor cells overexpressing CA IX and XII was tested under normoxic and hypoxic conditions, using 2D and 3D in vitro cellular models. The study identified a nanomolar potent PEGylated bis-sulfonamide CA inhibitor (25) able to significantly reduce the viability of colon HT-29, breast MDA-MB231, and ovarian SKOV-3 cancer cell lines, thus revealing the potential of polymer conjugates in CA inhibition and cancer treatment.

Conventionally, scanning electron or transmission microscopy, Raman and near infrared (NIR) spectroscopy, terahertz, florescence, and nuclear magnetic resonance imaging have been used to characterize functional coating structure. This study highlights the use of fluorescence microscopy to investigate the physicochemical stability and coating integrity of the commercially available enteric-coated omeprazole pellets containing a basic excipient and prepared by extrusion and spheronization or drug layering on the nonpareil seed, immediately followed by enteric coating (i.e., absence of protective sub-coat). The nature of coating interface and the likely development of an in situ interfacial layer after the application of enteric coating solution was examined using HPLC, NMR, differential scanning calorimetry (DSC), and fluorescent imaging methods. Likewise for the characterization of the solid pellet structure via fluorescence microscopy, a new approach based on fracturing technique (to avoid surface contamination) rather than microtome sectioning was used and validated. Analytical data showed that the pellets containing omeprazole remained chemically stable (>99.5% recovered). Control of the microenvironmental pH by the addition of alkalinizing excipient within a core formulation or as part of drug layering on top of nonpareil seed appears to efficiently neutralize the acidic effect of enteric coating dispersion. Fluorescence images further illustrate the absence of any discernable in situ layer formation at the coat-core interface.

A series of ethylene bis-imidazoles was synthesized via a novel microwave-mediated synthesis. Biological testing on eight isozymes of carbonic anhydrase (CA) present in the human brain revealed compounds with nanomolar potency against CA VA and CA VII, also displaying excellent selectivity against other CA isozymes present in this organ.