Umit M. Kocyigit

Synthesis, characterization, anticancer, antimicrobial and carbonic anhydrase inhibition profiles of novel (3aR,4S,7R,7aS)-2-(4-((E)-3-(3-aryl)acryloyl) phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione derivatives

In the present study, a series of new hybrid compounds containing chalcone and methanoisoindole units 7a-n ((3aR,4S,7R,7aS)-2-(4-((E)-3-(3-aryl)acryloyl) phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione) were synthesized, characterized and investigated for their anticancer activity against C6 gliocarcinoma cell in rats, and antimicrobial activity against some human pathogen microorganisms. The compounds 7e, 7h, 7j, 7k, 7L and 7n showed very high anticancer activity with the inhibition range of 80.51-97.02% compared to 5-FU. Some of the compounds exhibited anti-microbial activity. Also, they evaluated for inhibition effects against human carbonic anhydrase I, and II isoenzymes (hCA I and II) with Ki values in the range of 405.26-635.68pM for hCA I, and 245.40-489.60pM for hCA II, respectively. These results demonstrated that 3aR,4S,7R,7aS)-2-(4-((E)-3-(3-aryl)acryloyl)phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione derivatives could be used in different biomedical applications.

Synthesis and Carbonic Anhydrase Inhibition of Novel 2-(4-(Aryl)thiazole-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione Derivatives

Carbonic anhydrase (CA, EC 4.2.1.1) is a member of the metalloenzyme family. It catalyzes the rapid conversion of carbon dioxide (CO2) and water to bicarbonate (HCO3−) and protons (H+) and also plays an important role in biochemical and physiological processes. In this study, a number of novel 2‐(4‐(aryl)thiazole‐2‐yl)‐3a,4,7,7a‐tetrahydro‐1H‐4,7‐methanoisoindole‐1,3(2H)‐dione derivatives were synthesized and evaluated for their inhibitory characteristics against the human CA isoenzymes I and II (hCA I and hCA II). The structures of the new molecules 8a–i were confirmed by means of IR, 1H NMR, 13C NMR, and elemental analysis. These compounds exhibited excellent inhibitory effects, in the low nanomolar range, with Ki values in the range of 27.07–37.80 nM against hCA I and in the range of 11.80–25.81 nM against hCA II. Our findings suggest that the new isoindolylthiazole derivatives have superior inhibitory effect over acetazolamide (AZA), which is used as clinical CA inhibitor with Ki values of 34.50 and 28.93 nM against the hCA I and hCA II isoenzymes, respectively.

Synthesis, carbonic anhydrase I and II isoenzymes inhibition properties, and antibacterial activities of novel tetralone-based 1,4-benzothiazepine derivatives.

Benzothiazepine compounds have a wide range of applications such as antibacterial, antidepressants, anticonvulsants, antihypertensives, antibiotics, antifungal, hypnotic, enzyme inhibitors, antitumor, anticancer and anti‐HIV agents. In this study, the synthesis of novel tetralone‐based benzothiazepine derivatives (1–16) and their in vitro antibacterial activity and human carbonic anhydrase isoenzymes I and II (hCA I and II) inhibitory effects were investigated. Both isoenzymes were purified by sepharose‐4B‐l‐tyrosine‐sulfanilamide affinity chromatography from fresh human red blood cells. All compounds demonstrated the low nanomolar inhibitory effects on both isoenzymes using esterase activity. Benzothiazepine derivative 2 demonstrated the best hCA I inhibitory effect with Ki value of 18.19 nM. Also, benzothiazepine derivative 7 showed the best hCA II inhibitory effect with Ki value of 11.31 nM. On the other hand, acetazolamide clinically used as CA inhibitor, showed Ki value of 19.92 nM against hCA I and 33.60 nM against hCA II, respectively.

Evaluation of acetylcholinesterase and carbonic anhydrase inhibition profiles of 1,2,3,4,6‐pentasubstituted‐4‐hydroxy‐cyclohexanes

Carbonic anhydrase (CA; EC 4.2.1.1) is used for remedial purposes for several years, as there is significant focus on expanding more new activators (CAAs) and high affinity inhibitors. Alzheimer′s disease and other similar ailments such as dementia and vascular dementia with Lewy bodies reduce cholinergic activity in the important areas involved in cognition and memory. Prevalent drugs for the symptomatic therapy of dementia are significant in increasing the associated cholinergic deficiency by inhibiting acetylcholinesterase (AChE). These six‐membered carbocycles showed nice inhibitory action against AChE and human carbonic anhydrase (hCA) II and I isoforms. The hCA I, II, and AChE were efficiently inhibited by these molecules, with Ki values in the range of 6.70–35.85 nM for hCA I, 18.77–60.84 nM for hCA II, and 0.74–4.60 for AChE, respectively.

Synthesis of chalcone-imide derivatives and investigation of their anticancer and antimicrobial activities, carbonic anhydrase and acetylcholinesterase enzymes inhibition profiles

Abstract The new 1-(4-(3-(aryl)acryloyl)phenyl)-1H-pyrrole-2,5-diones (5a–g) were prepared from 4′-aminchalcones (3a–g) and screened for biological activities. All compounds (3a–g and 5a–g), except 3d and 3e displayed good cytotoxic activities with IC50 values in the range of 7.06–67.46 μM. IC50 value of 5-fluorouracil (5-FU) was 90.36 μM. Moreover, most of compounds 5a–g showed high antibacterial activity with 8–20 mm of inhibition zone (19–25 mm of Sulbactam-Cefoperazone (SCF)). In addition, they showed good inhibitory action against acetylcholinesterase (AChE), and human carbonic anhydrase I, and II (hCA I and hCA II) isoforms. Also, these compounds demonstrated effective inhibition profiles with Ki values of 426.47–699.58 nM against hCA I, 214.92–532.21 nM against hCA II, and 70.470–229.42 nM against AChE. On the other hand, acetazolamide, clinically used drug, showed a Ki value of 977.77 ± 227.4 nM against CA I, and 904.47 ± 106.3 nM against CA II, respectively. Also, tacrine inhibited AChE showed a Ki value of 446.56 ± 58.33 nM.

Inhibitory effects of oxytocin and oxytocin receptor antagonist atosiban on the activities of carbonic anhydrase and acetylcholinesterase enzymes in the liver and kidney tissues of rats

The aim of this study was to investigate the effects of oxytocin (OT), atosiban, which is an OT receptor antagonist, and OT‐atosiban chemicals injected to rats on the activities of carbonic anhydrase (CA) and acetylcholinesterase (AChE) enzymes in liver and kidney tissues of rats. For this purpose, four different groups, each consisting of six rats (n = 6), were formed (control group, OT administered group, atosiban administered group, and both OT and atosiban administered group). The rats were necropsied 60 min after intraperitoneal injection of chemicals into the rats. Liver tissues of rats were extracted. CA and AChE enzyme activities were measured for each tissue by using hydratase, esterase, and acetylcholiniodide methods. Activity values for each enzyme obtained were statistically calculated.

Synthesis and Carbonic Anhydrase Inhibition of Tetrabromo Chalcone Derivatives

In the present study, human carbonic anhydrase (hCA) enzyme was purified and characterized from fresh blood human red cells by Sepharose‐4B‐l‐tyrosine‐sulfanilamide affinity gel chromatography. Secondly, a series of new tetrabromo chalcone derivatives containing 4,7‐methanoisoindol‐1,3‐dione (2a–i) were synthesized from the addition of Br2 to related chalcone derivatives (1a–i). The structures of the new molecules (2a–i) were confirmed by means of 1H NMR, 13C NMR and elemental analysis. Finally, the inhibitory effects of 2a–i on CA activities were investigated using the esterase method under in vitro conditions. The compounds 2a–i exhibited excellent inhibitory effects, in the low nanomolar range, with Ki values in the range of 11.30–21.22 nM against hCA I and in the range of 8.21–12.86 nM against hCA II. Our findings suggest that the new compounds 2a–i have superior inhibitory effect over acetazolamide (AZA), which is used as clinical CA inhibitor, with obtained Ki values of 34.50 and 28.93 nM against the hCA I and II isozymes, respectively. In addition to the inhibition assays, molecular modeling approaches were implemented for prediction of the binding affinities of compounds 2a and 2c, which had the highest inhibition effects, against the hCA I and II isozymes.

Investigation of acetylcholinesterase and mammalian DNA topoisomerases, carbonic anhydrase inhibition profiles, and cytotoxic activity of novel bis(α-aminoalkyl)phosphinic acid derivatives against human breast cancer

The aim of this study was to evaluate biologically active novel molecules having potentials to be drugs by their antitumor properties and by activities of apoptotic caspase and topoisomerase. Following syntheses of novel eight bis(α‐aminoalkyl)phosphinic acid derivatives (4a–h) as a result of array of reactions, compounds were evaluated by cytotoxic effects in vitro on human breast cancer (MCF‐7) and normal endothelial (HUVEC) cell lines. All phosphinic acid derivatives were effective for cytotoxicity on both MCF‐7 and HUVEC lines, while 4c, 4e, and 4f compounds were found significantly more effective. For the evaluation of antitumor properties of compounds in a highly sensitive method, their effects on inhibiting topoisomerases I and II were investigated. Also, some of the bis(α‐aminoalkyl)phosphinic acid derivatives (4a, 4e–h) showed nice inhibitory action against acetylcholinesterase and human carbonic anhydrase isoforms I and II.

Synthesis and investigation of antibacterial activities and carbonic anhydrase and acetyl cholinesterase inhibition profiles of novel 4,5-dihydropyrazol and pyrazolyl-thiazole derivatives containing methanoisoindol-1,3-dion unit

ABSTRACT Novel 4,5-dihydropyrazole derivatives (3a–i), 3-(4-((3aR,4S,7R,7aS)-1,3-dioxo-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindol-2(3H)-yl)phenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-1-carbothio amide, were obtained by the addition of thiosemicarbazide (2) to the chalcones (1a–i). The addition–cyclization of 2,4′-dibromoacetophenone (4) to pyrazole derivatives (3a–i) gave the new pyrazolyl-thiazole derivatives (5a–i), (3aR,4S,7R,7aS)-2-(4-(1-(4-(4-bromophenyl)thiazol-2-yl)-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione. Antibacterial and acetylcholinesterase (AChE) enzyme and human carbonic anhydrase (hCA) I, and II isoform inhibitory activities of the compounds 3a–i and 5a–i were investigated. Some of the compounds showed promising antibacterial activity. In addition, the hCA II and I were effectively inhibited by the lately synthesized derivatives, with Ki values in the range of 18.90 ± 2.37 −58.25 ± 13.62 nM for hCA II and 5.72 ± 0.98 −37.67 ± 5.54 nM for hCA I. Also, the Ki parameters of these compounds for AChE were obtained in the range of 25.47 ± 11.11 − 255.74 ± 82.20 nM. Also, acetazolamide, clinical molecule, was used as a CA standard inhibitor that showed Ki value of 70.55 ± 12.30 nM against hCA II, and 67.17 ± 9.1 nM against hCA I, and tacrine inhibited AChE showed Ki value of 263.67 ± 91.95. GRAPHICAL ABSTRACT

Synthesis of some novel pyridine compounds containing bis-1,2,4-triazole/thiosemicarbazide moiety and investigation of their antioxidant properties, carbonic anhydrase, and acetylcholinesterase enzymes inhibition profiles

Some novel derivatives of thiosemicarbazide and 1,2,4‐triazole‐3‐thiol were synthesized and evaluated for their biological activities. The title compounds were prepared starting from readily available pyridine‐2,5‐dicarboxylic acid. The reaction carboxylic acid with absolute ethanol afforded the corresponding dimethyl pyridine‐2,5‐dicarboxylate (1). The reaction of dimethyl‐2,5‐pyridinedicarboxylate (1) with hydrazine hydrate good yielded pyridine‐2,5‐dicarbohydrazide (2). Refluxing compound 2 with alkyl/aryl isothiocyanate derivatives for 3–8 h afforded 1,4‐disubstituted thiosemicarbazides (3a–e). Base‐catalyzed intra‐molecular dehydrative cyclization of these intermediates furnished the 4,5‐disubstituted bis‐mercaptotriazoles (4a–e) in good yield (85%–95%). Among the target compounds, 2,2′‐(pyridine‐2,5‐diyldicarbonyl)bis[N‐(p‐methoxyphenyl)hydrazinecarbothioamide] (3c) showed very high activity with value of 72.93% against 1,1‐diphenyl‐2‐picrylhydrazyl free radical at the concentration of 25 μg/mL. The inhibitory effects of the target compounds against acetylcholinesterase (AChE), hCA I, and II were studied. AChE, cytosolic hCA I and II isoforms were potently inhibited by synthesized these derivatives with Kis in the range of 3.07 ± 0.76–87.26 ± 29.25 nM against AChE, in the range of 1.47 ± 0.37–10.06 ± 2.96 nM against hCA I, and in the range of 3.55 ± 0.57–7.66 ± 2.06 nM against hCA II, respectively.