Synthesis and biological evaluation of aminomethyl and alkoxymethyl derivatives as carbonic anhydrase,acetylcholinesterase and butyrylcholinesterase inhibitors

Compounds containing nitrogen and sulfur atoms can be widely used in various fields such as industry, medicine, biotechnology and chemical technology. Therefore, the reactions of aminomethylation and alkoxymethylation of mercaptobenzothiazole, mercaptobenzoxazole and 2-aminothiazole were developed. Additionally, the alkoxymethyl derivatives of mercaptobenzoxazole and 2-aminothiazole were synthesized by a reaction with hemiformals, which are prepared by the reaction of alcohols and formaldehyde. In this study, the inhibitory effects of these molecules were investigated against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) enzymes and carbonic anhydrase I, and II isoenzymes (hCA I and II). Both hCA isoenzymes were significantly inhibited by the recently synthesized molecules, with K_i values in the range of 58–157?nM for hCA I, and 81–215?nM for hCA II. Additionally, the K_i parameters of these molecules for BChE and AChE were calculated in the ranges 23–88 and 18–78?nM, respectively.     

Synthesis and investigation of the conversion reactions of pyrimidine‐thiones with nucleophilic reagent and evaluation of their acetylcholinesterase,carbonic anhydrase inhibition,and antioxidant activities

The conversion reactions of pyrimidine‐thiones with nucleophilic reagent were studied during this scientific research. For this purpose, new compounds were synthesized by the interaction between 1,2‐epoxy propane, 1,2‐epoxy butane, and 4‐chlor‐1‐butanol and pyrimidine‐thiones. These pyrimidine‐thiones derivatives ( A–K ) showed good inhibitory action against acetylcholinesterase (AChE), and human carbonic anhydrase (hCA) isoforms I and II. AChE inhibition was in the range of 93.1 ± 33.7–467.5 ± 126.9 nM. The hCA I and II were effectively inhibited by these compounds, with K_i values in the range of 4.3 ± 1.1–9.1 ± 2.7 nM for hCA I and 4.2 ± 1.1–14.1 ± 4.4 nM for hCA II. On the other hand, acetazolamide clinically used as CA inhibitor showed K_i value of 13.9 ± 5.1 nM against hCA I and 18.1 ± 8.5 nM against hCA II. The antioxidant activity of the pyrimidine‐thiones derivatives ( A–K ) was investigated by using different in vitro antioxidant assays, including Cu²⁺ and Fe³⁺ reducing, 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH^?) radical scavenging, and Fe²⁺ chelating activities.     

Inhibitory effects of some phenolic compounds on the activities of carbonic anhydrase: from in vivo to ex vivo

Carbonic anhydrase (CA) inhibitors have been used for more than 60 years for therapeutic purposes in many diseases table such as in medications against antiglaucoma and as diuretics. Phenolic compounds are a new class of CA inhibitor. In our study, we tested the effects of arachidonoyl dopamine, 2,4,6-trihydroxybenzaldehyde and 3,4-dihydroxy-5-methoxybenzoic acid on esterase and the CO₂-hydratase activities of CA I and II isozymes purified from in vivo to ex vivo. The K_i values of arachidonoyl dopamine, 2,4,6-trihydroxybenzaldehyde and 3,4-dihydroxy-5-methoxybenzoic acid were 203.80, 1170.00 and 910.00?μM, respectively for hCA I and 75.25, 354.00 and 1510.00?μM, respectively for hCA II. Additionally, IC₅₀ values from in vivo studies were found to be in the range of 173.25–1360.0?μM for CA I and II, respectively, using CO₂-hydratase activity methods. These results demonstrated that phenolic compounds used in in vivo studies could be used in different biomedical applications to inhibit approximately 30% of the CO₂-hydratase activity of the total CA enzyme of rat erythrocytes.     

The in vivo effects of cefazolin,cefuroxime, and cefoperazon on the carbonic anhydrase in different rat tissues

In this paper, the in vivo effects of some antibiotics including cefazolin, cefuroxime, and cefoperazon, on the activity of the carbonic anhydrase enzyme (CA) in heart, brain, eye, liver, and kidney tissues of rats were evaluated. For this purpose, 16 different groups, which each containing six rats (n = 6), were formed (control group, cefazolin groups, cefuroxime groups, and cefoperazon groups). The rats were necropsied 60 min after the intraperitoneal injection of the chemicals into the rats. The CA activities were measured for each tissue using esterase activity methods. The activity values for each tissue obtained were statistically calculated. The CA activities in the liver tissue were assessed, and the activities of the cefoperazon groups were decreased compared to the sham groups from the third hour (p < 0.05). In the cefuroxime and cefoperazon groups, the CA activities in the eye tissue were decreased during the first 3 h and then increased (p < 0.05).     

The susceptibility to autoxidation of erythrocytes in diabetic mice: Effects of melatonin and pentoxifylline

Oxidative stress had a great importance in development of complications in diabetes. We investigated effects of melatonin and pentoxifylline in diabetic mice. Swiss albino mice (n = 40) were divided into four groups: alloxan‐induced diabetes mellitus (DM), alloxan‐induced diabetes with melatonin supplementation (DM + MLT), alloxan‐induced diabetes with pentoxifylline supplementation (DM + PTX), and control. Glutathione‐peroxidase (GSH‐Px) activity, malondialdehyde (MDA) and reduced glutathione (GSH) levels, and susceptibility to oxidation of erythrocytes were measured. MDA levels were higher than control in the DM and DM + MLT. The DM had more MDA level than the DM + MLT and DM + PTX (P < 0.001). After in vitro oxidation, MDA levels of all groups were found higher than the control. However, they were significantly lower than the DM in DM + PTX and DM + MLT (P < 0.001). Although GSH levels of the DM and DM + PTX were less than the control, GSH‐Px activity of the DM was lower than the control and DM + PTX (P < 0.05). We suggest that there is increased oxidative stress and compromised antioxidant status of erythrocytes in diabetes; however, it can be effectively prevented by melatonin or pentoxifylline supplementation.     

Inhibition properties of some flavonoids on carbonic anhydrase I and II isoenzymes purified from human erythrocytes

Carbonic anhydrases (CAs, E.C.4.2.1.1) play a critical role in many important physiological events and treatment of some diseases. Flavonoids or phenolic compounds have been discovered as novel CAs inhibitors instead of the traditional sulfonamides, with different binding to CAs, pro‐drug activities, and new inhibition mechanisms. Here, we investigated the inhibition effects of some flavonoids including malvin, callistephin, oenin, pelargonin, silychristin, and 1‐(4‐methoxyphenyl)‐2‐methyl‐3‐nitro‐1‐H‐indol‐6‐ol (ID‐8) against hCA I and II, which purified from human erythrocytes by affinity column chromatography. Both hCA isoenzymes were inhibited by flavonoids, with IC₅₀ and K_i values in the range of 2.34 nM to 346.5 μM and 51.01–99.55 μM for hCA I and 86.60–750.00 μM for hCA II, respectively. These results showed that flavonoids especially malvin and oenin effectively inhibited hCA I and II isoenzymes. Hence, they may be used as an effective CA inhibitor in medical applications for treatment of certain diseases such as glaucoma, in the future.     

Detection of Se,Vit. E,Vit. A,MDA, 8-OHdG,and CoQ10 Levels and Histopathological Changes in Heart Tissue in Sheep with White Muscle Disease

Biological Trace Element Research - This study was carried out to determine vit. E, Se, vit. A, malondialdehyde (MDA), 8-hydroxy-2-deoxyguanosine (8-OHdG), and ubiquinone-10 (CoQ10) levels and...     

The protective effect of curcumin on cardiac markers and fibrosis in abemaciclib-induced cardiac damage in rats

Abemaciclib (ABE) is a cyclin-dependent kinase inhibitor used in combination with an antiestrogen in the treatment of breast cancer. In addition to the important therapeutic properties of this drug, its side effects are not fully known. In this study, we aimed to investigate the protective effect of curcumin (CUR) on cardiac damage caused by ABE administration. Forty rats were equally divided into control, dimethyl sulfoxide (150 µL), CUR (30 mg/kg/day), ABE (26 mg/kg/day), and ABE + CUR (26 mg/kg/day ABE and 30mg/kg/day CUR) groups (n = 8). Injections were administered daily for 28 days. Troponin-I, total cholesterol, and creatine kinase myocardial band (CK-MB) levels and cardiac fibrosis were higher in the ABE group than in the control group (p < 0.05), and were lower in the ABE + CUR group than in the ABE group (p < 0.05). The results showed that ABE administration can cause cardiac damage and increase cardiac fibrosis. However, they showed that coadministration of CUR with ABE could suppress increases in CK-MB, troponin-I, and total cholesterol levels and also cardiac fibrosis associated with cardiac damage. Therefore, we can infer that the subsequent administration of CUR ABE treatment can be used as a therapeutic strategy for preventing cardiac damage.