Cigdem Bilen

In vitro inhibition effect and structure–activity relationships of some saccharin derivatives on erythrocyte carbonic anhydrase I and II

Abstract In this study, in vitro inhibitory effects of some saccharin derivatives on purified carbonic anhydrase I and II were investigated using CO2 as a substrate. The results showed that all compounds inhibited the hCA I and hCA II enzyme activities. Among the compounds, 6-(p-tolylthiourenyl) saccharin (6m) was found to be the most active one for hCA I activity (IC50 = 13.67 μM) and 6-(m-methoxyphenylurenyl) saccharin (6b) was found to be the most active one for hCA II activity (IC50 = 6.54 μM). Structure–activity relationships (SARs) study showed that, generally, thiourea derivatives (6l--v) inhibited more hCA I and hCA II than urea derivatives (6a–k). All compounds (excluding 6c and 6r) have higher inhibitory activity on hCA II than on hCA I.

Synthesis and Evaluation of New Phthalazine Urea and Thiourea Derivatives as Carbonic Anhydrase Inhibitors

A new series of phthalazine substituted urea and thiourea derivatives were synthesized, and their inhibitory effects on the activity of purified human carbonic anhydrases (hCAs I and II) were evaluated. 2H-Indazolo[2,1-b]phthalazine-trione derivative (1) was prepared with 4-nitrobenzaldehyde, dimedone, and phthalhydrazide in the presence of TFA in DMF, and nitro group was reduced to amine derivative (2) with SnCl2·2H2O. The compound was reacted with isocyanates and isothiocyanates to get the final products (3a–p). The results showed that all the synthesized compounds inhibited the CA isoenzymes activity. 3a (IC50 = 6.40 µM for hCA I and 6.13 µM for hCA II) has the most inhibitory effect. The synthesized compounds are very bulky to be able to bind near the zinc ion, and they much more probably bind as the coumarin derivatives.

Coumarin or benzoxazinone based novel carbonic anhydrase inhibitors: synthesis, molecular docking and anticonvulsant studies

Abstract Among many others, coumarin derivatives are known to show human carbonic anhydrase (hCA) inhibitory activity. Since hCA inhibition is one of the underlying mechanisms that account for the activities of some antiepileptic drugs (AEDs), hCA inhibitors are expected to have anti-seizure properties. There are also several studies reporting compounds with an imidazole and/or benzimidazole moiety which exert these pharmacological properties. In this study, we prepared fifteen novel coumarin-bearing imidazolium and benzimidazolium chloride, nine novel benzoxazinone-bearing imidazolium and benzimidazolium chloride derivatives and evaluated their hCA inhibitory activities and along with fourteen previously synthesized derivatives we scanned their anticonvulsant effects. As all compounds inhibited purified hCA isoforms I and II, some of them also proved protective against Maximal electroshock seizure (MES) and ScMet induced seizures in mice. Molecular docking studies with selected coumarin derivatives have revealed that these compounds bind to the active pocket of the enzyme in a similar fashion to that previously described for coumarin derivatives.

Antipsychotic agents screened as human carbonic anhydrase I and II inhibitors

Abstract The antipsychotic drugs currently used to treat schizophrenia can be divided into two distinct classes, typical and atypical antipsychotics. Many drug molecules are enzyme inhibitors that bind reversibly or irreversibly to their target through intermolecular interactions. That’s why enzyme inhibition studies are an important issue for drug design and biochemical applications. In this study, in vitro inhibition effect of some antipsychotic drugs on the purified carbonic anhydrase (CA) I and II isoenzymes were investigated by using CO2 as a substrate. CA I and II were purified from human erythrocytes by a simple one step procedure using Sepharose 4B-L-tyrosine-sulfonamide affinity column. The results showed that all the drugs inhibited the cytosolic carbonic anhydrases enzyme activity in a concentration-dependent fashion. Among the studied drugs, aripiprazole and pramipexole were found to be the most active one for hCA I (IC50: 3.64 and 5.37 μM) and hCA II (IC50: 4.16 and 4.81 μM) activity, respectively.

Synthesis, antioxidant and carbonic anhydrase I and II inhibitory activities of novel sulphonamide-substituted coumarylthiazole derivatives

Abstract New secondary benzenesulphonamide-substituted coumarylthiazole derivatives were synthesized and their inhibitory effects on purified carbonic anhydrase I and II were evaluated using CO2 as a substrate. The result showed that all the synthesized compounds exhibited inhibitory activity on both hCA I and hCA II with N-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)naphthalene-2-sulphonamide (5f, IC50 value of 5.63 and 8.48 µM, against hCA I and hCA II, respectively) as the strongest inhibitor revealed from this study. Structure–activity relationship revealed that the inhibitory activity of the synthesized compounds is related to the type of the halogen and bulky substituent on the phenyl ring. In addition, the cupric reducing antioxidant capacities (CUPRAC) and ABTS cation radical scavenging abilities of the synthesized compounds were assayed. 4-methoxy-N-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)benzenesulphonamide (5e) exhibited the strongest ABTS and CUPRAC activity with IC50 value of 48.83 µM and A0.50 value of 23.29 µM, respectively.

Synthesis and evaluation of new phthalazine substituted β-lactam derivatives as carbonic anhydrase inhibitors

A new series of phthalazine substituted β-lactam derivatives were synthesized and their inhibitory effects on the activity of purified human carbonic anhydrase (hCA I and II) were evaluated. 2H-Indazolo[2,1-b]phthalazine-trione derivative was prepared with 4-nitrobenzaldehyde, dimedone, and phthalhydrazide in the presence of TFA in DMF, and the nitro group was reduced to 13-(4-aminophenyl)-3,3-dimethyl-3,4-dihydro-2H-indazolo[1,2-b]phthalazine-1,6,11(13H)-trione with SnCl2 · 2H2O. The reduced compound was reacted with different aromatic aldehydes, and phthalazine substituted imines were synthesized. The imine compounds undergo (2+2) cycloaddition reactions with ketenes to produce 2H-indazolo[2,1-b]phthalazine-trione substituted β-lactam derivatives. The β-lactam compounds were tested as inhibitors of the CA isoenzyme activity. The results showed that all the synthesized compounds inhibited the CA isoenzyme activity. 1-(4-(3,3-dimethyl-1,6,11-trioxo-2,3,4,6,11,13-hexahydro-1H-indazolo[1,2b]phthalazin-13-yl)phenyl)-2-oxo-4-p-tolylazetidin-3-yl acetate (IC50 = 6.97 µM for hCA I and 8.48 µM for hCA II) had the most inhibitory effect.

In vitro inhibition effect of some chalcones on erythrocyte carbonic anhydrase I and II

Abstract In this study, 4’-(phenylurenyl/thiourenyl)chalcones (14–25) were prepared from 4’-(phenylurenyl/thiourenyl)acetophenones and benzaldehyde derivatives by Claisen-Schmidt condensation. In vitro inhibition effects of chalcone derivatives on purified carbonic anhydrase I and carbonic anhydrase II were investigated by using the CO2 hydration method of Maren. The result showed that all the synthesized compounds inhibited the CA isoenzymes activity. 18 and 19 were found to be most active (IC50 = 25.41 μM and 23.06 μM) for hCA I, respectively. For hCA II, 24 is the most active compound (IC50 = 14.40 μM).

Synthesis and In Vitro Inhibition Effect of New Pyrido[2,3-d]pyrimidine Derivatives on Erythrocyte Carbonic Anhydrase I and II

In vitro inhibition effects of indolylchalcones and new pyrido[2,3-d]pyrimidine derivatives on purified human carbonic anhydrase I and II (hCA I and II) were investigated by using CO2 as a substrate. The results showed that all compounds inhibited the hCA I and hCA II enzyme activities. Among all the synthesized compounds, 7e (IC50 = 6.79 µM) was found to be the most active compound for hCA I inhibitory activity and 5g (IC50 = 7.22 µM) showed the highest hCA II inhibitory activity. Structure-activity relationships study showed that indolylchalcone derivatives have higher inhibitory activities than pyrido[2,3-d]pyrimidine derivatives on hCA I and hCA II. Additionally, methyl group bonded to uracil ring increases inhibitory activities on both hCA I and hCA II.

Synthesis and carbonic anhydrase inhibitory properties of 1,3-dicarbonyl derivatives of methylaminobenzene-sulfonamide

Abstract 1,3-Dicarbonyl derivatives of methylaminobenzene-sulfonamide were synthesized and their inhibitory effects on the activity of purified human carbonic anhydrase (hCA) I and hCA II were evaluated. hCA I and hCA II from human erythrocytes were purified by a simple one-step procedure by using Sepharose 4B-L-tyrosine-sulfanilamide affinity column. Our results show that the synthesized compounds inhibited the activity of carbonic anhydrase (CA) I and CA II. Among them, 2b and 2e were found to be the most active (IC50 = 2.12 and 2.52 µM) for hCA I and hCA II, respectively.

In vitro effects of estrogen and progesterone containing drugs on human erythrocyte carbonic anhydrase I and II isozymes in women smokers and nonsmokers

Background Carbonic anhydrases (CAs), a group of metalloenzymes, are involved in numerous physiological and pathological processes such as acid–base balance, gluconeogenesis, lipogenesis, ureagenesis, electrolyte secretion in various tissues, bone resorption and calcification, and tumorigenicity. In the current study, we aimed to determine and compare possible alterations in the activity of carbonic anhydrase I (CA I) and carbonic anhydrase II (CA II) isozymes by using estrogens and progestagens in female smokers and nonsmokers. Methods Blood samples from 30 smoker and 30 nonsmoker volunteers were drawn after obtaining informed consent. The blood samples were centrifuged to separate the plasma and erythrocytes. Thereafter, hemolysate was prepared from the red cells. CA I and CA II were purified from human erythrocytes with a simple one‐step procedure using Sepharose 4B‐l‐tyrosine‐sulfonamide affinity column. CAI and CA II isozymes were treated with estrogen and progesterone‐containing drugs, after which the inhibition or activation of the enzyme was determined. Results CA I and CA II enzyme activity was observed to be increased in female smokers. The results of this study show that dienogest is the most effective inhibitor for human erythrocytes CA I when compared with micronized progesterone, hydroxyprogesterone caproate, estradiol valerate, and estradiol hemihydrate in both female smokers and nonsmokers. All active ingredients have been shown to have a stronger inhibition in smokers than nonsmokers for CA I activity. Additionally, estradiol valerate and hydroxyprogesterone caproate have stronger inhibition against CA II enzyme activity in women who smoke. Conclusion The results of the current study provide important information to clinicians about how to consider the possible adverse effects of these drugs which are produced as a result of inhibition of CA I and CA II enzyme. Clinicians should take into consideration the side effects caused by CA I and CA II enzyme inhibition when prescribing these drugs in the treatment of different clinical conditions, especially in women who smoke.