Mustafa Kucukislamoglu

Solvent-free synthesis of dihydropyrimidinones catalyzed by alumina sulfuric acid at room temperature

A simple, efficient and practical procedure for the Biginelli reaction using alumina sulfuric acid (ASA) as a novel acid catalyst is described under solvent-free conditions. The catalyst exhibited remarkable reactivity at room temperature. The method offers several advantages including high yields, environmentally friendly procedure, short reaction times and simple work up procedure.

New saccharin derivatives as tyrosinase inhibitors

A newly series of 6-(phenylurenyl/thiourenyl) saccharin (6a-y) derivatives were synthesized and their inhibitory effects on the diphenolase activity of banana tyrosinase were evaluated. A 70-fold purification of the enzyme with 6.85% yield was achieved by using a Sepharose 4B-l-tyrosine-p-amino benzoic acid affinity column. The result showed that all the synthesized compounds inhibited the tyrosinase enzyme activity. Among the compounds synthesized, 6-(3-iodophenylthiourenyl) saccharin (6s) was found to be most active one (K(i)=3.95 μM) and the inhibition kinetics analyzed by Lineweaver-Burk double reciprocal plots revealed that compound 6s was a competitive inhibitor. Structure-activity relationships study showed that generally, most of the 6-(phenylthiourenyl) saccharin derivatives (6m-y) exhibited higher inhibitory activity than 6-(phenylurenyl) saccharin derivatives (6a-l). An electron-withdrawing group at 3-position of phenylurenyl-ring increased in activity and the halogen series at 3-position of phenylthiourenyl-ring showed a qualitative relationship for higher inhibitory activity with increasing size and polarizability. We also calculated HOMO-LUMO energy levels and dipole moments of some selected the synthesized compounds (6a, 6h, 6m and 6s) using Gaussian software.

Synthesis, antioxidant and anticholinesterase activities of novel coumarylthiazole derivatives.

A newly series of coumarylthiazole derivatives containing aryl urea/thiourea groups were synthesized and their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. The result showed that all the synthesized compounds exhibited inhibitory activity to both cholinesterases. Among them, 1-(4-(8-methoxy-2-oxo-2H-chromen-3-yl)thiazol-2-yl)-3-(4-chlorophenyl)thiourea (f8, IC50 = 4.58 μM) was found to be the most active compound against AChE, and 1-(4-fluorophenyl)-3-(4-(6-nitro-2-oxo-2H-chromen-3-yl)thiazol-2-yl)urea (e31) exhibited the strongest inhibition against BuChE with IC50 value of 4.93 μM, which was 3.5-fold more potent than that of galantamine. The selectivity of f8 and e31 were 2.64 and 0.04, respectively. In addition, the cupric reducing antioxidant capacities (CUPRAC) and ABTS cation radical scavenging abilities of the synthesized compounds were investigated for antioxidant activity. Among them, f8, f4 and f6 (IC50=1.64, 1.82 and 2.69 μM, respectively) showed significantly better ABTS cation radical scavenging ability than standard quercetin (IC50 = 15.49 μM).

Potential of aryl-urea-benzofuranylthiazoles hybrids as multitasking agents in Alzheimer's disease.

New benzofuranylthiazole derivatives containing the aryl-urea moiety were synthesized and evaluated in vitro as dual acetylcholinesterase (AChE)-butyrylcholinesterase (BuChE) inhibitors. In addition, the cupric reducing antioxidant capacities (CUPRAC) and ABTS cation radical scavenging abilities of the synthesized compounds were assayed. The result showed that all the synthesized compounds exhibited inhibitory activity on both AChE and BuChE with 1-(4-(5-bromobenzofuran-2-yl)thiazol-2-yl)-3-(2-fluorophenyl)urea (e25, IC50 value of 3.85 μM) and 1-(4-iodophenyl)-3-(4-(5-nitrobenzofuran-2-yl)thiazol-2-yl)urea (e38, IC50 value of 2.03 μM) as the strongest inhibitors against AChE and BuChE, respectively. Compound e38 was 8.5-fold more potent than galanthamine. The selectivity index of e25 and e38 was 2.40 and 0.37 against AChE and BuChE, respectively. Compound e2, e4 and e11 (IC50 = 0.2, 0.5 and 1.13 μM, respectively) showed a better ABTS cation radical scavenging ability than the standard quercetin (IC50 = 1.18 μM). Best poses of compounds e38 on BuChE and e25 on AChE indicate that the thiazole ring and the amidic moiety are important sites of interaction with both ChEs. In addition, the benzofuran ring and phenyl ring are anchored to the side chains of both enzymes by π-π(pi-pi) interactions.

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.

Design, synthesis and docking study of novel coumarin ligands as potential selective acetylcholinesterase inhibitors

Abstract New coumaryl-thiazole derivatives with the acetamide moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and in vitro tested as acetylcholinesterase (AChE) inhibitors. 2-(diethylamino)-N-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)acetamide (6c, IC50 value of 43 nM) was the best AChE inhibitor with a selectivity index of 4151.16 over BuChE. Kinetic study of AChE inhibition revealed that 6c was a mixed-type inhibitor. Moreover, the result of H4IIE hepatoma cell toxicity assay for 6c showed negligible cell death. Molecular docking studies were also carried out to clarify the inhibition mode of the more active compounds. Best pose of compound 6c is positioned into the active site with the coumarin ring wedged between the residues of the CAS and catalytic triad of AChE. In addition, the coumarin ring is anchored into the gorge of the enzyme by H-bond with Tyr130.

An environmentally benign synthesis of flavones from 1,3-diketones using silica gel supported NaHSO4 catalyst

A simple and enviromentaly benign method for synthesis of flavones is described via dehydrative cyclisation of o-hydroxydibenzoylmethane using silica gel supported NaHSO4 catalyst.

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.

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, biological activity and multiscale molecular modeling studies for coumaryl-carboxamide derivatives as selective carbonic anhydrase IX inhibitors

Abstract New coumaryl-carboxamide derivatives with the thiourea moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and their inhibitory activity against the human carbonic anhydrase (hCA) isoforms hCA I, II, VII and IX were evaluated. While the hCA I, II and VII isoforms were not inhibited by the investigated compounds, the tumour-associated isoform hCA IX was inhibited in the high nanomolar range. 2-Oxo-N-((2-(pyrrolidin-1-yl)ethyl)carbamothioyl)-2H-chromene-3-carboxamide (e11) exhibited a selective inhibitory action against hCA IX with the Ki of 107.9 nM. In order to better understand the inhibitory profiles of studied molecules, multiscale molecular modeling approaches were used. Different molecular docking algorithms were used to investigate binding poses and predicted binding energies of studied compounds at the active sites of the CA I, II, VII and IX isoforms.