Inhibitory effects of sulfenimides on human and bovine carbonic anhydrase enzymes.

A series of sulfenimide derivatives (1a-i) were investigated as inhibitors of human (hCA-I, hCA-II) and bovine (bCA) carbonic anhydrase enzymes. The compounds were synthesised by the reaction of substituted thiophenols with phthalimide by means of an effective, simple and eco-friendly method and the structures were confirmed by IR, 1H NMR, 13C NMR, MS and elemental analysis. All derivatives except for the methyl derivative (1b) exhibited effective inhibitory action at low micromolar concentrations on human isoforms, but only four derivatives (1e, 1f, 1h, 1i) inhibited the bovine enzyme. The bromo derivative (1f) was found to be strongest inhibitor of all three enzymes with KI values of 0.023, 0.044 and 20.57 µM for hCA-I, hCA-II and bCA, respectively. Results of our study will make valuable contributions to carbonic anhydrase inhibition studies for further investigations since inhibitors of this enzyme are important molecules for medicinal chemistry.

Detection of hip osteoarthritis by using plain pelvic radiographs with deep learning methods.

OBJECTIVE: The incidence of osteoarthritis is gradually increasing in public due to aging and increase in obesity. Various imaging methods are used in the diagnosis of hip osteoarthritis, and plain pelvic radiography is the first preferred imaging method in the diagnosis of hip osteoarthritis. In this study, we aimed to develop a computer-aided diagnosis method that will help physicians for the diagnosis of hip osteoarthritis by interpreting plain pelvic radiographs. MATERIALS AND METHODS: In this retrospective study, convolutional neural networks were used and transfer learning was applied with the pre-trained VGG-16 network. Our dataset consisted of 221 normal hip radiographs and 213 hip radiographs with osteoarthritis. In this study, the training of the network was performed using a total of 426 hip osteoarthritis images and a total of 442 normal pelvic images obtained by flipping the raw data set. RESULTS: Training results were evaluated with performance metrics such as accuracy, sensitivity, specificity, and precision calculated by using the confusion matrix. We achieved accuracy, sensitivity, specificity and precision results at 90.2%, 97.6%, 83.0%, and 84.7% respectively. CONCLUSION: We achieved promising results with this computer-aided diagnosis method that we tried to develop using convolutional neural networks based on transfer learning. This method can help clinicians for the diagnosis of hip osteoarthritis while interpreting plain pelvic radiographs, also provides assistance for a second objective interpretation. It may also reduce the need for advanced imaging methods in the diagnosis of hip osteoarthritis.

Synthesis and characterization of some new pyrazolines and their inhibitory potencies against carbonic anhydrases.

The inhibition of the two human cytosolic carbonic anhydrase (hCA; EC 4.2.1.1) isozymes I and II with some new pyrazoline derivatives was investigated for the first time. The structures of the newly synthesized pyrazoline derivatives were characterized by Fourier transform-infrared spectroscopy, 1 H-/13 C-nuclear magnetic resonance, and mass spectrometry, and elemental analysis. Compounds 1-6 showed Ki values in the range of 16.4-205.9 nM for hCA I and of 6.08-93.21 nM against hCA II. These hydroxyl and amino group-containing compounds generally were competitive inhibitors. The compounds investigated here showed effective hCA I and II inhibitory effects, in the same range as the clinically used acetazolamide, and might be used as leads for generating enzyme inhibitors, possibly targeting other CA isoforms that have not yet been assayed for their interactions with such agents.

Design, synthesis and molecular modelling studies of some pyrazole derivatives as carbonic anhydrase inhibitors.

In this study, newly synthesised compounds 6, 8, 10 and other compounds (1-5, 7 and 9) and their inhibitory properties against the human isoforms hCA I and hCA II were reported for the first time. Compounds 1-10 showed effective inhibition profiles with KI values in the range of 5.13-16.9 nM for hCA I and of 11.77-67.39 nM against hCA II, respectively. Molecular docking studies were also performed with Glide XP to get insight into the inhibitory activity and to evaluate the binding modes of the synthesised compounds to hCA I and II. More rigorous binding energy calculations using MM-GBSA protocol which agreed well with observed activities were then performed to improve the docking scores. Results of in silico calculations showed that all compounds obey drug likeness properties. The new compounds reported here might be promising lead compounds for the development of new potent inhibitors as alternatives to classical hCA inhibitors.

Design, synthesis, characterization of peripherally tetra-pyridine-triazole-substituted phthalocyanines and their inhibitory effects on cholinesterases (AChE/BChE) and carbonic anhydrases (hCA I, II and IX).

In this study, phthalocyanine precursors (5 and 9) and 1,2,3-triazole-substituted metal-free and metallo phthalocyanines (9a-c) were designed and synthesized for the first time and evaluated in vitro for key molecular targets. The structures of the novel compounds were characterized via FT-IR, 1H/13C NMR, UV-Vis, and mass spectroscopy. The inhibitory activities of the compounds were tested against human carbonic anhydrase isoforms hCA I, II (cytosolic, ubiquitous isozymes), and IX (transmembrane, cancer-associated isozyme) and cholinesterases (AChE and BChE, which are associated with Alzheimer's disease). Among the three phthalocyanines and starting compounds, 9b showed the most interesting profile as a nanomolar selective inhibitor of hCA I (Ki = 37.2 nM) and 9c showed the most effective inhibitory effect on hCA II, IX, AChE and BChE (Ki = 41.9, 27.4, 5.8 and 45.8 nM, respectively). This study is also the first example of cancer-associated isozyme hCA IX inhibition by phthalocyanines.

Triazole substituted metal-free, metallo-phthalocyanines and their water soluble derivatives as potential cholinesterases inhibitors: Design, synthesis and in vitro inhibition study.

In this study, 1,2,3-triazole substituted metal-free and metallo phthalocyanines (4, 5, 6) and their water soluble derivatives (4a, 5a, 6a) were designed, synthesized for the first time and tested in vitro on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Most phthalocyanines exhibited good inhibitory activities on these enzymes. Among the six phthalocyanines and starting compounds, 4a showed the most interesting profile as a submicromolar selective inhibitor of AChE (IC50 = 0.040 µM) and 5a showed the most effective inhibitor of BChE (IC50 = 0.1198 µM).

The synthesis of axially disubstituted silicon phthalocyanines, their quaternized derivatives and first inhibitory effect on human cytosolic carbonic anhydrase isozymes hCA I and II.

In this study a novel silicon(iv) phthalocyanine bearing [(2E)-3-[4-(dimethylamino)phenyl]-1-(4-phenoxy)prop-2-en-1-one] group and its quaternized derivative at their axial positions were synthesized for the first time. Axially disubstituted silicon(iv) phthalocyanines were also characterized by various spectroscopic techniques. The inhibition of two human cytosolic carbonic anhydrase (hCA, EC 4.2.1.1) isozymes I and II, with axially disubstituted silicon phthalocyanines and their quaternized derivatives were investigated by using the esterase assay, with 4-nitrophenyl acetate as substrate. Silicon phthalocyanines ZM-1-Si, ZM-5-Si, ZT-Si and their quaternized derivatives ZM-1-SiQ, ZM-5-SiQ, ZT-SiQ showed IC50 values in the range of 0.0178-0.1653 µM for hCA I and of 0.0172-0.1212 µM against hCA II, respectively. This study is the first example of carbonic anhydrase enzyme inhibition of phthalocyanines.

Synthesis and carbonic anhydrase inhibitory properties of novel chalcone substituted benzenesulfonamides.

Carbonic anhydrases (CAs, EC 4.2.1.1) are crucial metalloenzymes involved in many bioprocesses, through catalysis of the reversible hydration/dehydration process of CO2/HCO3-. The inhibition of human CA isoforms I and II with a new series of sulfonamide derivatives incorporating substituted chalcone moieties were studied in this study. All these newly synthesized sulfonamides demonstrated important inhibitory profiles to these CA isoforms with KIs in the range of 9.88 to 55.43nM, making these compounds interesting leads, with potential applications in medicinal chemistry.

Synthesis and Biological Evaluation of Novel Bischalcone Derivatives as Carbonic Anhydrase Inhibitors.

Design and synthesis of a new type of bischalcones as an alternative to natural and synthetic bischalcones are reported for the first time. Key steps involved the solvent-free Claisen-Schmidt condensation of chalcones, and the successful first application of the diazotization-diazocoupling reaction in the synthesis of CNNC-linked bischalcones by simple structural modification of p-aminoacetophenone. The structures of all compounds were confirmed by means of FT-IR, (1) H and (13) C NMR, ESI/MS, and elemental analysis. In addition, the newly synthesized compounds were screened for carbonic anhydrase inhibition activities. Almost all bischalcones exhibited moderate-to-good inhibitory activities.

An effect of the substituent position and metal type on the electropolymerization properties of chalcone substituted metallophthalocyanines.

Cobalt(II) and manganese(III) phthalocyanines bearing peripherally and non-peripherally tetra substituted {(2E)-3-[4-(dimethylamino)phenyl]prop-2-enoyl}phenoxy groups were synthesized by cyclotetramerization of the phthalonitrile derivatives and their electrochemical properties were examined using CV and SWV techniques for the first time. The novel compounds were characterized by using IR, (1)H-NMR, (13)C-NMR, UV-Vis and MS spectral data. Cyclic and square wave voltammetry revealed well-defined metal-based and ligand-based reduction processes within the complexes. Electrochemical measurements exhibit that all complexes oxidatively electropolymerized on the Pt working electrode during repetitive cyclic voltammetry measurements. This study is the first example of electropolymerization of peripherally and non-peripherally tetra chalcone substituted cobalt(II) and manganese(III) phthalocyanines. The types of the metal centers of the complexes and the position of substituents affect the character of the polymerization processes.