Stereospecific synthesis of highly substituted novel carbasugar as carbonic anhydrase inhibitors: decahydronaphthalene-1,2,3,4,5,6,7-heptol

Decahydronaphthalene-1,2,3,4,5,6,7-heptol, a new polycyclitol, was synthesized starting from p-benzoquinone. An endo selective Diels-Alder cycloaddition between p-benzoquinone and 1-acetoxybutadiene followed by stereoselective reduction with NaBH₄/CeCl₃·7H₂O led to the formation of an allylic cis-diol. The formed diol was converted into its acetate with Ac₂O/pyridine, in a transformation that required inert atmosphere conditions to suppress a competing aromatization. Controlled oxidation by OsO₄ of two olefinic bonds followed by acetylation yielded the heptaacetate whose structure was established unequivocally via application of X-ray crystallographic methods. Removal of the acetate groups by NH₃ provided the target heptol. In addition, the carbonic anhydrase inhibitory potency of the title compound was investigated and it was shown to be a potent inhibitor compared to the standard CA inhibitors.     

The design of fluoroquinolone-based cholinesterase inhibitors: Synthesis,biological evaluation and in silico docking studies

An enhanced acetylcholinesterase (AChE) activity is a hallmark in early stages of Alzheimer's ailment that results in decreased acetylcholine (ACh) levels, which in turn leads to cholinergic dysfunction and neurodegeneration. Consequently, inhibition of both AChE and butyrylcholinesterase (BChE) is important to prolong ACh activity in synapses for the enhanced cholinergic neurotransmission. In this study, a series of new fluoroquinolone derivatives (7a-m) have synthesized and evaluated for AChE and BChE inhibitory activities. The screening results suggested that 7 g bearing ortho fluorophenyl was the most active inhibitor against both AChE and BChE, exhibiting IC₅₀ values of 0.70 ± 0.10 µM and 2.20 ± 0.10 µM, respectively. The structure–activity relationship (SAR) revealed that compounds containing electronegative functions (F, Cl, OMe, N and O) at the ortho position of the phenyl group exhibited higher activities as compared to their meta- and/or para substituted counterparts. Molecular docking studies of synthesized compounds 7a, 7g, 7j and 7l docked into the active site of AChE and 7a-f docked into the active site of BChE revealed that these compounds exhibited conventional H-bonding along with π-π interaction with the active residues of AChE through their electronegative functions and phenyl ring, respectively. All the synthesized compounds are characterized by spectroscopic methods including FT-IR, ¹H- and ¹³C NMR as well as elemental analysis. This is the first example of fluoroquinolone-based cholinesterase inhibitors.     

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

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 K_i 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 K_i 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 K_i value of 70.55?±?12.30?nM against hCA II, and 67.17?±?9.1?nM against hCA I, and tacrine inhibited AChE showed K_i value of 263.67?±?91.95.     

Exploration of carbonic anhydrase inhibition of bioactive metabolites from Pistacia integerrima by molecular docking and first-principles investigations

Bioassay guided fractionation of Pistacia integerrima crude methanolic extract gave Pistacide-A (1) and Pistacide-B (2), along with ten known phytochemicals (3–12). Biochemical analysis of crude plant extract, in-vitro and in-silico carbonic anhydrase inhibitory potential of newly isolated compounds Pistacide-A (1) and Pistacide-B (2) were performed. The cytotoxicity of extract in methanol, ethylacetate and n-butanol against Artemia salina brine-shrimp was 34.98 g/ml, 160.81 g/ml, and 135.77 g/ml, respectively. The significant antimicrobial activity was exhibited by crude, ethyl acetate, and n-butanol fractions. Compounds 1 (IC₅₀ = 6.51 ± 0.42 mM) and 2 (IC₅₀ = 2.85 ± 0.09 mM) showed good carbonic anhydrase inhibition compared with standard zonisamide drug (IC₅₀ = 1.87 ± 0.003 mM). In addition, we have also clarified the electronic properties, absorption wavelengths, molecular electrostatic potential and Hirshfeld analysis by first-principles studies. The coherent intra-molecular charge transfer was seen from occupied to unoccupied molecular orbitals. The absorption wavelengths calculated at time dependent B3LYP/6-31G** level in methanol provided excellent accord with the experimental evidence. Molecular docking score revealed that Pistacide-B would be an efficient drug than its other counterpart that is rational to the experimental data.     

Screening and docking studies of natural phenolic inhibitors of carbonic anhydrase II

Carbonic anhydrase II (CA II) is an important enzyme complex with Zn²⁺, which is involved in many physiological and pathological processes, such as calcification, glaucoma and tumorigenicity. In order to search for novel inhibitors of CA II, inhibition assay of carbonic anhydrase II was performed, by which seven natural phenolic compounds, including four phenolics (grifolin, 4-O-methyl-grifolic acid, grifolic acid, and isovanillic acid) and three flavones (eriodictyol, quercetin and puerin A), showed inhibitory activities against CA II with IC₅₀s in the range of 6.37–71.73 μmol/L. Grifolic acid is the most active one with IC₅₀ of 6.37 _μmol/L. These seven phenolic compounds were proved to be novel natural carbonic anhydrase II inhibitors, which were obtained in flexible docking study with GOLD 3.0 software. Results indicated that the aliphatic chain and polar groups of hydroxyl and carboxyl are important to their inhibitory activities, providing a new insight into study on CA II potent inhibitors. Authors with the equal contribution Supported by the National Natural Science Foundation of China (Grant No. 30725048) and the Foundation of Chinese Academy of Sciences (West Light Program).     

Conformational analysis of carbonic anhydrase inhibitors using ab initio molecular orbital methods. 1. Rotational isomerism in methane sulfonamide anion, CH3-SO2-NH−

Ab initio calculations have been performed on methane sulfonamide anion. Geometries have been optimized using Hartree-Fock basis sets up to 6-31+G*, and single-point calculations employing those Hartree-Fock geometries have been performed at levels up to MP2/6-311++G**. In addition, geometry optimizations for the 0°, 90°, 150°, and 180° conformers have been carried out at the MP2/6-31G*, MP2/6-31+G*, and MP2/6-311++G** levels. Vibrational frequencies have been calculated using the HF/4-31G*, MP2/6-31G*, and MP2/6-31+G* geometries. All calculations at or above the 4-31G* level agree that H—N—S—C ˜90° is the global minimum. The H—N—S—C = 180° conformer is clearly higher in energy although the relative energy of this conformer varies from 0.36 to 1.03 kcal/mol for the post-HF calculations depending on basis set. The H—N—S—C = 180° conformer appears to be a very shallow local minimum. However, the potential energy surface is quite flat in this region, and the highest-level calculations, including MP2 optimizations and vibrational frequency analysis, are ambiguous on this point. The conformer with an H—N—S—C torsion of 0° is a transition state with a relative energy ˜8 kcal/mol. Received: 3 December 1996 / Accepted: 2 January 1997     

Synthesis and pharmacological effects of novel benzenesulfonamides carrying benzamide moiety as carbonic anhydrase and acetylcholinesterase inhibitors

N -(1-(4-Methoxyphenyl)-3-oxo-3-((4-( N -(substituted)sulfamoyl)phenyl)amino)prop-1-en-1-yl)benzamides 3a – g were designed since sulfonamide and benzamide pharmacophores draw great attention in novel drug design due to their wide range of bioactivities including acetylcholinesterase (AChE) and human carbonic anhydrase I and II (hCA I and hCA II) inhibitory potencies. Structure elucidation of the compounds was carried out by 1H NMR, 13C NMR, and HRMS spectra. In vitro enzyme assays showed that the compounds had significant inhibitory potential against hCA I, hCA II, and AChE enzymes at nanomolar levels. Ki values were in the range of 4.07 ± 0.38 – 29.70 ± 3.18 nM for hCA I and 10.68 ± 0.98 – 37.16 ± 7.55 nM for hCA II while Ki values for AChE were in the range of 8.91 ± 1.65 – 34.02 ± 5.90 nM. The most potent inhibitors 3g (Ki = 4.07 ± 0.38 nM, hCA I), 3c (Ki = 10.68 ± 0.98 nM, hCA II ) , and 3f (Ki = 8.91 ± 1.65 nM, AChE) can be considered as lead compounds of this study with their promising bioactivity results. Secondary sulfonamides showed promising enzyme inhibitory effects on AChE while primary sulfonamide derivative was generally effective on hCA I and hCA II isoenzymes.     

Evaluation of carbonic anhydrase and paraoxonase inhibition activities and molecular docking studies of highly water-soluble sulfonated phthalocyanines

The investigation of carbonic anhydrase and paraoxonase enzyme inhibition properties of water-soluble zinc and gallium phthalocyanine complexes ( 1 and 2 ) are reported for the first time. The binding of p-sulfonylphenoxy moieties to the phthalocyanine structure favors excellent solubilities in water, as well as providing an inhibition effect on carbonic anhydrase (CA) I and II isoenzymes and paraoxonase (PON1) enzyme. According to biological activity results, both complexes inhibited hCA I, hCA II, and PON1. Whereas 1 and 2 showed moderate hCA I and hCA II (off-target cytosolic isoforms) inhibitory activity (Ki values of 26.09 µM and 43.11 µM for hCA I and 30.95 µM and 33.19 µM for hCA II, respectively), they exhibited strong PON1 (associated with high-density lipoprotein [HDL]) inhibitory activity (Ki values of 0.37 µM and 0.27 µM, respectively). The inhibition kinetics were analyzed by Lineweaver–Burk double reciprocal plots. It revealed that 1 and 2 were noncompetitive inhibitors against PON1, hCA I, and hCA II. These complexes can be more advantageous than other synthetic CA and PON inhibitors due to their water solubility. Docking studies were carried out to examine the interactions between hCA I, hCA II, and PON1 inhibitors and metal complexes at a molecular level and to predict binding energies.     

碳酸酐酶模型化合物的合成、表征及其催化性能研究

模拟碳酸酐酶的活性中心结构,以三(取代吡唑基)硼氢根[T~p^R^,^R^1]^-为配体,合成了一系列金属配合物[T~p^R^,^R^1]MX[R=Ph,2'-thie(2'-噻吩基),Me;R^1=Ph,2'-thie,Me;M=Co,Ni,Cu,Zn,Cd;X=Cl,NO~3,CH~3COO]共13个,均经元素分析,IR,^1HNMR谱表征。选取其中5个有代表性的配合物,采用Stopped-flow技术,研究了模型物催化CO~2可逆水合反应的动力学,结果表明具备酶促反应动力学的一般特征。详细考察了溶液pH值、模型物的结构(尤其是中心金属离子的电子结构)、浓度对该反应的影响,得出一些重要的结果。计算出该反应有、无催化剂时的活化能,从本质上阐明了反应活化能降低是模型物加速反应的根本原因。     

On origin and evolution of carbonic anhydrase isozymes: A phylogenetic analysis from whole-enzyme to active site

Genetic evolution of carbonic anhydrase enzyme provides an interesting instance of functional similarity in spite of structural diversity of the members of a given family of enzymes. Phylogenetic analysis of α-, β- and γ-carbonic anhydrase was carried out to determine the evolutionary relationships among various members of the family with the enzyme marking its presence in a wide range of cellular and chromosomal locations. The presence of more than one class of enzymes in a particular organism was revealed by phylogenetic time tree. The evolutionary relationships among the members of animal, plant and microbial kingdom were developed. The study revises a long-established notion of kingdom-specificity of the different classes of carbonic anhydrases and provides a new version of the presence of multiple classes of carbonic anhydrases in a single organism and the presence of a given class of carbonic anhydrase across different kingdoms.     

Ligand‐based design,virtual screening,and ADME/T‐based profiling on a dataset of 1,3,5‐triazine‐substituted benzene sulfonamides as carbonic anhydrase inhibitors

A quantitative structure–activity relationship (QSAR) analysis was performed on a dataset of 62 (1,3,5‐triazine‐substituted) benzene sulfonamides as carbonic anhydrase II and IX inhibitors using simulated annealing‐based multiple linear regression analysis. The selected QSAR model for carbonic anhydrase II inhibition (cross‐validated Q² = 0.689, , ) showed that aromaticity, lipophilicity, electronegativity, and molecular projection in the XZ plane influence the activity, whereas that for carbonic anhydrase IX inhibition (cross‐validated Q² = 0.767, , ) showed that activity was influenced by hydrophilicity, linker between the aromatic rings, electronegativity, and molecular weight. The QSAR model selected was internally and externally validated to define its predictability. Activity prediction of an external dataset containing nine compounds (within the same sphere of applicability) was performed to prove the models' specificity, selectivity, and sensitivity. The hypothesis in the form of the QSAR model was used for ligand‐based virtual screening on the ZINC database to obtain some potential hits. Similarly, docking studies on screened hits showed that the molecules interact and orient at the catalytic site in a way similar to acetazolamide. Additionally, an absorption, distribution, metabolism, excretion, and toxicity screening was also performed, and results showed that most of the compounds that can be possible drug candidates obey the Lipinski rule of five and Jorgensen rule of three. Copyright © 2013 John Wiley & Sons, Ltd.     

3D CoMFA,CoMSIA, topomer CoMFA and HQSAR studies on aromatic acid esters for carbonic anhydrase inhibitory activity

Molecular modelling studies [comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), topomer CoMFA and hologram quantitative structure–activity relationship (HQSAR)] have been performed on the series of 28 molecules belonging to the series of aromatic acid ester derivatives for their carbonic anhydrase inhibitory activity. The model exhibited good correlation coefficient (r²) and cross‐validated correlation coefficient (q²) for CoMFA, CoMSIA and HQSAR methods. On the basis of the findings from all these studies, a structure–activity relationship was established. Copyright © 2013 John Wiley & Sons, Ltd.     

Stereo- and regioselective azide/alkyne cycloadditions in carbonic anhydrase II via tethering, monitored by crystallography and mass spectrometry

The carbonic anhydrase II mutant His64Cys was prepared and applied to tethered alkyne/azide cycloaddition reactions. The azide component could be tethered to the enzyme surface through a disulfide bridge, while the alkyne component was reversibly coordinated through a sulfonamide anchor to the zinc ion in the original catalytic center of the enzyme. The incipient orientation of the reactants in the binding site and of the formed triazole product were characterized by crystallography. The reaction progression could be monitored by HPLC-MS analysis.     

Synthesis and bioactivities of 1-(4-hydroxyphenyl)-2-((heteroaryl)thio)ethanones as carbonic anhydrase I,II and acetylcholinesterase inhibitors

The discovery of enzyme targeting inhibitors is a popular area of drug research. Biological activities of the compounds bearing phenol and heteroaryl groups make them popular groups in drug design targeting important enzymes such as acetylcholinesterase (AChE, E.C.3.1.1.7) and carbonic anhydrases (CAs, EC 4.2.1.1). 1-(4-hydroxyphenyl)- 2-((aryl)thio)ethanones as possible AChE and CAs inhibitors were synthesized, and their chemical structures were confirmed by IR, ¹H NMR, ¹³C NMR, and HRMS. The compounds 2 and 4 were found potent AChE inhibitors with the Ki values of 22.13 ±1.96 nM and 23.71 ±2.95 nM, respectively, while the compounds 2 (Ki = 8.61 ±0.90 nM, on hCA I) and 1 (Ki = 8.76 ±0.84 nM, on hCA II) had considerable CAs inhibitory potency. The lead compounds may help the scientists for the rational designing of an innovative class of drug candidates targeting enzyme-based diseases.     

Bile acids and their oxo derivatives: Potential inhibitors of carbonic anhydrase I and II,androgen receptor antagonists and CYP3A4 substrates

Some biological properties of bile acids and their oxo derivatives have not been sufficiently investigated, although the interest in bile acids as signaling molecules is rising. The aim of this work was to evaluate physico‐chemical parametar b (slope) that represents the lipophilicity of the examined molecules and to investigate interactions of bile acids with carbonic anhydrase I, II, androgen receptor and CYP450s. Thirteen candidates were investigated using normal‐phase thin‐layer chromatography in two solvent systems. Retention parameters were used in further quantitative structure–activity relationship analysis and docking studies to predict interactions and binding affinities of examined molecules with enzymes and receptors. Prediction of activity on androgen receptor showed that compounds 3α ‐hydroxy‐12‐oxo‐5β ‐cholanoic and 3α ‐hydroxy‐7‐oxo‐5β ‐cholanoic acid have stronger antiandrogen activity than natural bile acids. The inhibitory potential for carbonic anhydrase I and II was tested and it was concluded that molecules 3α ‐hydroxy‐12‐oxo‐5β ‐cholanoic, 3α ‐hydroxy‐7‐oxo‐5β ‐cholanoic, 3,7,12‐trioxo‐5β ‐cholanoic acid and hyodeoxycholic acid show the best results. Substrate behavior for CYP3A4 was confirmed for all investigated compounds. Oxo derivatives of bile acids show stronger interactions with enzymes and receptors as classical bile acids and lower membranolytic activity compared with them. These significant observations could be valuable in consideration of oxo derivatives as building blocks in medicinal chemistry.     

A selectivity study of benzenesulfonamide derivatives on human carbonic anhydrase II/IX by 3D-QSAR,Molecular Docking and Molecular Dynamics Simulation

Nowadays, different approaches have been pursued with the intent to develop sulfonamide-like carbonic anhydrase inhibitors that possess better selectivity profiles toward the different human isoforms of the enzyme. Here, we used conventional 3D-QSAR methods, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and Topomer CoMFA, to construct three-dimensional quantitative structure-activity relationship (3D-QSAR) models for benzenesulfonamide derivatives as human carbonic anhydrase (hCA) II/IX inhibitors. The theoretical models had good reliability (R²>0.75) and predictability (Q²>0.55), and the contour maps could graphically present the contributions of the force fields for activity and identify the structural divergence between human carbonic anhydrase II inhibitors and human carbonic anhydrase IX inhibitors. Consequently, we explored the selectivity of inhibitor for human carbonic anhydrase II and IX through molecular docking, and the difference of activity coincides with the potential binding mode well. According to the results of the predicted values and the molecule docking, we found that the inhibitors published in the literature had stronger inhibition on the hCA IX; based on the theoretical models, we designed seven new compounds with good potential activity and reasonably good ADMET profile, which could selectively inhibit hCA IX. Molecular Dynamics Simulation showed that newly-designed compound D7 had good selectivity on hCA IX. The findings from 3D-QSAR and docking studies maybe helpful in the rational drug design of isoform-selective inhibitors.     

Synthesis,characterization, and photovoltaic properties of novel conjugated copolymers derived from phenothiazines

Two novel series of soluble alternating conjugated copolymers comprising 10‐alkylphenothiazine and bithiophene or 3‐pentylthieno[3,2‐b]thiophene moieties were synthesized using palladium‐catalyzed Suzuki coupling reaction. The structures of the polymers and their thermal, photophysical, electrochemical, and photovoltaic properties were characterized and investigated. The polymers exhibited good thermal stability with decomposition temperature in the region of 342–390 °C and their glass transition temperatures (T_g) ranging from 126 to 150 °C. All polymers demonstrate broad optical absorption in the region of 300–500 nm with efficient blue‐green light emission. They showed ambipolar redox properties with low HOMO levels around ?5.13 eV. Polymer solar cells were fabricated using blends of the copolymers and [6,6]‐phenyl‐C61‐butyric acid methyl ester (PCBM) in a 1:1 weight ratio. The maximum power conversion efficiency (η = 0.24%) was measured for the poly[3,7‐ (10‐hexylphenothiazine)‐alt‐bithiophene] as donor under simulated sun light (1000 W/m²). Open circuit voltages of up to 0.8 V have been obtained. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 5266–5276, 2007