scholarly journals Quinazolinones as Competitive Inhibitors of Carbonic Anhydrase-II (Human and Bovine): Synthesis, in-vitro, in-silico, Selectivity, and Kinetics Studies

2020 ◽  
Vol 8 ◽  
Author(s):  
Ajmal Khan ◽  
Majid Khan ◽  
Sobia Ahsan Halim ◽  
Zulfiqar Ali Khan ◽  
Zahid Shafiq ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Active Sites ◽  
Binding Mode ◽  
Competitive Inhibitor ◽  
Significant Inhibition ◽  
Carbonic Anhydrase Ii ◽  
Complete Agreement ◽  
Active Inhibitor ◽  
Kinetics Studies

Carbonic anhydrase-II (CA-II) is associated with glaucoma, malignant brain tumors, and renal, gastric, and pancreatic carcinomas and is mainly involved in the regulation of the bicarbonate concentration in the eyes. CA-II inhibitors can be used to reduce the intraocular pressure usually associated with glaucoma. In search of potent CA-II inhibitors, a series of quinazolinones derivatives (4a-p) were synthesized and characterized by IR and NMR spectroscopy. The inhibitory potential of all the compounds was evaluated against bovine carbonic anhydrase-II (bCA-II) and human carbonic anhydrase-II (hCA-II), and compounds displayed moderate to significant inhibition with IC50 values of 8.9–67.3 and 14.0–59.6 μM, respectively. A preliminary structure-activity relationship suggested that the presence of a nitro group on the phenyl ring at R position contributes significantly to the overall activity. Kinetics studies of the most active inhibitor, 4d, against both bCA-II and hCA-II were performed to investigate the mode of inhibition and to determine the inhibition constants (Ki). According to the kinetics results, 4d is a competitive inhibitor of bCA-II and hCA-II with Ki values of 13.0 ± 0.013 and 14.25 ± 0.017 μM, respectively. However, the selectivity index reflects that the compounds 4g and 4o are more selective for hCA-II. The binding mode of these compounds within the active sites of bCA-II and hCA-II was investigated by structure-based molecular docking. The docking results are in complete agreement with the experimental findings.

scholarly journals Dual inhibitors of urease and carbonic anhydrase-II from Iris species

2019 ◽  
Vol 91 (10) ◽  
pp. 1695-1707 ◽  
Author(s):  
Muhammad Saleem ◽  
Sumaira Hareem ◽  
Ajmal Khan ◽  
Suad Naheed ◽  
Muslim Raza ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Significant Inhibition ◽  
Carbonic Anhydrase Ii ◽  
Natural Organic Compounds ◽  
Mass Spectrogram ◽  
Urease Enzyme ◽  
Dual Inhibitors ◽  
Inhibition Studies ◽  
First Time

Abstract Twenty seven (1–27) known natural organic compounds were isolated for first time from two species of Iris, i.e. loczyi and Iris unguicularis. The structures of these compounds were deduced from the spectral data of NMR, IR, and mass spectrogram. These were evaluated against urease and carbonic anhydrase inhibition studies. For carbonic anhydrase-II inhibition studies, these compounds were evaluated by biochemical mechanism based in vitro bio-assay. Some compounds showed significant inhibition against CA-II enzyme. Compartively, compound (12) showed IC50 value of 17.60 ± 0.08 μM against urease enzyme, while compound (3) was found to be most active against carbonic anhydrase-II, having an IC50 value of 66.27 ± 0.89 μM. Izalpinin (3), 5,7-dihydroxy-2′,6-dimethoxyisoflavone (9), 4′,5,7-trihydroxy-6-methoxyflavanone (16), 4′,5,7-trihydroxy-3′,8-dimethoxyflavanone (20), 8-methoxyeriodictyol (21), and mangiferin (26) were found to be dual inhibitors of both the enyzmes. The most active compounds were docked using Autodock Vina and i-GEMDOCK softwares. The docking and in-vitro results are in agreement which showed secondary interactions with the enzymes. The compounds can serve as therapeutic agents to treat urease and carbonic anhydrase associated disorders.

1'-methylspiro[indoline-3,4'-piperidine] Derivatives: Design, Synthesis, Molecular Docking and Anti-tumor Activity Studies

2020 ◽  
Vol 17 ◽  
Author(s):  
Junjian Li ◽  
Lianbao Ye ◽  
Yuanyuan Wang ◽  
Ying Liu ◽  
Xiaobao Jin ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cell Lines ◽  
Active Sites ◽  
Biological Activities ◽  
Significant Inhibition ◽  
Alkaline Condition ◽  
Discovery Studio ◽  
Hela Cell Lines ◽  
Antiproliferative Activities

Background: Spirocyclic indoline compounds widely exist in numerous natural products with good biological activities and some drug molecules in many aspects. In recent years, it has attracted extensive attention as potent anti-tumor agents in the fields of pharmacology and chemistry. Objective: In this study, we focused on designing and synthesizing a set of novel 1'-H-spiro[indole-3,4'-piperidine] derivatives, which were evaluated by preliminary bioactivity experiment in vitro and molecular docking. Method: The key intermediate 1'-methylspiro[indoline-3,4'-piperidine] (B4) reacted with benzenesulfonyl chloride with different substituents under alkaline condition to obtain its sulfonyl derivatives (B5-B10). We evaluated their antiproliferative activities against A549, BEL-7402 and HeLa cells by MTT assay. We performed the CDOCKER module in Discovery Studio 2.5.5 software for molecular modeling of compound B5, and investigated the binding of compound B5 with the target proteins from PDB database. Results: The results indicated that compounds B4-B10 exhibited good antiproliferative activities against the above three types of cells, in which compound B5 with chloride atom as electron-withdrawing substituent on a phenyl ring showed the highest potency against BEL-7402 cells (IC50=30.03±0.43 μg/mL). By binging of the prominent bioactive compound B5 to CDK, c-Met, EGFR protein crystals, The binding energy of B5 with these three types receptors are -44.3583 kcal/mol, - 38.3292 kcal/mol, -33.3653 kcal/mol respectively. Conclusion: Six 1'-methylspiro[indoline-3,4'-piperidine] derivatives were synthesized and evaluated against BEL-7402, A- 549, HeLa cell lines. Compound B5 showed significant inhibition on BEL-7402 cell lines. Molecular docking revealed that B5 showed good affinity by the good fitting between B5 and these three targets with amino acid residues in active sites which encourage us to conduct further evaluation such as the kinase experiment.

scholarly journals Polymorphisms in Brucella Carbonic anhydrase II mediate CO2 dependence and fitness in vivo

2019 ◽  
Author(s):  
JM García-Lobo ◽  
Y Ortiz ◽  
C González-Riancho ◽  
A Seoane ◽  
B Arellano-Reynoso ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Primary Cultures ◽  
Low Frequency ◽  
Carbonic Anhydrase Ii ◽  
Carbonic Anhydrases ◽  
Significant Difference ◽  
Dependent Strain

AbstractSome Brucella isolates are known to require an increased concentration of CO2 for growth, especially in the case of primary cultures obtained directly from infected animals. Moreover, the different Brucella species and biovars show a characteristic pattern of CO2 requirement, and this trait has been included among the routine typing tests used for species and biovar differentiation. By comparing the differences in gene content among different CO2-dependent and CO2-independent Brucella strains we have confirmed that carbonic anhydrase II (CA II), is the enzyme responsible for this phenotype in all the Brucella strains tested. Brucella species contain two carbonic anhydrases of the β family, CA I and CA II; genetic polymorphisms exist for both of them in different isolates, but only those putatively affecting the activity of CA II correlate with the CO2 requirement of the corresponding isolate. Analysis of these polymorphisms does not allow the determination of CA I functionality, while the polymorphisms in CA II consist of small deletions that cause a frameshift that changes the C-terminus of the protein, probably affecting its dimerization status, essential for the activity.CO2-independent mutants arise easily in vitro, although with a low frequency ranging from 10−6 to 10−10 depending on the strain. These mutants carry compensatory mutations that produce a full length CA II. At the same time, no change was observed in the sequence coding for CA I. A competitive index assay designed to evaluate the fitness of a CO2-dependent strain compared to its corresponding CO2-independent strain revealed that while there is no significant difference when the bacteria are grown in culture plates, growth in vivo in a mouse model of infection provides a significant advantage to the CO2-dependent strain. This could explain why some Brucella isolates are CO2-dependent in primary isolation. The polymorphism described here also allows the in silico determination of the CO2 requirement status of any Brucella strain.

scholarly journals Development of a Fingerprint-Based Scoring Function for the Prediction of the Binding Mode of Carbonic Anhydrase II Inhibitors

2018 ◽  
Vol 19 (7) ◽  
pp. 1851 ◽  
Author(s):  
Giulio Poli ◽  
Vibhu Jha ◽  
Adriano Martinelli ◽  
Claudiu Supuran ◽  
Tiziano Tuccinardi
Keyword(s):  
Carbonic Anhydrase ◽  
Scoring Function ◽  
Binding Mode ◽  
Carbonic Anhydrase Ii

scholarly journals Azobenzene-based inhibitors of human carbonic anhydrase II

2015 ◽  
Vol 11 ◽  
pp. 1129-1135 ◽  
Author(s):  
Leander Simon Runtsch ◽  
David Michael Barber ◽  
Peter Mayer ◽  
Michael Groll ◽  
Dirk Trauner ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Catalytic Activity ◽  
Carbonic Anhydrase ◽  
Drug Class ◽  
Carbonic Anhydrase Ii ◽  
Carbonic Anhydrases ◽  
X Ray ◽  
X Ray Crystallography ◽  
Human Carbonic Anhydrase

Aryl sulfonamides are a widely used drug class for the inhibition of carbonic anhydrases. In the context of our program of photochromic pharmacophores we were interested in the exploration of azobenzene-containing sulfonamides to block the catalytic activity of human carbonic anhydrase II (hCAII). Herein, we report the synthesis and in vitro evaluation of a small library of nine photochromic sulfonamides towards hCAII. All molecules are azobenzene-4-sulfonamides, which are substituted by different functional groups in the 4´-position and were characterized by X-ray crystallography. We aimed to investigate the influence of electron-donating or electron-withdrawing substituents on the inhibitory constant K i. With the aid of an hCAII crystal structure bound to one of the synthesized azobenzenes, we found that the electronic structure does not strongly affect inhibition. Taken together, all compounds are strong blockers of hCAII with K i = 25–65 nM that are potentially photochromic and thus combine studies from chemical synthesis, crystallography and enzyme kinetics.

scholarly journals Mass Spectrometry Analysis of In Vitro Nitration of Carbonic Anhydrase II

2014 ◽  
Vol 35 (3) ◽  
pp. 709-714 ◽  
Author(s):  
Soo Jae Lee ◽  
Jeong Won Kang ◽  
Kyung Cho Cho ◽  
Mohammad Humayun Kabir ◽  
Byungjoo Kim ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Carbonic Anhydrase ◽  
Mass Spectrometry Analysis ◽  
Carbonic Anhydrase Ii ◽  
Spectrometry Analysis

scholarly journals Synthesis of New 1H-1,2,3-Triazole Analogs in Aqueous Medium via “Click” Chemistry: A Novel Class of Potential Carbonic Anhydrase-II Inhibitors

2021 ◽  
Vol 9 ◽  
Author(s):  
Satya Kumar Avula ◽  
Majid Khan ◽  
Sobia Ahsan Halim ◽  
Ajmal Khan ◽  
Samia Ahmed Al-Riyami ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Aqueous Medium ◽  
Coupling Reaction ◽  
Cross Coupling ◽  
Carbonic Anhydrase Ii ◽  
Polar Group ◽  
Active Site Residues ◽  
Cross Coupling Reaction ◽  
Inhibitory Potential

A series of novel 1H-1,2,3-triazole analogs (9a–j) were synthesized via “Click” chemistry and Suzuki–Miyaura cross-coupling reaction in aqueous medium. The compounds were evaluated for their carbonic anhydrase-II enzyme inhibitory activity in vitro. The synthesis of triazole 7a was accomplished using (S)-(-) ethyl lactate as a starting material. This compound (7a) underwent Suzuki–Miyaura cross-coupling reaction with different arylboronic acids in aqueous medium to afford the target molecules, 9a–j in good yields. All newly synthesized compounds were characterized by 1H NMR, 13C NMR, FT-IR, HRMS, and where applicable 19F NMR spectroscopy (9b, 9e, 9h, and 9j). The new compounds have shown moderate inhibition potential against carbonic anhydrase-II enzyme. A preliminary structure-activity relationship suggested that the presence of polar group at the 1H-1,2,3-triazole substituted phenyl ring in these derivatives (9a–j) has contributed to the overall activity of these compounds. Furthermore, via molecular docking, it was deduced that the compounds exhibit inhibitory potential through direct binding with the active site residues of carbonic anhydrase-II enzyme. This study has unraveled a new series of triazole derivatives as good inhibitors against carbonic anhydrase-II.

Appliance of the piperidinyl-hydrazidoureido linker to benzenesulfonamide compounds: Synthesis, in vitro and in silico evaluation of potent carbonic anhydrase II, IX and XII inhibitors

2020 ◽  
Vol 98 ◽  
pp. 103728 ◽  
Author(s):  
Davide Moi ◽  
Alessio Nocentini ◽  
Alessandro Deplano ◽  
Sameh M. Osman ◽  
Zeid A. AlOthman ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
In Silico ◽  
Carbonic Anhydrase Ii
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