Synthesis, molecular modelling and QSAR study of new <i>N-</i>phenylacetamide-2-oxoindole benzensulfonamide conjugates as carbonic anhydrase inhibitors with antiproliferative activity

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Abstract

In continuation of our previous studies to optimise potent carbonic anhydrase inhibitors, two new series of isatin N-phenylacetamide based sulphonamides were synthesised and screened for their human (h) carbonic anhydrase (EC 4.2.1.1) inhibitory activities against four isoforms hCA I, hCA II, hCA IX and hCA XII. The indole-2,3-dione derivative 2h showed the most effective inhibition profile against hCAI and hCA II (K _I = 45.10, 5.87 nM) compared to acetazolamide ( AAZ) as standard inhibitor. Moreover, 2h showed appreciable inhibition activity against the tumour-associated hCA XII, similar to AAZ showing K _I of 7.91 and 5.70 nM, respectively. The analogs 3c and 3d showed good cytotoxicity effects, and 3c revealed promising selectivity towards lung cell line A549. Molecular docking was carried out for 2h and 3c to predict their binding conformations and affinities towards the hCA I, II, IX and XII isoforms.

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We have developed a rapid, sensitive, and inexpensive method for measuring the cellular protein content of adherent and suspension cultures in 96-well microtiter plates. The method is suitable for ordinary laboratory purposes and for very large-scale applications, such as the National Cancer Institute's disease-oriented in vitro anticancer-drug discovery screen, which requires the use of several million culture wells per year. Cultures fixed with trichloroacetic acid were stained for 30 minutes with 0.4% (wt/vol) sulforhodamine B (SRB) dissolved in 1% acetic acid. Unbound dye was removed by four washes with 1% acetic acid, and protein-bound dye was extracted with 10 mM unbuffered Tris base [tris (hydroxymethyl)aminomethane] for determination of optical density in a computer-interfaced, 96-well microtiter plate reader. The SRB assay results were linear with the number of cells and with values for cellular protein measured by both the Lowry and Bradford assays at densities ranging from sparse subconfluence to multilayered supraconfluence. The signal-to-noise ratio at 564 nm was approximately 1.5 with 1,000 cells per well. The sensitivity of the SRB assay compared favorably with sensitivities of several fluorescence assays and was superior to those of both the Lowry and Bradford assays and to those of 20 other visible dyes. The SRB assay provides a colorimetric end point that is nondestructive, indefinitely stable, and visible to the naked eye. It provides a sensitive measure of drug-induced cytotoxicity, is useful in quantitating clonogenicity, and is well suited to high-volume, automated drug screening. SRB fluoresces strongly with laser excitation at 488 nm and can be measured quantitatively at the single-cell level by static fluorescence cytometry.

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Structure and function of carbonic anhydrases.

Claudiu Supuran (2016)

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyse the interconversion between CO2 and bicarbonate as well as other hydrolytic reactions. Among the six genetic families known to date, the α-, β-, γ-, δ-, ζ- and η-CAs, detailed kinetic and X-ray crystallographic studies have allowed a deep understanding of the structure-function relationship in this superfamily of proteins. A metal hydroxide nucleophilic species of the enzyme, and a unique active site architecture, with half of it hydrophilic and the opposing part hydrophobic, allow these enzymes to act as some of the most effective catalysts known in Nature. The CA activation and inhibition mechanisms are also known in detail, with a large number of new inhibitor classes being described in the last years. Apart from the zinc binders, some classes of inhibitors anchor to the metal ion coordinated nucleophile, others occlude the entrance of the active site cavity and more recently, compounds binding outside the active site were described. CA inhibition has therapeutic applications for drugs acting as diuretics, antiepileptics, antiglaucoma, antiobesity and antitumour agents. Targeting such enzymes from pathogens may lead to novel anti-infectives. Successful structure-based drug design campaigns allowed the discovery of highly isoform selective CA inhibitors (CAIs), which may lead to a new generation of drugs targeting these widespread enzymes. The use of CAs in CO2 capture processes for mitigating the global temperature rise has also been investigated more recently.

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Journal

Journal ID (nlm-ta): J Enzyme Inhib Med Chem

Journal ID (iso-abbrev): J Enzyme Inhib Med Chem

Title: Journal of Enzyme Inhibition and Medicinal Chemistry

Publisher: Taylor & Francis

ISSN (Print): 1475-6366

ISSN (Electronic): 1475-6374

Publication date (Electronic, pub): 15 February 2022

Publication date (Electronic, collection): 2022

Publication date PMC-release: 15 February 2022

Volume: 37

Issue: 1

Pages: 701-717

Affiliations

[a ]Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University , Cairo, Egypt

[b ]Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence , Florence, Italy

[c ]Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Modern University for Technology and Information MTI , Cairo, Egypt

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Supplemental data for this article can be accessed here.

CONTACT Riham F. George riham.eskandar@ 123456pharma.cu.edu.eg Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University , Cairo, Egypt

Claudiu T. Supuran claudiu.supuran@ 123456unifi.it Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence , Florence, Italy

Author information

Riham F. George https://orcid.org/0000-0002-2493-1315

Claudiu T. Supuran https://orcid.org/0000-0003-4262-0323

Article

Publisher ID: 2036137

DOI: 10.1080/14756366.2022.2036137

PMC ID: 8863381

PubMed ID: 35168458

SO-VID: 3c5190d6-cbb6-4d57-8d35-6fe0fd70aa08

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This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Synthesis, molecular modelling and QSAR study of new N-phenylacetamide-2-oxoindole benzensulfonamide conjugates as carbonic anhydrase inhibitors with antiproliferative activity

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Most cited references 57

New colorimetric cytotoxicity assay for anticancer-drug screening.

Partial least-squares regression: a tutorial

Structure and function of carbonic anhydrases.

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