Design, Synthesis, Kinetic Analysis and Pharmacophore-Directed Discovery of 3-Ethylaniline Hybrid Imino-Thiazolidinone as Potential Inhibitor of Carbonic Anhydrase II: An Emerging Biological Target for Treatment of Cancer

Abstract

Carbonic anhydrases (CA), having Zn2+ metal atoms, are responsible for the catalysis of CO2 and water to bicarbonate and protons. Any abnormality in the functioning of these enzymes may lead to morbidities such as glaucoma and different types of cancers including brain, renal and pancreatic carcinomas. To cope with the lack of presence of a promising therapeutic agent against these cancers, searching for an efficient and suitable carbonic anhydrase inhibitor is crucial. In the current study, ten novel 3-ethylaniline hybrid imino-thiazolidinones were synthesized and characterized by FTIR, NMR (1H, 13C), and mass spectrometry. Synthesis was carried out by diethyl but-2-ynedioate cyclization and different acyl thiourea substitutions of 3-ethyl amine. The CA (II) enzyme inhibition profile for all synthesized derivatives was determined. It was observed that compound 6e demonstrated highest inhibition of CA-II with an IC50 value of 1.545 ± 0.016 µM. In order to explore the pharmacophoric properties and develop structure activity relationship, in silico screening was performed. In silico investigations included density functional theory (DFT) studies, pharmacophore-guided model development, molecular docking, molecular dynamic (MD) simulations, and prediction of drug likeness scores. DFT investigations provided insight into the electronic characteristics of compounds, while molecular docking determined the binding orientation of derivatives within the CA-II active site. Compounds 6a, 6e, and 6g had a reactive profile and generated stable protein-ligand interactions with respective docking scores of −6.12, −6.99, and −6.76 kcal/mol. MD simulations were used to evaluate the stability of the top-ranked complex. In addition, pharmacophore-guided modeling demonstrated that compound 6e produced the best pharmacophore model (HHAAARR) compared to standard brinzolamide. In vitro and in silico investigations anticipated that compound 6e would be an inhibitor of carbonic anhydrase II with high efficacy. Compound 6e may serve as a potential lead for future synthesis that can be investigated at the molecular level, and additional in vivo studies are strongly encouraged.

Imidazole‐hydrazone derivatives: Synthesis, characterization, X‐ray structures and evaluation of anticancer and carbonic anhydrase I–II inhibition properties

“…Additionally, abundant in numerous tissues, CA II is important in many disease states, including glaucoma, epilepsy, edema, high altitude condition, and kidney illness [7] . Furthermore, several tumor cells and cell lines have been found to exhibit CAI and CAII [8] …”

“…[7] Furthermore, several tumor cells and cell lines have been found to exhibit CAI and CAII. [8] The heterocycles that include nitrogen are among a group of substances with a wealth of practical uses. Small-molecule pharmaceuticals of fused nitrogen heterocycles make up 59 % of U.S. FDA-approved medicines, particularly in the pharmaceutical industry.…”

Exploring the latest trends in chemistry, structure, coordination, and diverse applications of 1-acyl-3-substituted thioureas: a comprehensive review

“…Compound (26e) exhibited better inhibitory activity against CA II with IC 50 value 1.545 ± 0.016 mM (Scheme 7). 50 Amantadine thiazolidinone derivatives synthesized by Ahmad et al were found to exhibit good inhibitory activity against the enzyme elastase with IC 50 values ranging from 0.221 ± 0.059 to 3.257 ± 0.541 mM. Compound 5 g showed highest potency against elastase with an IC 50 value of 0.124 ± 0.022 mM which was 50 times higher than Oleanolic acid's value of 5.996 ± 0.882 mM.…”

“…49 Ahmed et al synthesized a series of iminothiazolidinone derivatives (26a-j) by reacting equimolar amount of acyl thioureas (24a-j) and ethyl 4-ethoxypent-4-en-2-ynoate (25) in dry methanol as solvent at room temperature (Scheme 7). 50 The same procedure was applied with success for the preparation of a novel series of amantadine thiazolidinones analogs from acyl thioureas and ethyl 4-ethoxypent-4-en-2-ynoate. 51 A new methodology was developed by Pokotylo et al for the synthesis of 2H-1,3,5-oxadiazine-2,4(3H)-diimines derivatives (30a-g) by dehydrosulfurization of acyl thiourea (29a-g) with dicyclohexyl carbodiimide.…”

Redox Regulation of Protein Functioning

“…Disorders associated with this enzyme lead to the development of glaucoma, as well as a number of cancers. In their work [ 8 ], Ahmed et al describe the development of a number of inhibitors of the carbonic anhydrase as potential therapeutic agents. Based on results obtained from vitro and in in silico screening, the authors propose the most promising drug candidate.…”