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 (H-1, C-13), 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 mu M. 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.