Evaluation of indole-picolinamide hybrid molecules as carbonic anhydrase-II inhibitors: Biological and computational studies

The present study reports the successful synthesis and evaluation of a series of indole-picolinamide hy-brids as potent inhibitors of bovine carbonic anhydrase II, a promising therapeutic target for the treat-ment of neurological disorders, osteoporosis, glaucoma, cancer, and obesity. Various multistep synthetic approaches were utilized to access the desired structures having exclusive sites for chemical modifications and diverse spots for biological interactions between the ligand and enzyme. Compound 1a was observed as a potent inhibitor of the bovine CA-II with an IC50 value of 0.0440 +/- 0.009 mu M. The inhibition po-tency was about 22-fold higher than the standard drug acetazolamide (IC50 = 0.9618 +/- 0.180 mu M). Several impactful structure-activity relationships were deduced that enlighten the crucial role of substituents as well as the key pharmacophores involved in the inhibition process. Molecular docking tools reinforced the in vitro assay results. The most active compound 1a was also investigated for anticancer potential using sulforhodamine B assay and results showed two-fold efficacy against HeLa cells when compared to standard drug cisplatin (IC50 = 8.045 +/- 3.791 mu g/mL and 4.128 +/- 1.473 mu g/mL, respectively). These find-ings were also confirmed by flow cytometry and comet tests. Moreover, fluorescence microscopy with DAPI staining revealed apoptosis as a mechanism of cancer cell death. (c) 2022 Elsevier B.V. All rights reserved.