Coumarin-amino acid hybrids as promising anticancer agents: design, synthesis, docking studies and CK2 inhibition.

A series of mono-peptide, di-peptide and tri-peptide derivatives linked to a coumarin scaffold (5a-c, 7a-c, and 9a-c) were synthesized via the azide-coupling method from corresponding hydrazides 4, 6, and 8. These compounds were tested for anticancer activity against HepG-2, PC-3, and Hct-116 cell lines. Compounds, 7c, and 5b showed significant cytotoxicity, outperforming doxorubicin, with IC50 values of 34.07, 16.06, and 16.02 µM for 7c and 42.16, 59.74, and 35.05 µM for 5b. Compound 7b also displayed promising results with IC50 values of 72.13, 70.82, and 61.01 µM. Moreover, the key structural features of amino acids indicated that mono-peptide and di-peptide derivatives play a key role in increasing their anticancer activities compared with tri-peptides. In addition, the most potent compound 5b also exhibited strong CK2 kinase inhibition with an IC50 value of 0.117 ± 0.005 µM compared with roscovetine as a control drug with an IC50 value of 0.251 ± 0.011 µM. Finally, the binding mode of the chemical inhibitors at the active site of CK2 receptor was also investigated using a docking study which confirmed that the presence of the amino acid functionality is an important feature for anticancer activity and the synthesized compounds showed favorable ADME properties. Besides that, SAR analysis was implemented for the target compounds.

New pyrrole derivatives as DNA gyrase and 14α-demethylase inhibitors: Design, synthesis, antimicrobial evaluation, and molecular docking.

An efficient one-pot reaction utilizing readily available chemical reagents was used to prepare novel 2-amino-1,5-diaryl-1H-pyrrole-3-carbonitrile derivatives and the structures of these compounds were validated by spectroscopic data and elemental analyses. All the synthetic compounds were evaluated for their antimicrobial activities (MZI assay). The tested compounds proved high activities on Staphylococcus aureus (Gram-positive bacteria) and Candida albicans (Pathogenic fungi). However, they did not show any activity on Escherichia coli (Gram-negative bacteria). The most effective compounds in MZI assay 7c, 9a, 9b, 11a, and 11b were selected to determine their MIC on S. aureus and C. albicans. Furthermore, DNA gyrase and 14-α demethylase inhibitory assays were performed to study the inhibitory activities of 7c, 9a, 9b, 11a, and 11b. The results illustrated that compound 9b was the most DNA gyrase inhibitor (IC50 of 0.0236 ± 0.45 µM, which was 1.3- fold higher than gentamicin reference IC50 values of 0.0323 ± 0.81 µM). In addition, compound 9b demonstrated the highest 14-α demethylase inhibitory effect with IC50 of 0.0013 ± 0.02 µM, compared to ketoconazole (IC50 of 0.0008 ± 0.03 µM) and fluconazole (IC50 of 0.00073 ± 0.01 µM), as antifungal reference drugs. Lastly, docking studies were performed to rationalize the dual inhibitory activities of the highly active compounds on both DNA gyrase and 14-α demethylase enzymes.