Discovery of new symmetrical and asymmetrical nitrile-containing 1,4-dihydropyridine derivatives as dual kinases and P-glycoprotein inhibitors: synthesis, in vitro assays, and in silico studies

Abstract

Two new series of symmetric (1a-h) and asymmetric (2a-l) 1,4-DHP derivatives were designed, synthesised, and evaluated as anticancer agents. In vitro anticancer screening of target compounds via National cancer institute “NCI” revealed that analogues 1g, 2e, and 2l demonstrated antiproliferative action with mean growth inhibition percentage “GI%” = 41, 28, and 64, respectively. The reversal doxorubicin (DOX) effects of compounds 1g, 2e, and 2l were examined and illustrated better cytotoxic activity with IC₅₀ =1.12, 3.64, and 3.57 µM, respectively. The most active anticancer analogues, 1g, 2e, and 2l, were inspected for their putative mechanism of action by estimating their epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER-2), and Bruton’s tyrosine kinase (BTK) inhibitory activities. Furthermore, the antimicrobial activity of target compounds was assessed against six different pathogens, followed by determining the minimum inhibitory concentration “MIC” values for the most active analogues. Molecular docking study was achieved to understand mode of interactions between selected inhibitors and different biological targets.

Keywords:

• 1,4-DHPs
• anticancer
• multidrug resistance (MDR)
• P-glycoprotein
• receptor tyrosine kinases (RTKs)
• apoptosis
• antimicrobial

Acknowledgements

The authors thank Faculty of Pharmacy, Tanta University for financial support and the Deanship of scientific research at Umm Al-Qura University for supporting this work by grant code (22UQU4290565DSR70).

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

Deanship of scientific research at Umm Al-Qura University supported this work by grant code (22UQU4290565DSR70).