Quinoline–1,3,4-Oxadiazole Conjugates: Synthesis, Anticancer Evaluation, and Molecular Modelling Studies

Abstract

Cancer continues to have overwhelming impacts on human health and the development of new chemotherapeutics. Molecular hybridization has thus been valued as a structure-based drug design approach to drugs with enhanced efficacy. Herein, we report the multistep synthesis of quinoline–2-mercapto-1,3,4-oxadiazole conjugates and their cytotoxicity evaluation. Compound 4j 2-[(5-bromopentyl)thio]-5-[(quinolin-8-yloxy)methyl]-1,3,4-oxadiazole showed the best cytotoxicity to pancreatic (MIA PaCa-2) and colorectal (HCT116) cancer cells with IC₅₀ values of 29.19 ± 0.99 and 75.10 ± 1.87 µM, respectively. The compound is also less cytotoxic to non-cancerous human primary dermal fibroblast cells with IC₅₀ = 91.87 ± 1.29 µM compared to the parent compound 8-hydroxyquinoline (IC₅₀ = 72.36 ± 4.23 µM). ADME properties prediction suggested the drug-likeness of potent compounds while molecular docking and molecular dynamics simulations with doublecortin-like kinase (DCLK1) revealed the compounds’ stable binding interactions at the kinase domain. Overall, the results illuminate compound 4j as a structural model to furnish new cytotoxic agents against pancreatic and colorectal cancer.

Keywords:

• Anticancer
• molecular hybridization
• 1,3,4-oxadiazole
• DCLK1
• molecular dynamics

Acknowledgment

The authors gratefully acknowledge the Centre for High-Performance Computing (CHPC), Cape Town (South Africa), for the supercomputing facilities.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

NC appreciates the National Research Foundation (NRF) South Africa for the S&F – Innovation Doctoral Scholarships [Grant No. 113402]. PS also thanks NRF South Africa for a Competitive Grant for unrated Researchers [Grant No. 121276] and rated researcher funding [Grant No. 126963].