Abstract

Aim: Synthesis and characterization of quinoline derivatives as an anticancer agent via green chemistry approach and their molecular docking.

Background: In comparison to classical synthesis, green chemistry is a powerful tool for the more affordable and ecologically benign synthesis of organic molecules, such as quinoline derivatives via an efficient base-mediated/metal-free approach.

Objective: The primary objective of the work presented in this article was to prepare N-(2-(tertbutylamino)- 1-(2-chloro-5,7-dimethylquinolin-3-yl)-2-oxoethyl)-3-methoxy-N-phenylbenzamide derivatives via single-step Multicomponent Reaction. Characterized it, docking it, and their anticancer activities against different cell lines are evaluated.

Methods: In a sealed glass vial, one of the starting materials 2-chloro-5-7-dimethylquinoline-3- carbaldehyde 1 was synthesized by the Vilsmeier-hack reaction. Substituted N-(2-(tertbutylamino)- 1-(2-chloro-5,7-dimethylquinolin-3-yl)-2-oxoethyl)-3-methoxy-N-phenylbenzamide were obtained by the Ugi-Multi Component reaction of 2-chloro-5-7-dimethylquinoline-3- carbaldehyde 1, aniline 2a, 3-methoxybenzoic acid 3 and t-butyl isocyanides 4 were dissolved sequence vise in 2,2,2-trifluoroethanol (TFE) reaction solvent. This method is an efficient basemediated/ metal-free approach to synthesizing quinoline derivatives.

Results: We have successfully synthesized the quinoline derivatives via Ugi-multicomponent reaction via an efficient base-mediated/metal-free approach. The structures of the compounds were confirmed through various spectroscopic techniques. Characterized it, docking it, and their anticancer activities against different cell lines are evaluated.

Conclusion: The reported protocol is advantageous over conventional methods of quinoline derivatives via an efficient base-mediated/metal-free approach. Quinoline derivatives were tested for anticancer efficacy against 9 distinct subpanels of NCI-60 cell lines among which 5d and 5j have been found to be more potent against different cell lines. In order to get mechanistic insights into this antitumor activity, molecular docking analysis against critical target CDK2 was performed to aid in understanding the molecular basis of anticancer activity. The results of binding affinity were in harmony with the anticancer activity providing valuable insights into the various thermodynamic interactions governing the binding affinity. By using the potential of quinoline derivatives via an efficient base-mediated/metal-free approach, more effective and accurate cancer treatments can be designed in the future.

Keywords: Heterocyclic Chemistry, medicinal chemistry, Ugi-4CC condensation, quinoline derivatives, anticancer, NCI-60 cell line, molecular docking.

Graphical Abstract