Highlights

New 2-anilinoquinoline based arylamides were designed and synthesized.

Piperazine derivatives 9a and 9c exerted superior anticancer potencies to imatinib.

9a and 9c showed sub-micromolar GI₅₀ values over multiple MDR cancer cells.

9a and 9c trigger apoptosis and cell cycle arrest at G0/G1 phase in HCT-116 colon cancer cell.

9c disclosed potent nanomolar activity over B-RAF^V600E and C-RAF kinases.

Abstract

Prompted by the urgent demand for identification of new anticancer agents with improved potency and efficacy, a new series of arylamides incorporating the privileged 2-anilinoquinoline scaffold has been designed, synthesized, and biologically assessed. Aiming at extensive evaluation of the target compounds’ potency and spectrum, a panel of 60 clinically important cancer cell lines representing nine cancer types has been used. Compounds 9a and 9c, with piperazine substituted phenyl ring, emerged as the most active members surpassing the anticancer potencies of the FDA-approved drug imatinib. They elicited sub-micromolar or one-digit micromolar GI₅₀ values over the majority of tested cancer cells including multidrug resistant (MDR) cells like colon HCT-15, renal TK-10 and UO-31, and ovarian NCI/ADR-RES. In vitro mechanistic study showed that compounds 9a and 9c could trigger morphological changes, apoptosis and cell cycle arrest in HCT-116 colon cancer cells. Besides, compound 9c altered microtubule polymerization pattern in a similar fashion to paclitaxel. Kinase screening of 9c disclosed its inhibitory activity over B-RAF^V600E and C-RAF kinases with IC₅₀ values of 0.888 μM and 0.229 μM, respectively. Taken together, the current report presents compounds 9a and 9c as promising broad-spectrum potent anticancer candidates, which could be considered for further development of new anticancer drugs.