Design and synthesis of 4-piperazinyl quinoline derived urea/thioureas for anti-breast cancer activity by a hybrid pharmacophore approach

Abstract

In an attempt to improve anti-breast cancer activity, a new series of 4-piperazinylquinoline derivatives based on the urea/thiourea scaffold were designed and synthesised by a pharmacophore hybrid approach. We then examined for their antiproliferative effects on three human breast tumor cell lines, MDA-MB231, MDA-MB468 and MCF7, and two non-cancer breast epithelial cell lines, 184B5 and MCF10A. Among those 26 novel compounds examined, 5, 9, 17, 18, 21, 23 and 29 showed significantly improved antiproliferative activity on breast cancer cells. Compound 23 (4-(7-chloro-quinolin-4-yl)-piperazine-1-carbothioic acid (2-morpholin-4-yl-ethyl)-amide) (RL-15) is especially desirable, since its antigrowth/cell-killing activity is 7-11 fold higher on cancer than non-cancer cells. Data from cell biological studies demonstrated that cancer cells compromised plasma membrane integrity in the presence of compound 23. The cancer cell-specific property of compound 23 shown in cell culture stands in vivo test, this compound can be an excellent lead for effective and safe anticancer drug.

Navigating the Synthesis of Quinoline Hybrid Molecules as Promising Anticancer Agents

“…In addition to that, quinoline having X = Cl acts as a more effective anticancer agent over X = CF 3 (Scheme 17). [74]…”

Structural and biological survey of 7‐chloro‐4‐(piperazin‐1‐yl)quinoline and its derivatives

“…Later on, they identified compound 57 as the most active and safe against breast cancer among a series of hybrids from 4‐piperazinylquinoline derivatives and urea/thiourea scaffolds. It exhibited GI 50 (μM) with 7 to 11 fold higher on cancer (MDA‐MB231: 3.0 ± 0.1, MDA‐MB468: 4.6 ± 0.6, MCF7: 4.5 ± 0.1) than noncancer cells (184B5: 34.4 ± 0.6, MCF10A: 32.3 ± 0.8) (Viswas, Pundir, & Lee, 2019; Figure 8).…”

Novel N‐Acyl‐1H‐imidazole‐1‐carbothioamides: Design, Synthesis, Biological and Computational Studies

“…TU pharmacophores possess specific binding sites like hydrogen binding area (NH), complementary area (S) and auxiliary binding area (1,3‐substituents) . This favorable pharmacokinetic profile impart TU based heterocycles potent biological applications including antimalarial, antitubercular, anti‐HIV, analgesic and anticancer . Symmetrical and asymmetrical TU derivatives serve as potent antimicrobial drug candidates .…”

“…[13] This favorable pharmacokinetic profile impart TU based heterocycles potent biological applications including antimalarial, [14] antitubercular, [15] anti-HIV, [16] analgesic [17] and anticancer. [18] Symmetrical and asymmetrical TU derivatives serve as potent antimicrobial drug candidates. [19] Pyrimidine based TU possess promising antimicrobial potential against bacterial and fungal pathogens.…”