New 3‐(1H‐benzo[d]imidazol‐2‐yl)quinolin‐2(1H)‐one‐based triazole derivatives: Design, synthesis, and biological evaluation as antiproliferative and apoptosis‐inducing agents

Abstract

A series of 1,2,3‐triazole derivatives based on the quinoline–benzimidazole hybrid scaffold was designed, synthesized, and screened against a panel of NCI‐60 humanoid cancer cell lines for in vitro cytotoxicity evaluation, which revealed that compound Q6 was the most potent cytotoxic agent with excellent GI50, TGI, and LC50 values on multiple cancer cell lines. Q6 was tested further on the BT‐474 breast cancer line to evaluate the mechanism of action. Preliminary screening studies based on the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assay revealed that compound Q6 had an excellent antiproliferative effect against human breast cancer cells, BT‐474, with IC50 values of 0.59 ± 0.01 μM. The detailed study based on the acridine orange/ethidium bromide staining (AO/EB) and the 4′,6‐diamidino‐2‐phenylindole (DAPI) assay suggested that the antiproliferative activity shown was due to the induction of apoptosis on exposure to Q6. Further, DCFDA staining showed the generation of reactive oxygen species, altering the mitochondrial potential and leading to the initiation of apoptosis. This was further supported by JC‐1 staining, indicating that this scaffold can contribute to the development of more potent derivatives.

Current Development in the Synthesis of Benzimidazole-Quinoline Hybrid Analogues and Their Biological Applications

“…Synthesised compounds were screened against a panel of NCI-60 human cancer cell lines for in vitro cytotoxicity evaluation. The compound (XXIX) showed an excellent antiproliferative effect with a significant IC 50 value of 0.59 μM against the human breast cancer BT-474 cell line [45]. [4,5]imidazo [1,2-a]quinoline-6-carbonitrile derivatives.…”

An Overview of the Biological Evaluation of Selected Nitrogen-Containing Heterocycle Medicinal Chemistry Compounds

“…Furthermore, the compounds bearing an ester functional group 107 exhibited moderate to good activity (see Figure 27). Gaikwad and co-workers' [101] modeled 1,2,3-triazole containing a 2-oxoquinolinebenzimidazole moiety by minimizing the pharmacophoric characteristics. The synthesized derivatives were screened against the NCI-60 cancer cell lines' panel to evaluate their in vitro antiproliferative activity.…”

Benzimidazole hybrids as anticancer drugs: An updated review on anticancer properties, structure–activity relationship, and mechanisms of action (2019–2021)

“…[ 34 ] The SAR illustrated that the ethoxy group at the C‐2 position of benzimidazole moiety was not critical for the activity and hybrid 10 (IC 50 : 0.6–3.0 µM, MTT assay) was not inferior to 5‐fluorouracil (IC 50 : 0.8–3.2 µM) against MCF‐7, MDA‐MB‐231, A549, NCI‐H460, and HaCaT cancer cell lines. [ 35 ] Mechanistically, hybrid 10 induced apoptosis via arresting cell cycle at Sub‐G1 phase, decreasing mitochondrial membrane potential (MMP), increasing apoptotic cells by annexin V. Further studies revealed that replacement of 1,2,3‐triazole by 1,2,4‐triazole led to loss of activity, [ 36 ] whereas incorporation of pyrazole or quinolin‐2‐one between benzimidazole and 1,2,3‐triazole moieties was permitted as evidenced by that hybrids 11a , b (IC 50 : 102.0–243.0 nM, MTT assay) were comparable to cisplatin (IC 50 : 122.0 and 596.0 nM) against C6 and MCF‐7 cancer cell lines and hybrid 12 (GI 50 : 1.4–8.6 µM, SRB assay) possessed promising broad‐spectrum activity against a panel of 60 cancer cell lines derived from nine different types of cancer [ 37,38 ] ; introduction of thiazole or the second 1,2,3‐triazole motif into benzimidazole moiety was also tolerated and hybrids 13 (IC 50 : 1.3–7.7 µM against HT29, MDA‐MB‐231 and SKBR3 cancer cell lines, MTT assay) and 14 (IC 50 : 3.1–6.3 µM against MCF‐7, A549 and HeLa cancer cell lines, MTT assay) were not inferior to doxorubicin (IC 50 : 1.6 to >100.0 µM). [ 39,40 ] Accordingly, these benzimidazole‐1,2,3‐triazole hybrids were useful scaffolds for the discovery of novel anticancer agents.…”

“…(IC 50 : 122.0 and 596.0 nM) against C6 and MCF-7 cancer cell lines and hybrid 12 (GI 50 : 1.4-8.6 µM, SRB assay) possessed promising broad-spectrum activity against a panel of 60 cancer cell lines derived from nine different types of cancer [37,38] ; introduction of thiazole or the second 1,2,3-triazole motif into benzimidazole moiety was also tolerated and hybrids 13 (IC 50 : 1.3-7.7 µM against HT29, MDA-MB-231 and SKBR3 cancer cell lines, MTT assay) and 14 (IC 50 : 3.1-6.3 µM against MCF-7, A549 and HeLa cancer cell lines, MTT assay) were not inferior to doxorubicin (IC 50 : 1.6 to >100.0 µM). [39,40] Accordingly, these benzimidazole-1,2,3-triazole hybrids were useful scaffolds for the discovery of novel anticancer agents.…”