Design and synthesis of 5-aryl-4-(4-arylpiperazine-1-carbonyl)-2H-1,2,3-triazole derivatives as colchicine binding site inhibitors

Abstract

A series of 5-aryl-4-(4-arylpiperazine-1-carbonyl)-2H-1,2,3-triazol derivatives were designed as potential microtubule targeting agents. The regioselective alkylation of 5-aryl-4-(4-arylpiperazine-1-carbonyl)-2H-1,2,3-triazole was predicted by computations and confirmed by an unambiguous synthetic route. The antiproliferative activity of the synthesized compounds was tested in vitro using three human cancer cell lines and some compounds exhibited significant antiproliferative activity, which suggested the reasonability of introduction of the 1,2,3-triazole fragment. Among them, compound 7p showed highest activity with the IC50 values at nanomolar level towards all three cell lines, which were comparable to the positive control, CA-4. Tubulin polymerization assay, immunofluorescence studies, cell cycle analysis and competitive tubulin-binding assay strongly proved that 7p is a colchicine binding site inhibitor of tubulin. Thus, 7p was identified as a promising drug candidate for further development of colchicine binding site inhibitors.

Design, Synthesis, and Biological Evaluation of 2‐(4‐Aminophenyl)benzothiazole Analogues as Antiproliferative Agents

“…The existence of this piperazine heterocycle can be witnessed in several identified drugs, belonging to different pharmacological classes . Several researchers have developed piperazine‐based anticancer agents . Piperazine containing few anticancer analogues ( E , F , G , and H ) are depicted in Figure .…”

Design, synthesis and biological evaluation of 1-Aryl-5-(4-arylpiperazine-1-carbonyl)-1H-tetrazols as novel microtubule destabilizers

“…It is well known that most tubulin inhibitors induce cell cycle arrest in the G2/M phase 7 . Thus, the effect of compound 6-31on the cell cycle of SGC-7901 cells was analysed by flow cytometry.…”

“…Among them, compound 4 showed excellent antiproliferative in vitro and effectively reduced tumour growth in vivo using a tumour xenograft model 6 . Our groups discovered a series of aryltriazole derivatives as a result of structural modifications of the lead compound XRP44X 7 . The most potent compound 5 exhibited excellent antiproliferative activity via disrupting cytoskeleton.…”

“….6.13. 1-Phenyl-5-(4-(3,5-dimethoxyphenyl)piperazine-1-carbonyl)-1H-tetrazol(6)(7)(8)(9)(10)(11)(12)(13). Light yellow Solid; yield: 61%; Mp: 121.3-123.2 C;1 H NMR (600 MHz, CDCl 3 ): d ¼ 7.57 (5H, m),6.07 (3H, m), 3.91 (2H, t, J ¼ 4.9 Hz),3.77 (6H, s), 3.69 (2H, t, J ¼ 4.7 Hz), 3.23 (2H, t, J ¼ 4.9 Hz), 3.13 (2H, t, J ¼ 5.0 Hz) 13.…”

“…1-(2-Bromophenyl)-5-(4-(3,5-dimethoxyphenyl)piperazine-1-carbonyl)-1H-tetrazol. Yellow Solid; yield: 80%; Mp: 71.1-72.4 C;1 H NMR (600 MHz, CDCl 3 ): d ¼ 7.74 (1H, dd, J ¼ 7.9 Hz, J ¼ 1.0 Hz),7.56 (2H, m),7.47 (1H, m),6.09 (2H, s),6.08 (1H, d, J ¼ 2.0 Hz), 4.10 (2H, t, J ¼ 5.0 Hz), 3.86 (2H, t, J ¼ 5.4 Hz), 3.78 (6H, s), 3.29 (2H, t, J ¼ 5.0 Hz), 3.24 (2H, t, J ¼ 5.4 Hz) 13. C NMR (150 MHz, CDCl 3 ): d ¼ 160.5 (2 C), 153.5, 151.5, 147.9, 132.6, 132.5, 131.4, 127.8, 127.7, 118.7, 94.7 (2 C), 91.5, 54.3 (2 C), 48.8, 48.1, 46.1, 41.4; HRMS calcd for C 20 H 22 BrN 6 O 3 [M þ H] þ 473.0937, found 473.0954.…”