Modulation Effect on Tubulin Polymerization, Cytotoxicity and Antioxidant Activity of 1H-Benzimidazole-2-Yl Hydrazones

Abstract

1H-benzimidazol-2-yl hydrazones with varying hydroxy and methoxy phenyl moieties were designed. Their effect on tubulin polymerization was evaluated in vitro on porcine tubulin. The compounds elongated the nucleation phase and slowed down the tubulin polymerization comparably to nocodazole. The possible binding modes of the hydrazones with tubulin were explored by molecular docking at the colchicine binding site. The anticancer activity was evaluated against human malignant cell lines MCF-7 and AR-230, as well as against normal fibroblast cells 3T3 and CCL-1. The compounds demonstrated a marked antineoplastic activity in low micromolar concentrations in both screened in vitro tumor models. The most active were the trimethoxy substituted derivative 1i and the positional isomers 1j and 1k, containing hydroxy and methoxy substituents: they showed IC50 similar to the reference podophyllotoxin in both tumor cell lines, accompanied with high selectivity towards the malignantly transformed cells. The compounds exerted moderate to high ability to scavenge peroxyl radicals and certain derivatives—1l containing metha-hydroxy and para-methoxy group, and 1b–e with di/trihydroxy phenyl moiety, revealed HORAC values high or comparable to those of well-known phenolic antioxidants. Thus the 1H-benisimidazol-2-yl hydrazones with hydroxy/methoxy phenyl fragments were recognized as new agents exhibiting promising combined antioxidant and antineoplastic action.

Synthesis and Evaluation of Novel Metacetamol Derivatives with Hydrazone Moiety as Anticancer and Antimicrobial Agents

“…Numerous structural scaffolds have been identified due to their potential to inhibit tubulin and thus display anticancer activity. Among them, hydrazone‐based molecules, illustrated in Figure 7, are frequently reported as anti‐tubulin agents that specifically target the colchicine binding site [39–41] …”

“…Among them, hydrazone-based molecules, illustrated in Figure 7, are frequently reported as anti-tubulin agents that specifically target the colchicine binding site. [39][40][41] Inspired by the structural similarity between our compounds and the hydrazones previously identified as colchicine binding site inhibitors of tubulin, we employed molecular modeling techniques to perform docking studies of compound 3 e within the corresponding binding pocket of tubulin (Figure 8).…”

Аntiproliferative, Pro-apoptotic Activity and Tubulin Dynamics Modulation of 1H-Benzimidazole-2-Yl Hydrazones in Human Breast Cancer Cell Line Mda-Mb-231

“…The diverse representatives of the benzimidazole family exhibiting potent tubulin polymerization such as denibulin, NSC:761109/1 and 2-aryl-benzimidazoles derivatives of dehydroabietic acid, outlines the benzimidazole nuclei as a useful pharmacophore for the design of novel tubulin polymerization inhibitors [22][23][24][25][26]. Recently we have reported the synthesis of a library 1H-benzimidazol-2-yl hydrazones containing hydroxy, methoxy and fluoro groups in the phenyl moiety or 1,3-benzodioxolyl substituent [27,28]. The compounds exhibited excellent in vitro anthelmintic activity against isolated Trichinella spiralis muscle larvae and cytotoxicity against human malignant cell lines MCF-7 and AR-230, and normal fibroblast cell line 3T3 and CCL-1 [27][28][29].…”

“…Recently we have reported the synthesis of a library 1H-benzimidazol-2-yl hydrazones containing hydroxy, methoxy and fluoro groups in the phenyl moiety or 1,3-benzodioxolyl substituent [27,28]. The compounds exhibited excellent in vitro anthelmintic activity against isolated Trichinella spiralis muscle larvae and cytotoxicity against human malignant cell lines MCF-7 and AR-230, and normal fibroblast cell line 3T3 and CCL-1 [27][28][29]. The compounds also showed radical-scavenging activity against stable free radicals such as DPPH, ABTS and biologically relevant peroxyl radicals, significant protective effect in model systems, containing deoxyribose and lecithin, and metal-chelating activity.…”

Novel Fluorescent Benzimidazole-Hydrazone-Loaded Micellar Carriers for Controlled Release: Impact on Cell Toxicity, Nuclear and Microtubule Alterations in Breast Cancer Cells

“…For this reason, in recent years, clinical trials have been conducted to repurpose them as anticancer agents [ 11 ]. Inspiringly, these medications do exhibit good antitumor properties with antiproliferative and cytotoxic effects on different cancer cell lines [ 12 , 13 , 14 ].…”