Cervical cancer is one of the most common malignant tumors in women worldwide [1]. Human papillomavirus (HPV) is the main factor contributing to the development of cervical cancer [2], [3]. Despite the introduction of HPV vaccines globally, the incidence of cervical cancer continues to rise and is showing a trend toward affecting younger women [4], [5], [6]. The standard treatment for early-stage cervical cancer is usually postoperative radiotherapy, which may lead to tumor recurrence and is mainly associated with several factors, such as cell proliferation, apoptosis, and metastasis. Concurrent chemoradiotherapy with cisplatin is the standard treatment for advanced cervical cancer, but the development of resistance to cisplatin often leads to chemotherapy failure [7], [8], [9], [10]. Overexpression of P-glycoprotein (P-gp) in tumor cells is a major cause of cisplatin resistance in cervical cancer [11]. Therefore, it is of great significance to explore the mechanisms of tumor resistance, identify new targets, and design novel anticancer compounds based on the structure of these targets.

Microtubules are essential components of the cytoskeleton in eukaryotic cells, and they are formed by the polymerization of α-, β-heterodimers and function through the dynamic equilibrium of assembly and disassembly of α-, β-heterodimers [12], [13], [14], [15]. The dynamics of microtubule assembly and disassembly are central to the biological functions of cells [16]. Microtubule assembly agents or microtubule inhibitors play important roles in regulating mitosis, cell cycle arrest, apoptosis signaling, and disruption of microtubule dynamics [17], [18], [19]. Therefore, disrupting the dynamic equilibrium of microtubule proteins leads to cell cycle arrest at the G2/M phase and ultimately induces cell apoptosis [20], [21], [22]. Colchicine (1) (Fig. 1) is a typical microtubule inhibitor that targets the colchicine-binding site. However, colchicine cannot be used for cancer treatment due to severe side effects and poor bioavailability [23]. Microtubules have been a popular target for developing anticancer drugs, and drugs targeting the colchicine site are often not substrates of P-gp, thus avoiding the multidrug resistance (MDR) mechanism regulated by P-gp [24], [25], [26]. In recent years, there have been many studies on chalcone derivatives to develop novel and effective microtubule inhibitors, as well as overcome drug resistance in cancer treatment [27], [28].

Chalcone (2) (1,3-diphenylprop-2-en-1-one, as shown in Fig. 1) belongs to the flavonoid class of compounds and is widely present in edible and medicinal plants. Chalcone serves as a precursor for plant flavonoids [29]. Chalcone and its derivatives are products of the crossed aldol condensation of aromatic aldehydes and ketones. Due to the presence of α-, β-unsaturated ketone in their molecular structure, chalcone derivatives exhibit significant flexibility and can bind to various targets [30]. Therefore, chalcone and its derivatives have a wide range of biological activities, such as anticancer [31], antibacterial [32], antimalarial [33], antioxidant [34], and anti-tuberculosis [35] activities, as well as the ability to modulate P-gp-mediated MDR [36], [37]. Studies have shown that chalcone is a favorable scaffold for the design and development of novel anticancer drugs [38], [39]. Chalcone derivatives that target the colchicine-binding site have a certain inhibitory effect on P-gp and are not substrates of the P-gp efflux pump, thus overcoming tumor resistance [40]. Chalcone conjugated with other anticancer pharmacophores has demonstrated good antitumor and resistance-modifying effects [41], [42]. Imidazole is a five-membered heterocyclic compound with two adjacent nitrogen atoms in its molecular structure, making it prone to form hydrogen bonds with protein receptors and enzymes in the body. Imidazole is an important pharmacophore for anticancer drugs [43], [44], [45]. Imidazoled compounds have been used as an effective anticancer agent (Fig. 1 (3-6)) and is employed in the clinical treatment of various cancers [46], [47]. Studies have shown that certain imidazole derivatives exhibit potent inhibitory activity against microtubule polymerization [48], [49], [50], [51], [52]. However, derivatives with an imidazole ring as the core structure also induce G2/M cell cycle arrest and apoptosis in HeLa and HeLa/DDP cells, making them potential effective compounds for treating cervical cancer [53], [54].

Therefore, the present study utilized licorice chalcone as the lead compound scaffold and introduced an imidazole ring and other active groups to synthesize a series of novel imidazole-chalcone derivatives (7) (Fig. 1) via the Claisen-Schmidt reaction. The anticancer activity of these compounds against cervical cancer cells and cisplatin-resistant cervical cancer cells was evaluated to identify novel chalcone derivatives with high anticancer activity, low toxicity, and cisplatin resistance. The present study provides a foundation for the development of microtubule protein inhibitors as anticancer drugs with the ability to reverse cisplatin resistance.