Globally, hepatocellular carcinoma (HCC) has been nominated as the 3rd most commonly lethal cause members in malignancies due to high proliferative capacity which reflecting on accelerated growth and division rates [1]. Various factors contribute to this heightened proliferation rate, including genetic mutations, dysregulation of signaling pathways (such as the Wnt/β-catenin pathway), and interactions with tumor microenvironment [2]. Aggressive proliferation of HCC cells often leads to formation of large and invasive tumors [2]. Understanding the mechanisms driving this proliferation is critical in devising targeted therapies, which then ultimately improving the prognosis and treatment outcomes for individuals affected by HCC [3]. Antimitotic drugs, classified based on their mechanism of action, play a pivotal role in HCC treatment by disrupting cell division [4]. They can be broadly categorized into spindle poisons, microtubule stabilizers, and inhibitors of topoisomerase II [5]. Spindle poisons, like the well-known taxanes and vinca alkaloids, hinder spindle fiber formation during mitosis, preventing proper chromosome isolation [5]. Further, microtubule (MT) stabilizers promote microtubule assembly, impeding their disassembly and causing cell cycle arrest [6]. Moreover, kinesins family are microtubule based motor proteins that have crucial role in various cellular functions such as chromosome segregation and mitotic spindle building in mitotic process. Being adenosine triphosphatases (ATPases), kinesins utilize ATP hydrolysis to produce motor force along MTs [7]. Mitotic kinesins represent kinesins sub-family members that act only during mitotic phase of cell division. In fact, kinesin spindle enzyme (KSP) or Eg5 has been considered as most interesting member of the later subgroup that controls bipolar spindle formation and chromosome separation in mitosis process [8]. Notably, Eg5 has been overexpressed in abundant tumors including soft and solid ones in particular HCC, while almost no Eg5 enzyme is detected especially in non-divided tissues. Indeed, Eg5 as promising target for cancer therapy, its inhibition leads to apoptotic induction and also arrests mitotic spindle assembly which thereby mitotic shutdown [9]. Therefore, Eg5 inhibitors may not have severe undesirable effects particularly, neurotoxicity effects that associated with traditional antimitotic agents such as taxanes and vinca alkaloids [9]. Considerable Eg5 inhibitors have been discovered including Monastrol, Ispinesib, Enastron and Dimethylenastron (Fig. 1) [10]. These inhibitors are effective against taxol-resistant cancer cells, however, tolerable effects resulted from tubulin mutations is attributed to their limitation [10]. On the other hand, Colchicine (CLC), Combretastatin A4 and Phenstatin (Fig. 1) symbolize colchicine binding site inhibitors (CBSIs) models that widely used in treatment of enormous soft and solid cancer types. These models have the benefits of structures simplicity, small molecular weight and flexible modifications with respect to enhancement of pharmacological index values [10]. In a related direction, chalcone as Michael acceptor motif has gained attention due to its crucial ability to modulate cellular pathways in cancer progression which through various mechanistic routes such as apoptosis inducing, microtubule-binding and cell cycle arrest, drug metabolizing enzyme inhibition, novel notch signaling inhibitors and selective targeting of cancer cells [11], [12]. For instance, chalcones I, II and III are examples of antineoplastic agents that induce apoptosis by cell cycle arrest at G2/M phase (Fig. 1) [12]. On the other hand, nearly 50 % of malignant cases are accommodating radiotherapy (RT). Albeit this promising activity, RT is limited duo to multiple obstacles such as tumor cells radio-resistance and radio damage to adjacent normal cells. For these limitations, seeking for novel radio chemotherapeutics agents that increase sensitivity and selectivity towards necrotic cells represents an urgent demand [13].

From the above aspects, it has been declared that, Dimethylenastron as model for Eg5 inhibitors include 1,3-dihydropyrimidine as significant scaffold that penetrates into DNA groves or ATP domain of Eg5 isozyme (Fig. 2) [14]. By the same direction, essential pharmacophore of Combretastatin A4 as CBSIs involves aromatic head with trimethoxy moiety with the advantage of extra hydrogen bond acceptor-donner (HB A-D) affinities and hydrophobic character, and linker with π-π stacking interactions, (Fig. 2) [15]. Albeit the promising activity of these later candidates, high tolerance rate i.e. low survival benefits is still questionable for both of them, individually so, searching for low tolerable antiproliferative drugs is a matter of necessity. Accordingly, our strategic is to generate a novel compact scaffold through hybrid tactic of these candidates with the benefit of being Eg5 and tubulin polymerization inhibitors, as antimitotic candidate, to overcome such tolerance challenge [16]. This protocol has been considered with respect to the fact of dual action has synergetic significance than mono one with regard to efficacy and resistance as well [13]. In this study, modified Dimethylenastron and Combretastatin A4 scaffolds were introduced into series of novel octahydroquinazoline derivatives via chalcone linker (Fig. 2). Chalcone spacer has been crucially elected as a Michael acceptor due to its highly efficient chemotherapeutic and apoptotic induction characters [17], [18]. The trimethoxy aryl hydrophobic moiety was substantially chosen as an essential pharmacophore model for tubulin polymerization inhibition activities based on previous reports [15]. This moiety was sometimes replaced with variable bio-isosteres such as mono MeO, di MeO, methyl, halo, dihalo, NO2 and hetero-aryl moieties or no substitution to study the impact of electronic enrichment of these hybrids on Eg5 and tubulin polymerization inhibition activities (Fig. 2).