Colorectal cancer (CRC) constitutes a formidable global health burden and ranks among the leading causes of cancer-related mortality worldwide, with its highly aggressive biological characteristics posing a severe threat to human health [1,2]. Clinically, early-stage CRC typically manifests with non-specific symptoms, such as mild abdominal discomfort or altered bowel habits, contributing to delayed diagnosis in more than 40% of cases [3,4]. By the time overt clinical manifestations arise, the majority of tumors have progressed to locally invasive or metastatic stages. Distant metastasis to the liver, lungs, and regional lymph nodes represents a defining hallmark of advanced CRC, which drastically reduces the 5-year survival rate from over 90% in patients with localized disease to less than 15% in those with metastatic lesions [5,6]. Furthermore, the acquisition of multidrug resistance to first-line chemotherapeutic agents and targeted therapeutics further impairs treatment efficacy, culminating in dismal prognosis and markedly diminished quality of life for affected patients [7,8]. Beyond its direct lethal effects, CRC also imposes considerable socioeconomic burdens, including prolonged hospitalization, repeated therapeutic interventions, and reduced workforce productivity. This underscores the urgent need to prioritize CRC as a public health concern and develop innovative therapeutic strategies.

Indole and azole derivatives are both privileged scaffolds for CRC drug development, offering distinct advantages in anti-CRC therapy [9,10]. Indole derivatives exert potent anti-CRC effects by targeting key oncoproteins, such as histone deacetylases (HDACs) and topoisomerase I, thereby disrupting cell cycle progression and inducing mitochondrial apoptosis [11,12]. Notably, their structural flexibility enables facile structural modification to enhance CRC-selective efficacy. In contrast, azole derivatives inhibit angiogenesis by targeting vascular endothelial growth factor receptor (VEGFR) and reverse multidrug resistance (MDR) by suppressing ATP-binding cassette (ABC) transporter activity, thereby restoring chemotherapeutic efficacy in drug-resistant CRC cells [13,14]. Indole-azole hybrids, constructed by covalently linking these two privileged scaffolds, integrate and amplify the inherent advantages of both parent structures while overcoming their individual limitations, emerging as a highly promising class of next-generation anti-CRC agents [15,16]. Firstly, their dual-heterocyclic architecture enables multi-pathway synergistic targeting: they can simultaneously modulate CRC-associated oncogenic cascades, including the wingless-related integration site (Wnt)/β-catenin, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), and TP53 phosphorylation pathways, achieving more comprehensive inhibition of tumor cell proliferation, migration, and invasion than single-scaffold indole or azole derivatives [17,18]. Secondly, these hybrids exhibit favorable pharmacokinetic profiles, characterized by enhanced aqueous solubility, improved oral bioavailability, and prolonged tumor retention time [19,20]. These properties effectively mitigate the poor aqueous solubility of certain indole derivatives and the rapid metabolic clearance of some azole compounds. Thirdly, these hybrids exert superior efficacy in reversing MDR, as they can effectively sensitize drug-resistant CRC cells to conventional chemotherapeutic agents via the concurrent inhibition of ABC transporter-mediated drug efflux and modulation of resistance-associated signaling pathways [21,22]. Finally, their structural modularity enables rational optimization of structure-activity relationships (SARs), thereby facilitating the design of derivatives with enhanced target binding affinity, robust in vivo antitumor efficacy, and minimal off-target adverse effects. Collectively, indole-azole hybrids represent a transformative strategy to advance CRC therapy by harnessing the synergistic potential of two validated anticancer scaffolds.

This review aims to comprehensively dissect the current research landscape of indole-azole hybrids endowed with anti-CRC therapeutic potential, covering relevant literature published from 2021 to the present. Two core objectives underpin this work: (1) to systematically screen and summarize promising indole-azole hybrids with favorable preclinical profiles that exhibit great potential for progression to advanced preclinical development; (2) to refine the current understanding of their SARs, decipher the underlying mechanisms of action, and summarize the results of molecular docking studies. By fulfilling these objectives, this review is anticipated to provide valuable insights for the rational design of next-generation anti-CRC agents based on indole-azole hybrids, with the merits of enhanced potency and attenuated systemic toxicity.