Introduction: Tubulin polymerization inhibitors have emerged as interesting
anticancer therapies. We present the design, synthesis, and structural
elucidation of novel thiazole-based derivatives to identify novel tubulin
inhibitors with potent antiproliferative efficacy and strong inhibition of tubulin
polymerization.
Methods: The novel compounds consist of two scaffolds. Scaffold A compounds
10a-e and scaffold B compounds 13a-e. the structures of the newly synthesized
compounds 10a-e and 13a-e were validated using 1H NMR, 13C NMR, and
elemental analysis.
Results and Discussion: The most effective antitubulin derivative was 10a,
exhibiting an IC50 value of 2.69 μM. Subsequently, 10o and 13d exhibited IC50
values of 3.62 μM and 3.68 μM, respectively. These compounds exhibited more
potency than the reference combretastatin A-4, which displayed an IC50 value of
8.33 μM. These compounds had no cytotoxic effects on normal cells, preserving
over 85% cell viability at 50 μM. The antiproliferative experiment demonstrated
that compounds 10a, 10o, and 13d displayed significant activity against four
cancer cell lines, with average GI50 values of 6, 7, and 8 μM, equivalent to the
reference’s doxorubicin and sorafenib. Compounds 10a, 10o, and 13d were
demonstrated to activate caspases 3, 9, and Bax, while down-regulating the
anti-apoptotic protein Bcl2. Molecular docking studies demonstrated superior
binding affinities for 10a (-7.3 kcal/mol) at the colchicine binding site of tubulin,
forming key hydrophobic and hydrogen bonding interactions that enhance itsactivity. ADMET analysis confirmed favorable drug-like properties, establishing
these compounds as promising candidates for further development as
anticancer agents targeting tubulin polymerization.

Cancer is one of the leading causes of morbidity and mortality worldwide. One of the primary causes of
cancer development and progression is epigenetic dysregulation, which is a heritable modification that
alters gene expression without changing the DNA sequence. Therefore, targeting these epigenetic
changes has emerged as a promising therapeutic strategy. Benzimidazole derivatives have gained
attention for their potent epigenetic modulatory effects as they interact with various epigenetic targets,
including DNA methyltransferases, histone deacetylases and histone methyltransferases. This review
provides a comprehensive overview of benzimidazole derivatives that inhibit different acetylation and
methylation reader, writer and eraser epigenetic targets. Herein, we emphasize the therapeutic potential
of these compounds in developing targeted, less toxic cancer therapies. Presently, some promising
benzimidazole derivatives have entered clinical trials and shown great advancements in the fields of
hematological and solid malignancy therapies. Accordingly, we highlight the recent advancements in
benzimidazole research as epigenetic agents that could pave the way for designing new multi-target
drugs to overcome resistance and improve clinical outcomes for cancer patients. This review can help
researchers in designing new anticancer benzimidazole derivatives with better properties.