Nitrogen-containing heterocyclic rings are common structural components of marketed drugs. Among these heterocycles, imidazole/fused imidazole rings are present in a wide range of bioactive compounds. The unique properties of such structures, including high polarity and the ability to participate in hydrogen bonding and coordination chemistry, allow them to interact with a wide range of biomolecules, and imidazole-/fused imidazole-containing compounds are reported to have a broad spectrum of biological activities. This review summarizes recent reports of imidazole/fused imidazole derivatives as anticancer agents appearing in the peer-reviewed literature from 2018 through 2020. Such molecules have been shown to modulate various targets, including microtubules, tyrosine and serine-threonine kinases, histone deacetylases, p53-Murine Double Minute 2 (MDM2) protein, poly (ADP-ribose) polymerase (PARP), G-quadraplexes, and other targets. Imidazole-containing compounds that display anticancer activity by unknown/undefined mechanisms are also described, as well as key features of structure-activity relationships. This review is intended to provide an overview of recent advances in imidazole-based anticancer drug discovery and development, as well as inspire the design and synthesis of new anticancer molecules.

Imidazoles as Potential Anticancer Agents: An Update on Recent Studies.

Progress of tubulin polymerization activity detection methods

Design, synthesis and biological evaluation of a novel tubulin inhibitor SKLB0565 targeting the colchicine binding site.

Herein, we synthesized some new imidazole-tetrazole-amide hybrids (7 a–o) and investigated their antiproliferative activity on three human cancer cell lines like HEPG2, A549 and MCF-7. Generally, most of them displayed more activity on A549 than other two cell lines. Specifically, compounds N-(3,5-dimethoxyphenyl)-2-(5-(1-methyl-1H-imidazol-2-yl)-2H-tetrazol-2-yl)acetamide (7 b) and N-(4-chloro-3,5-dimethoxyphenyl)-2-(5-(1-methyl-1H-imidazol-2-yl)-2H-tetrazol-2-yl)acetamide (7 m) had almost similar potency on A549, while, they had significant activity on MCF-7 in comparison to the standard drug Combretastatin A-4 (CA-4). Besides, compounds 4-(2-(5-(1-methyl-1H-imidazol-2-yl)-2H-tetrazol-2-yl)acetyl)benzonitrile (7 j) and N-(3,5-dichlorophenyl)-2-(5-(1-methyl-1H-imidazol-2-yl)-2H-tetrazol-2-yl)acetamide (7 k) showed most promising activity against A549 as compared to the CA-4. The uppermost activity against A549 found for the compounds 7 j and 7 m have IC50 values 1.09 and 1.26 μM respectively. The ability of potent compounds 7 b, 7 j, 7 k and 7 m to inhibit the tubulin polymerization was then studied and found that compounds 7 b and 7 m exhibited promising potency in comparison to the CA-4. Further, molecular docking studies of compounds 7 b, 7 j, 7 k and 7 m into the tubulin's colchicine-binding site revealed the possible interactions with tubulin. Finally, in silico ADMET studies revealed that compounds 7 b, 7 j, 7 k and 7 m showed high GI absorption and followed rules of Lipinski, Ghose, Veber, Egan and Muegge without any deviation. Further anticancer mechanism studies are under progress. 

Synthesis of Amide Derivatives as Tubulin Polymerization Inhibiting Antiproliferative Agents

N6-Adenosine methylation (m6A) is a prevalent post-transcriptional modification of mRNA, with YTHDC1 being the reader protein responsible for recognizing this modification in the cell nucleus. Here, we present a protein structure-based medicinal chemistry campaign that resulted in the YTHDC1 inhibitor 40, which shows an equilibrium dissociation constant (Kd) of 49 nM. The crystal structure of the complex (1.6 Å resolution) validated the design. Compound 40 is selective against the cytoplasmic m6A-RNA readers YTHDF1-3 and YTHDC2 and shows antiproliferative activity against the acute myeloid leukemia (AML) cell lines THP-1, MOLM-13, and NOMO-1. For the series of compounds that culminated into ligand 40, the good correlation between the affinity in the biochemical assay and antiproliferative activity in the THP-1 cell line provides evidence of YTHDC1 target engagement in the cell. The binding to YTHDC1 in the cell is further supported by the cellular thermal shift assay. Thus, ligand 40 is a tool compound for studying the role of YTHDC1 in AML.

Structure-Based Design of a Potent and Selective YTHDC1 Ligand.

Discovery of 3-(((9H-purin-6-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one derivatives as novel tubulin polymerization inhibitors for treatment of cancer.

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Discovery of 3-(((9H-purin-6-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one derivatives as novel tubulin polymerization inhibitors for treatment of cancer.