Design and Synthesis of Novel Imidazole Derivatives Possessing Triazole Pharmacophore with Potent Anticancer Activity, and In Silico ADMET with GSK-3β Molecular Docking Investigations

Abstract

A library of novel imidazole-1,2,3-triazole hybrids were designed and synthesized based on the hybrid pharmacophore approach. Therefore, copper(I)catalyzed click reaction of thiopropargylated-imidazole 2 with several organoazides yielded two sets of imidazole-1,2,3-triazole hybrids carrying different un/functionalized alkyl/aryl side chains 4a–k and 6a–e. After full spectroscopic characterization using different spectral techniques (IR, 1H, 13C NMR) and elemental analyses, the resulted adducts were screened for their anticancer activity against four cancer cell lines (Caco-2, HCT-116, HeLa, and MCF-7) by the MTT assay and showed significant activity. In-silico molecular docking study was also investigated on one of the prominent cancer target receptors, i.e., glycogen synthase kinase-3β (GSK-3β), revealing a good binding interaction with our potent compound, 4k and was in agreement with the in vitro cytotoxic results. In addition, the ADMET profile was assessed for these novel derivatives to get an insight on their pharmacokinetic/dynamic attributes. Finally, this research design and synthesis offered click chemistry products with interesting biological motifs mainly 1,2,3 triazoles linked to phenyl imidazole as promising candidates for further investigation as anticancer drugs.

Functionalized hybrid magnetic catalytic systems on micro- and nanoscale utilized in organic synthesis and degradation of dyes

“…The imidazole nucleus acts as the leading scaffold to form signicant biological active molecules with antibacterial, antifungal, anti-inammation, anticancer, antiviral, anti-diabetic, anti-allergic, analgesic and herbicidal functionalities. 199,200 Some aromatic aldehydes were used in the synthesis of 2,4,5-triaryl-1H-imidazole derivatives. The aromatic aldehydes produced the desirable corresponding products in 82-92% yield due to their electron withdrawing and donating substituents.…”

1,2,3-Triazole Scaffold in Recent Medicinal Applications: Synthesis and Anticancer Potentials

“…Molecular docking studies suggested that the 1,2,3-triazole based compounds could occupy in the binding sites of DNA topoisomerase-II, 68 histone deacetylase 2 (HDAC2), 69 cyclooxygenase-2 (COX-2), 70 metalloproteinases (MMP-2 and MMP-9), 71 oncogenic kinase PAK1, 72 c-MET, 41 some cancer proteins, 73 carbonic anhydrase, 74 EGFR, 75 and glycogen synthase kinase-3 (GSK-3). 76 The significant roles of the triazole ring (presented in the molecule) in the formation of ligand-binding interactions of the triazole-containing compounds were noted from several studies. The study on the binding of imidazopyridine-1,2,3-triazoles against the c-MET suggested that the triazole ring plays key role in the formation of hydrogen bond with the Lys1110 residue as well as the hydrophobic interactions with Ala1221, Leu1140, Lys1110 and Leu1157 residues of the target.…”

Imidazole as a Promising Medicinal Scaffold: Current Status and Future Direction

“…Overall, compound C14 showed the best cytotoxic activity through the inhibitory effect of glycogen synthase kinase 3 beta (GSK-3β) and could be a potential anti-cancer agent with less toxicity. 24 …”

“… 19 However, compound C14 was reported to work on GSK-3β which is one of the kinase enzymes but our target prediction score of −0.34 did not correlate with Al-Blewi et al study. 24 All the proposed mechanisms for imidazole derivatives are summarized in Figure 1 .…”

“…Overall, compound C14 showed the best cytotoxic activity through the inhibitory effect of glycogen synthase kinase 3 beta (GSK-3β) and could be a potential anti-cancer agent with less toxicity. 24 On the other hand, several studies had promising results of imidazole compounds as anticancer agents but unfortunately, their mechanisms of action were not determined. As seen in Chen et al study which investigated seventeen imidazole derivatives with potential antiproliferative activity in two cell lines.…”