Synthesis, Structural Investigations, DNA/BSA Interactions, Molecular Docking Studies, and Anticancer Activity of a New 1,4-Disubstituted 1,2,3-Triazole Derivative

We report herein a new 1,2,3-triazole derivative, namely,
4-((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-hydroxybenzaldehyde,
which
was synthesized by copper(I)-catalyzed azide–alkyne cycloaddition
(CuAAC). The structure of the compound was analyzed using Fourier
transform infrared spectroscopy (FTIR), 1H NMR, 13C NMR, UV–vis, and elemental analyses. Moreover, X-ray crystallography
studies demonstrated that the compound adapted a monoclinic crystal
system with the P21/c space group. The dominant interactions formed in the crystal packing
were found to be hydrogen bonding and van der Waals interactions according
to Hirshfeld surface (HS) analysis. The volume of the crystal voids
and the percentage of free spaces in the unit cell were calculated
as 152.10 Å3 and 9.80%, respectively. The evaluation
of energy frameworks showed that stabilization of the compound was
dominated by dispersion energy contributions. Both in vitro and in
silico investigations on the DNA/bovine serum albumin (BSA) binding
activity of the compound showed that the CT-DNA binding activity of
the compound was mediated via intercalation and BSA binding activity
was mediated via both polar and hydrophobic interactions. The anticancer
activity of the compound was also tested by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide (MTT) assay using human cell lines including MDA-MB-231, LNCaP,
Caco-2, and HEK-293. The compound exhibited more cytotoxic activity
than cisplatin and etoposide on Caco-2 cancer cell lines with an IC50 value of 16.63 ± 0.27 μM after 48 h. Annexin
V suggests the induction of cell death by apoptosis. Compound 3 significantly increased the loss of mitochondrial membrane
potential (MMP) levels in Caco-2 cells, and the reactive oxygen species
(ROS) assay proved that compound 3 could induce apoptosis
by ROS generation.