Cytotoxicity, antimutagenicity and molecular docking of benzimidazole derivatives as anticancer agents
Benzimidazole, a fused heterocyclic compound comprising benzene and imidazole rings, is a well-known moiety that has garnered considerable interest in medicinal chemistry due to its wide range of pharmacological activity in a variety of disease models, including cancer. Due to its broad spectrum...
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| Format: | Thesis |
| Language: | English |
| Published: |
2021
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| Subjects: | |
| Online Access: | http://psasir.upm.edu.my/id/eprint/103866/1/NURUL%20HAFIZAN%20BINTI%20-%20IR.pdf |
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| Summary: | Benzimidazole, a fused heterocyclic compound comprising benzene and
imidazole rings, is a well-known moiety that has garnered considerable interest
in medicinal chemistry due to its wide range of pharmacological activity in a
variety of disease models, including cancer. Due to its broad spectrum of
therapeutic potential, many modifications and optimizations have been made to
its backbone, resulting in the production of many of its derivatives. The purpose
of this study was to assess the cytotoxicity, mutagenicity, and antimutagenicity
of four benzimidazole derivatives: (E)-4-(5,6-dimethyl-1H-benzo[d]imidazol-2-
yl)-N’-(3-hydroxybenzylidene) benzohydrazide (1), (E)-N’-(2,5-
dihydroxybenzylidene)-4-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)
benzohydrazide (2), (E)-N’-(2,4-dihydroxybenzylidene)-4-(5,6-dimethyl-1Hbenzo[
d]imidazol-2-yl) benzohydrazide (3), and (E)-4-(5,6-dimethyl-1Hbenzo[
d]imidazol-2-yl)-N’-(2-hydroxybenzylidene) benzohydrazide (4). To our
knowledge, these benzimidazole derivatives have not been explored for the
stated activities. The potential molecular interactions of these compounds with
the target proteins Bcl-2, Bcl-xL, and mutant p53-R273H were also investigated.
The MTT assay was conducted to determine the cytotoxic effects of
benzimidazole derivatives (1 – 4) on HeLa, HT-29, and MDA-MB-231 cancer cell
lines. Following that, the Ames test was performed to evaluate the mutagenic
and antimutagenic potential of the compounds. Then, the structure-activity
relationship (SAR) of benzimidazole derivatives was analyzed based on the
results obtained. Further, molecular docking was employed to predict the
possible interactions of the selected benzimidazole derivatives with the Bcl-2,
Bcl-xL, and mutant p53-R273H proteins. Except for compound 2, all
benzimidazole derivatives demonstrated varying degrees of cytotoxicity against
the tested cancer cells. When compared to 5-fluorouracil (5-FU), compound 4
showed the most promising cytotoxicity with lower IC50 values against HeLa (48
h: 9.86 ± 1.50 μM), HT-29 (48 h: 4.66 ± 0.16 μM) and MDA-MB-231 (24 h: 7.80 ±
0.19 μM; 48 h: 8.83 ± 0.64 μM) cells. Compound 3 also presented high cytotoxicity
compared to 5-FU, with IC50 values of 8.89 ± 2.62 μM (48 h) in HT-29 and 10.88 ±
1.39 μM (24 h) and 10.10 ± 2.90 μM (48 h) in MDA-MB-231 cells. Likewise,
compound 1 had lower IC50 values in HeLa (48 h: 9.09 ± 0.46 μM) and HT-29 (48
h: 13.47 ± 3.50 μM) cells, in comparison to 5-FU. The mutagenicity assessment
showed all benzimidazole derivatives were not mutagenic against the TA98 and
TA100 strains in the absence of metabolic activation. In the presence of metabolic
activation, it was observed that compound 1 induced a frameshift mutation in
the TA98 strain, whereas other compounds were not mutagenic in both tester
strains. Additionally, all derivatives showed significant antimutagenicity in both
tester strains. The SAR analysis proposed that the ortho-OH substitution on the
phenyl ring has a substantial influence on the cytotoxicity, mutagenicity, and
antimutagenicity of benzimidazole derivatives. The molecular docking analysis
demonstrated a high-affinity binding of compound 3 to the Bcl-2 protein and
compounds 3 and 4 to the mutant p53-R273H protein relative to the reference
standards. The results suggested that compound 3 may act as a ligand inhibitor
for Bcl-2 and that compounds 3 and 4 may act as ligand activators for the mutant
p53-R273H. |
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