Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan.
Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan.
J Biomol Struct Dyn. 2020 Apr;38(6):1670-1682. doi: 10.1080/07391102.2019.1617783. Epub 2019 May 22.
In search of achieving less toxic and more potent chemotherapeutics, three novel heterocyclic benzimidazole derivatives: 2-(1H-benzo[d]imidazol-2-yl)-4-chlorophenol (BM1), 4-chloro-2-(6-methyl-1H-benzo[d]imidazol-2-yl)phenol (BM2) and 4-chloro-2-(6-nitro-1H-benzo[d]imidazol-2-yl)phenol (BM3) with DNA-targeting properties, were synthesized and fully characterized by important physicochemical techniques. The DNA binding properties of the compounds were investigated by UV-Visible absorption titrations and thermal denaturation experiments. These molecules exhibited a good binding propensity to fish sperm DNA (FS-DNA), as evident from the high binding constants () values: 1.9 × 10, 1.39 × 10 and 1.8 × 10 M for BM1, BM2 and BM3, respectively. Thermal melting studies of DNA further validated the absorption titration results and best interaction was manifested by with Δ = 4.96 °C. The experimental DNA binding results were further validated theoretically by molecular docking study. It was confirmed that the molecules (BM1-BM3) bind to DNA an intercalative and groove binding mode. The investigations showed a correlation between binding constants and energies obtained experimentally and through molecular docking, indicating a binding preference of benzimidazole derivatives with the minor groove of DNA. BM1 was the preferential candidate for DNA binding because of its flat structure, π-π interactions and less steric hindrance. To complement the DNA interaction, antimicrobial assays (antibacterial & antifungal) were performed. It was observed that compound showed promising activity against all bacterial strains (, , and ) and fungi ( and ), while rest of the compounds were active against selective strains. The MIC values of were found to be in the range of 12.5 ± 2.2-25 ± 1.5 µg/mL. Thus, the compound was found to be the effective DNA binding antimicrobial agent. Furthermore, the preliminary cytotoxic properties of synthesized compounds were evaluated by brine shrimps lethality assay to check their nontoxic nature towards healthy normal cells.Communicated by Ramaswamy H. Sarma.
为了寻找毒性更低、药效更强的化疗药物，我们合成了三种新型杂环苯并咪唑衍生物：2-(1H-苯并[d]咪唑-2-基)-4-氯苯酚（BM1）、4-氯-2-(6-甲基-1H-苯并[d]咪唑-2-基)苯酚（BM2）和 4-氯-2-(6-硝基-1H-苯并[d]咪唑-2-基)苯酚（BM3），它们都具有靶向 DNA 的性质，并通过重要的物理化学技术对其进行了全面表征。通过紫外可见吸收滴定和热变性实验研究了化合物与 DNA 的结合性质。这些分子与鱼精子 DNA（FS-DNA）具有良好的结合倾向，从高结合常数（）值中可以看出：BM1、BM2 和 BM3 分别为 1.9×10、1.39×10 和 1.8×10 M。DNA 热融实验进一步验证了吸收滴定结果，其中以 表现出最佳的相互作用，Δ=4.96°C。实验 DNA 结合结果通过分子对接研究进一步得到理论验证。结果证实，这些分子（BM1-BM3）以嵌入和沟结合模式与 DNA 结合。研究表明，实验和分子对接获得的结合常数和能量之间存在相关性，表明苯并咪唑衍生物优先与 DNA 的小沟结合。由于其平面结构、π-π 相互作用和较小的空间位阻，BM1 是 DNA 结合的首选候选物。为了补充 DNA 相互作用，我们进行了抗菌（抗细菌和抗真菌）检测。结果表明，化合物 对所有细菌菌株（、、和）和真菌（和）都表现出良好的活性，而其他化合物则对选择性菌株具有活性。的 MIC 值在 12.5±2.2-25±1.5μg/mL 范围内。因此，化合物 被发现是一种有效的 DNA 结合抗菌剂。此外，通过卤虫致死试验评估了合成化合物的初步细胞毒性，以检查它们对健康正常细胞的非毒性。由 Ramaswamy H. Sarma 传达。
