Conjugation of Benzylvanillin and Benzimidazole Structure Improves DNA Binding with Enhanced Antileukemic Properties

Abstract

Benzyl-o-vanillin and benzimidazole nucleus serve as important pharmacophore in drug discovery. The benzyl vanillin (2-(benzyloxy)-3-methoxybenzaldehyde) compound shows anti-proliferative activity in HL60 leukemia cancer cells and can effect cell cycle progression at G2/M phase. Its apoptosis activity was due to disruption of mitochondrial functioning. In this study, we have studied a series of compounds consisting of benzyl vanillin and benzimidazole structures. We hypothesize that by fusing these two structures we can produce compounds that have better anticancer activity with improved specificity particularly towards the leukemia cell line. Here we explored the anticancer activity of three compounds namely 2-(2-benzyloxy-3-methoxyphenyl)-1H-benzimidazole, 2MP, N-1-(2-benzyloxy-3-methoxybenzyl)-2-(2-benzyloxy-3-methoxyphenyl)-1H-benzimidazole, 2XP, and (R) and (S)-1-(2-benzyloxy-3-methoxyphenyl)-2, 2, 2-trichloroethyl benzenesulfonate, 3BS and compared their activity to 2-benzyloxy-3-methoxybenzaldehyde, (Bn1), the parent compound. 2XP and 3BS induces cell death of U937 leukemic cell line through DNA fragmentation that lead to the intrinsic caspase 9 activation. DNA binding study primarily by the equilibrium binding titration assay followed by the Viscosity study reveal the DNA binding through groove region with intrinsic binding constant 7.39 µM/bp and 6.86 µM/bp for 3BS and 2XP respectively. 2XP and 3BS showed strong DNA binding activity by the UV titration method with the computational drug modeling showed that both 2XP and 3BS failed to form any electrostatic linkages except via hydrophobic interaction through the minor groove region of the nucleic acid. The benzylvanillin alone (Bn1) has weak anticancer activity even after it was combined with the benzimidazole (2MP), but after addition of another benzylvanillin structure (2XP), stronger activity was observed. Also, the combination of benzylvanillin with benzenesulfonate (3BS) significantly improved the anticancer activity of Bn1. The present study provides a new insight of benzyl vanillin derivatives as potential anti-leukemic agent.

Benzimidazole and its derivatives as cancer therapeutics: The potential role from traditional to precision medicine

“…Compound 4c is a pyrrolobenzodiazepine (PBD)-conjugated benzimidazole derivative that has demonstrated remarkable DNA-binding affinity at GI 50 value and potent inhibition of cancer cell growth with concentration less than 10 nmol/L in the 60 cancer cell lines screen of NCI, comprising of leukaemia, melanoma, lung, ovarian, colon, renal, breast, prostate, and CNS cancers 64 . In 2013, Al-Mudaris and colleagues 65 successfully synthesized the benzyl vanillin (2-(benzyloxy)-3-methoxybenzaldehyde) analogues, 2MP , 2-(2-benzyloxy-3-methoxyphenyl)-1 H -benzimidazole) and 2XP ( N -1-(2-benzyloxy-3-methoxybenzyl)-2-(2-benzyloxy-3-methoxyphenyl)-1 H -benzimidazole), and screened them for anticancer potentials. The addition of benzimidazole moiety to the side chain has improved the DNA binding affinity, and enhanced the cytotoxic effect of 2MP and 2XP compared to their parent structure.…”

Identification of potential drug candidates to treat gastritis and associated oxidative stress based on some novel 2-aryl-1H-naphtho[2,3-d]imidazole: synthesis, in vitro and in silico analysis

“…17 Benzimidazole derivatives continue to spark an interest in the field of medicinal chemistry. Consequently, a wide assortment of derivatives of benzimidazole have been reported for their favorable physiological and pharmacological properties, such as enzyme inhibition, 18–20 antimicrobial, cytotoxic, antidiabetic, 21 antiasthmatic, antileukemic, 22 antihypertensive and antihepatitis B virus, 23 antileishmanial, 2 anti-HIV and cardiotonic, anti-inflammatory and analgesic, 25,26 diuretic, 27 antitumor and antiasthmatic, 26 anthelmintic and antihistaminic 24 properties. Benzimidazole derivatives have shown tremendous potential in remedying infections, obesity, epilepsy, and ulcers.…”