Novel donor-π-acceptor benzimidazole-based chromophores: synthesis, antitumor assessment, and pharmacokinetics

Abstract

Targeted chromophores, 2-(N,N-dialkyl-/diaryl-aminophenyl)benzimidazole hybrids 2a, 2b, 4a, and 4b, were designed and synthesized. The designed hybrids were identified as donor-π-acceptor (D-π-A) structures, incorporating N,N-dialkyl/diarylamino groups as the donor moiety and nitro or pyridinyl Schiff-base groups as the acceptor moiety. The hybrids were found to exhibit significant solvent-dependent properties, especially in polar solvents such as DMSO, which enhanced their fluorescence properties. Conjugate 2a exhibited absorbance and fluorescence maxima at 390 and 528 nm, respectively, in DMSO, while hybrid 2b demonstrated absorbance and fluorescence maxima at 396 and 536 nm, respectively. Hybrids 4a and 4b exhibited similar solvent-dependent activity. The cytotoxicity of all the synthesized chromophores was tested against several human cancer cell lines using an MTT assay, and their inhibitory activity against VEGFR-2 was determined using an anti-phosphotyrosine-based quantitative kinase assay. Chromophore 4a exhibited the highest overall cytotoxicity, with IC₅₀ = 12.64 ± 0.29 µM towards HepG2 cells and IC₅₀ = 12.19 ± 0.30 µM towards PC3 cells. Meanwhile, the four targeted chromophores were tested towards VEGFR-2 using the reference sorafenib, which is a noticeable target in anti-angiogenic cancer therapy. The docking results revealed that hybrid 4b exhibited the strongest binding score, which was close to that of sorafenib (reference), suggesting that it shows the most promising profile. Analysis by SwissADME revealed that hybrids 2a and 4a exhibited good pharmacokinetic properties, such as high gastrointestinal absorption and blood–brain barrier permeability. In conclusion, the combined experimental and computational approach presented here suggests the potential of these benzimidazole chromophores as early leads for anticancer and anti-angiogenic agents.