Optimizing 2-furylated imidazole π-bridges for NIR lipid droplet imaging

Lipid droplets (LDs) are globular biological organelles found in the human body, essential for lipid storage, homeostasis, energy reserve, cellular stress response, membrane biogenesis, and cellular signaling. Dysregulated accumulation of LDs leads to various diseases, including breast and liver cancers. Therefore, the development of diagnostic tools for monitoring LDs using suitable probes for bio-imaging applications is imperative. However, identifying promising probes with near-infrared emission characteristics is still a challenging and intriguing task, requiring extensive exploration of the structure-emission property relationship to design efficient probes for LDs. In this context, we envision the impact of 2-furylated imidazole as a π-bridge and have designed nine LD probes by substituting it with electron-releasing groups like CH₃, NH₂, NH(CH₃), and N(CH₃)₂ at the 3^rd and 4^th positions via DFT, TD-DFT, FMO, ESP, NCI, and QTAIM analyses. Our results demonstrate that LDP7 with NH(CH₃) at the 3^rd position is the most promising molecule, exhibiting the highest emission maxima (772.02 nm) with a lower HOMO-LUMO gap, suggesting its suitability for a range of biomedical applications. An enhancement of ∼200 nm is achieved through tailoring the molecular structure using the designed 2-furylated imidazole-derived π-bridge. ADMET and molecular docking analysis followed by molecular dynamics simulations with the human pyruvate kinase protein reveal these LDPs' bioavailability, binding ability and their stability towards their bio-imaging applications. In summary, our study offers valuable insights to aid researchers in developing and refining various π-linkers for lipid droplet bio-imaging applications.