Synthesis and spectroscopic characterization of carboxamide ligands: anti-cancer potential validation by in vitro interaction studies with HSA, DFT, molecular docking

Human serum albumin (HSA) is one of the basic components of blood plasma and it serves as a storage andcarrier protein. Understanding and characterizing the interaction of drugs with HSA has attracted greatresearch interests from decades. The nature and importance of these bindings have direct consequence ondrug delivery, pharmacokinetics, pharmacodynamics, therapeutic efficacy and drug designing. Herein, twocarboxamide ligands have been synthesised by the reaction of adenine with picolinic acid (HL۱) and adeninewith pyrazine-۲-carboxylic acid (HL۲) and characterised by UV–Vis, FT-IR, ۱H-NMR, and Massspectroscopy. Also, the optimized structures of these ligands have been investigated using the DFT/B۳LYPmethod with the ۶–۳۱۱++G(d,p) basis set. These show the results of the calculations to be in accordance withthe experimental ones.In the current work, we studied the mechanism of interaction between the anticancer drug and carrier proteinhuman serum albumin (HSA) by using a variety of spectroscopic techniques (fluorescence spectroscopy, andcircular dichroism (CD) spectroscopy) and computational methods (molecular docking and moleculardynamic simulation). Fluorescence data indicated that interaction of drug with HSA changed themicroenvironment around the tryptophan residue with excellent binding constant (۳۸.۲۷ mM-۱ for HL۱).Also considering that the Kq values for these ligands are >۲.۰ × ۱۰۱۰ M−۱ s−۱, indicated that thefluorescence of HSA was quenched by ligands with a static quenching mechanism. Computational moleculardocking was carried out to investigate the HSA-binding pose of the compounds. the study of moleculardocking also indicated that our ligands could strongly bind to the site I (subdomain IA) of HSA. Accordingto the CD results these ligands can bind to the main blood carrier protein (HSA) and change the secondarystructure of the protein.