One-step synthesis of picolinohydrazides from fusaric acid: DFT, structural characterization and molecular inhibitory studies on metastatic tumor-derived exosomal and non-exosomal proteins

A new class of picolinohydrazide analogs (5-7) was synthesized via the one-pot reaction between fusaric acid (1) and aryl hydrazines (2-4) using amide coupling reagents. The synthesized compounds (5-7) were characterized using density-functional theory (DFT) computational spectroscopy, and instrumental methods. Global and local reactivity descriptors of these compounds were calculated at the B3LYP/6311++g(d) level of theory to predict the reactivity and the reactive sites. The evaluated electronic properties (HOMO and LUMO) gave an insight into the molecular properties of the molecule. The charge distribution and molecular electrostatic potential facilitated the prediction of either the electrophilic or nucleophilic reactivity of these compounds. Extracellular heat shock protein-90 (HSP90) plays an essential role in tumor invasion while epidermal growth factor receptor (EGFR) is found at high levels on the surface of metastatic tumors. Blocking EGFR and HSP90 may predict metastatic spread. Molecular docking and molecular dynamics showed that picolinohydrazide analogs (5-7) act as inhibitors to the active-site cavity of the target proteins, i.e., EGFR and HSP90. The fluorine scaffold (6) has a potential binding free energy of -31.01 kcal mol(-1) and -30.54 kcal mol(-1) for EGFR and HSP90, respectively. The binding complex of fluorine scaffold (6) with EGFR and HSP90, respectively has also shown substantial stability in the post-dynamics analysis. Our results implicate the potential efficacy of novel adjunct therapeutic insights in treating advanced cancer. (C) 2022 Elsevier B.V. All rights reserved.