Gram-Scale Synthesis of 1,8-Naphthyridines in Water: The Friedlander Reaction Revisited

[Image: see text] The products of the Friedlander reaction, i.e., 1,8-naphthyridines, have far-reaching impacts in materials science, chemical biology, and medicine. The reported synthetic methodologies elegantly orchestrate the diverse synthetic routes of naphthyridines but require harsh reaction conditions, organic solvents, and expensive metal catalysts. Here, we introduce gram-scale synthesis of 1,8-naphthyridines in water using an inexpensive and biocompatible ionic liquid (IL) as a catalyst. This is the first-ever report on the synthesis of naphthyridines in water. This is a one-step reaction, and the product separation is relatively easy. The choline hydroxide (ChOH) is used as a metal-free, nontoxic, and water-soluble catalyst. In comparison to other catalysts reported in the literature, ChOH has the advantage of forming an additional hydrogen bond with the reactants, which is the vital step for the reaction to happen in water. Density functional theory (DFT) and noncovalent interaction (NCI) plot index analysis provide the plausible reaction mechanism for the catalytic cycle and confirm that hydrogen bonds with the IL catalyst are pivotal to facilitate the reaction. Molecular docking and molecular dynamics (MD) simulations are also performed to demonstrate the potentialities of the newly synthesized products as drugs. Through MD simulations, it was established that the tetrahydropyrido derivative of naphthyridine (10j) binds to the active sites of the ts3 human serotonin transporter (hSERT) (PDB ID: 6AWO) without perturbing the secondary structure, suggesting that 10j can be a potential preclinical drug candidate for hSERT inhibition and depression treatment.