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

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.

Quantification of the electric field inside protein active sites and fullerenes.

While electrostatic interactions are exceedingly accountable for biological functions, no simple method exists to directly estimate or measure the electrostatic field in protein active sites. The electrostatic field inside the protein is generally inferred from the shift in the vibrational stretching frequencies of nitrile and thionitrile probes at the active sites through several painstaking and time-consuming experiments like vibrational Stark effect spectroscopy (VSS). Here we present a simple, fast, and reliable methodology, which can efficiently predict the vibrational Stark tuning rates (VSRs) of a large variety of probes within 10% error of the reported experimental data. Our methodology is based on geometry optimization and frequency calculations in the presence of an external electric field to predict the accurate VSR of newly designed nitrile/thionitrile probes. A priori information of VSRs is useful for difficult experiments such as catalytic/enzymatic study and in structural biology. We also applied our methodology successfully to estimate the electric field inside fullerenes and nano-onions, which is encouraging for researchers to adopt it for further applications in materials science and supramolecular chemistry.