Pfitzinger Synthesis, Tautomeric Behavior, and in Silico ADMET Evaluation of Novel Quinoline-4-carboxylic Acid Derivatives
Abstract
Two new quinoline-4-carboxylic acid derivatives were obtained through the classical Pfitzinger reaction using two structurally different β-dicarbonyl compounds. The molecular structures of the obtained compounds were verified using 1H NMR, 13C NMR, FT-IR, and HR-ESI-MS spectroscopic techniques. Spectroscopic data showed that Compound 1 existed as a tautomeric equilibrium between the open-chain quinoline-4-carboxylic acid form (74%) and the corresponding cyclic lactone form (26%), whereas Compound 2 was obtained exclusively as the fused lactone structure. To investigate the influence of tautomerism on the predicted pharmacokinetic properties, the individual tautomeric forms together with Compound 2 were subjected to in silico ADMET analysis. All investigated structures fulfilled Lipinski's Rule of Five without any violations, supporting their favorable drug-likeness. Among the investigated structures, Compound 2 showed the highest predicted intestinal absorption and Caco-2 permeability, while the open-chain tautomer of Compound 1 was predicted to be AMES negative, suggesting the most favorable toxicity profile. These results indicate that tautomeric structure influences the predicted ADMET properties of quinoline derivatives and provide useful information for the future design of biologically active quinoline-based compounds.
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