Quinolone-Hydroxyquinoline Tautomerism in Quinolone 3-Esters. Preserving the 4-Oxoquinoline Structure To Retain Antimalarial Activity. | - CCMAR -

Journal Article

TitleQuinolone-Hydroxyquinoline Tautomerism in Quinolone 3-Esters. Preserving the 4-Oxoquinoline Structure To Retain Antimalarial Activity.
Publication TypeJournal Article
AuthorsHorta, P, Kuş, N, Henriques, MSofia C, Paixão, JA, Coelho, L, Nogueira, F, O'Neill, PM, Fausto, R, Cristiano, MLS
Year of Publication2015
JournalJ Org Chem
Date Published2015 Dec 18
KeywordsAntimalarials, Hydroxyquinolines, Malonates, Molecular Structure, Oxyquinoline, Photochemistry, Quinolines, Quinolones, Spectroscopy, Fourier Transform Infrared

Recent publications report in vitro activity of quinolone 3-esters against the bc1 protein complex of Plasmodium falciparum and the parasite. Docking studies performed in silico at the yeast Qo site established a key role for the 4-oxo and N-H groups in drug-target interactions. Thus, the possibility of 4-oxoquinoline/4-hydroxyquinoline tautomerism may impact in pharmacologic profiles and should be investigated. We describe the synthesis, structure, photochemistry, and activity against multidrug-resistant P. falciparum strain Dd2 of ethyl 4-oxo-7-methylquinoline-3-carboxylate (7Me-OQE) and ethyl 4-hydroxy-5-methylquinoline-3-carboxylate (5Me-HQE), obtained from diethyl 2-[((3-methylphenyl)amino)methylene]malonate. Theoretically (B3LYP/6-311++G(d,p)), 5Me-HQE and 7Me-OQE show clear preference for the hydroxyquinoline form. The difference between the lowest energy hydroxyquinoline and quinolone forms is 27 and 38 kJ mol(-1), for 5Me-HQE and 7Me-OQE, respectively. Calculations of aromaticity indexes show that in 5Me-HQE both rings are aromatic, while in the corresponding oxo tautomers the nitrogen-containing ring is essentially non-aromatic. The structure of monomeric 5Me-HQE was studied using matrix isolation coupled to FTIR spectroscopy. No traces of 4-oxoquinoline tautomers were found in the experimental IR spectra, revealing that the species present in the crystal, 5Me-HQE·HCl, was lost HCl upon sublimation but did not tautomerize. Continuous broadband irradiation (λ > 220 nm; 130 min) of the matrix led to only partial photodecomposition of 5Me-HQE (ca. 1/3).



Alternate JournalJ. Org. Chem.
PubMed ID26551438