Journal Article
Título | Quinolone-Hydroxyquinoline Tautomerism in Quinolone 3-Esters. Preserving the 4-Oxoquinoline Structure To Retain Antimalarial Activity. |
Publication Type | Journal Article |
Authors | Horta, P, Kuş, N, Henriques, MSofia C, Paixão, JA, Coelho, L, Nogueira, F, O'Neill, PM, Fausto, R, Cristiano, MLS |
Year of Publication | 2015 |
Journal | J Org Chem |
Volume | 80 |
Questão | 24 |
Date Published | 2015 Dec 18 |
Pagination | 12244-57 |
ISSN | 1520-6904 |
Palavras-chave | Antimalarials, Hydroxyquinolines, Malonates, Molecular Structure, Oxyquinoline, Photochemistry, Quinolines, Quinolones, Spectroscopy, Fourier Transform Infrared |
Abstract | 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). |
DOI | 10.1021/acs.joc.5b02169 |
Sapientia | |
Alternate Journal | J. Org. Chem. |
PubMed ID | 26551438 |