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J Org Chem ; 80(24): 12244-57, 2015 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-26551438

RESUMO

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).


Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Hidroxiquinolinas/química , Hidroxiquinolinas/farmacologia , Oxiquinolina/química , Quinolinas/química , Quinolinas/farmacologia , Quinolonas/química , Malonatos/química , Estrutura Molecular , Fotoquímica , Quinolonas/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier
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