title: Quinolone-Hydroxyquinoline Tautomerism in Quinolone 3-Esters. Preserving the 4-Oxoquinoline Structure To Retain Antimalarial Activity.
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).
authors.affiliation: CCMAR and Department of Chemistry and Pharmacy, FCT, University of Algarve , P-8005-039 Faro, Portugal.|Department of Chemistry, University of Liverpool , Liverpool L69 7ZD, United Kingdom.
authors.forename: Pedro
authors.initials: P
authors.lastname: Horta
authors.affiliation: CQC, Department of Chemistry, University of Coimbra , P-3004-535 Coimbra, Portugal.|Department of Physics, Anadolu University , 26470 Eskişehir, Turkey.
authors.forename: Nihal
authors.initials: N
authors.lastname: Kuş
authors.affiliation: CFisUC, Department of Physics, University of Coimbra , P-3004-516 Coimbra, Portugal.
authors.forename: Marta Sofia C
authors.initials: MS
authors.lastname: Henriques
authors.affiliation: CFisUC, Department of Physics, University of Coimbra , P-3004-516 Coimbra, Portugal.
authors.forename: José A
authors.initials: JA
authors.lastname: Paixão
authors.affiliation: CMDT and Institute of Hygiene and Tropical Medicine, New University of Lisbon , P-1349-008 Lisboa, Portugal.
authors.forename: Lis
authors.initials: L
authors.lastname: Coelho
authors.affiliation: CMDT and Institute of Hygiene and Tropical Medicine, New University of Lisbon , P-1349-008 Lisboa, Portugal.
authors.forename: Fátima
authors.initials: F
authors.lastname: Nogueira
authors.affiliation: Department of Chemistry, University of Liverpool , Liverpool L69 7ZD, United Kingdom.
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Neill
authors.affiliation: CQC, Department of Chemistry, University of Coimbra , P-3004-535 Coimbra, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Fausto
authors.affiliation: CCMAR and Department of Chemistry and Pharmacy, FCT, University of Algarve , P-8005-039 Faro, Portugal.
authors.forename: Maria Lurdes Santos
authors.initials: ML
authors.lastname: Cristiano
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D006912:Hydroxyquinolines / Q000737:chemistry* / Q000494:pharmacology*; D008314:Malonates / Q000737:chemistry; D015394:Molecular Structure; D015125:Oxyquinoline / Q000737:chemistry*; D010777:Photochemistry; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000962:Antimalarials; D006912:Hydroxyquinolines; D008314:Malonates; D011804:Quinolines; D015363:Quinolones; C000607871:diethyl 2-(((3-methylphenyl)amino)methylene)malonate; C000607870:ethyl 4-hydroxy-5-methylquinoline-3-carboxylate; C000607869:ethyl 4-oxo-7-methylquinoline-3-carboxylate; D015125:Oxyquinoline; C034010:4-hydroxyquinoline