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Docking studies performed in silico at the yeast Qo site established a key role for the 4-oxo and N\u2013H 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)\u00adamino)\u00admethylene]\u00admalonate. Theoretically (B3LYP\/6-311++G\u00ad(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\u20131, 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\u00b7HCl, was lost HCl upon sublimation but did not tautomerize. Continuous broadband irradiation (\u03bb &amp;gt; 220 nm; 130 min) of the matrix led to only partial photodecomposition of 5Me-HQE (ca. 1\/3).<\/jats:p>","DOI":"10.1021\/acs.joc.5b02169","type":"journal-article","created":{"date-parts":[[2015,11,9]],"date-time":"2015-11-09T16:40:45Z","timestamp":1447087245000},"page":"12244-12257","source":"Crossref","is-referenced-by-count":25,"title":["Quinolone\u2013Hydroxyquinoline\nTautomerism in Quinolone\n3\u2011Esters. Preserving the 4\u2011Oxoquinoline Structure To\nRetain Antimalarial Activity"],"prefix":"10.1021","volume":"80","author":[{"given":"Pedro","family":"Horta","sequence":"first","affiliation":[{"name":"University of Algarve , , P-8005-039 Faro ,","place":["Portugal"]},{"name":"University of Liverpool , , Liverpool L69 7ZD ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nihal","family":"Kus\u0327","sequence":"additional","affiliation":[{"name":"University of Coimbra , , P-3004-535 Coimbra ,","place":["Portugal"]},{"name":"Anadolu University , , 26470 Eskis\u0327ehir ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta Sofia C.","family":"Henriques","sequence":"additional","affiliation":[{"name":"University of Coimbra , , P-3004-516 Coimbra ,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose\u0301 A.","family":"Paixa\u0303o","sequence":"additional","affiliation":[{"name":"University of Coimbra , , P-3004-516 Coimbra ,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lis","family":"Coelho","sequence":"additional","affiliation":[{"name":"New University of Lisbon , , P-1349-008 Lisboa ,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fa\u0301tima","family":"Nogueira","sequence":"additional","affiliation":[{"name":"New University of Lisbon , , P-1349-008 Lisboa ,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"O\u2019Neill","sequence":"additional","affiliation":[{"name":"University of Liverpool , , Liverpool L69 7ZD ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Fausto","sequence":"additional","affiliation":[{"name":"University of Coimbra , , P-3004-535 Coimbra ,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Lurdes Santos","family":"Cristiano","sequence":"additional","affiliation":[{"name":"University of Algarve , , P-8005-039 Faro ,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2015,11,9]]},"reference":[{"key":"2026081810335186300_cit1","doi-asserted-by":"publisher","first-page":"439","DOI":"10.2174\/1568011033482279","volume":"3","author":"Sissi","year":"2003","journal-title":"Curr. 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