Quinolone鈥揌ydroxyquinoline Tautomerism in Quinolone 3-Esters. Preserving the 4-Oxoquinoline Structure To Retain Antimalarial Activity

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• 作者：Pedro Horta ; Nihal Ku艧 ; Marta Sofia C. Henriques ; Jos茅 A. Paix茫o ; Lis Coelho ; F谩tima Nogueira ; Paul M. O鈥橬eill ; Rui Fausto ; Maria Lurdes Santos Cristiano
• 刊名：Journal of Organic Chemistry
• 出版年：2015
• 出版时间：December 18, 2015
• 年：2015
• 卷：80
• 期：24
• 页码：12244-12257
• 全文大小：750K
• ISSN：1520-6904

文摘

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 Q_o site established a key role for the 4-oxo and N鈥揌 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^鈥?, 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路HCl, was lost HCl upon sublimation but did not tautomerize. Continuous broadband irradiation (位 > 220 nm; 130 min) of the matrix led to only partial photodecomposition of 5Me-HQE (ca. 1/3).