On the ordeal of quinolone preparation via cyclisation of aryl-enamines; synthesis and structure of ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylate

Horta, Pedro, Henriques, Marta SC, Bras, Elisa M, Murtinheira, Fernanda, Nogueira, Fatima, O'Neill, Paul M, Paixao, Jose A, Fausto, Rui and Cristiano, Maria LS (2017) On the ordeal of quinolone preparation via cyclisation of aryl-enamines; synthesis and structure of ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylate. PURE AND APPLIED CHEMISTRY, 89 (6). pp. 765-780.

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Abstract

<jats:title>Abstract</jats:title> <jats:p>Recent studies directed to the design of compounds targeting the <jats:italic>bc</jats:italic> <jats:sub>1</jats:sub> protein complex of <jats:italic>Plasmodium falciparum,</jats:italic> the parasite responsible for most lethal cases of malaria, identified quinolones (4-oxo-quinolines) with low nanomolar inhibitory activity against both the enzyme and infected erythrocytes. The 4-oxo-quinoline 3-ester chemotype emerged as a possible source of potent <jats:italic>bc</jats:italic> <jats:sub>1</jats:sub> inhibitors, prompting us to expand the library of available analogs for SAR studies and subsequent lead optimization. We now report the synthesis and structural characterization of unexpected ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylate, a 4-aryloxy-quinoline 3-ester formed during attempted preparation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate (4-oxo-quinoline 3-ester). We propose that the 4-aryloxy-quinoline 3-ester derives from 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate (4-hydroxy-quinoline 3-ester), the enol form of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate. Formation of the 4-aryloxy-quinoline 3-ester confirms the impact of quinolone/hydroxyquinoline tautomerism, both on the efficiency of synthetic routes to quinolones and on pharmacologic profiles. Tautomers exhibit different cLogP values and interact differently with the enzyme active site. A structural investigation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate and 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, using matrix isolation coupled to FTIR spectroscopy and theoretical calculations, revealed that the lowest energy conformers of 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, lower in energy than their most stable 4-oxo-quinoline tautomer by about 27 kJ mol<jats:sup>−1</jats:sup>, are solely present in the matrix, while the most stable 4-oxo-quinoline tautomer is solely present in the crystalline phase.</jats:p>

Item Type:	Article
Uncontrolled Keywords:	antimalarial activity, ICPOC-23, quinoline 4-ethers, quinolone-hydroxyquinoline tautomerism, quinoline-type P. falciparum bc1 complex inhibitors, structural studies, synthesis of quinolones
Depositing User:	Symplectic Admin
Date Deposited:	31 Jan 2020 09:44
Last Modified:	19 Jan 2023 00:05
DOI:	10.1515/pac-2016-1119
Open Access URL:	https://doi.org/10.1515/pac-2016-1119
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3072807