Quinolone–Hydroxyquinoline Tautomerism in Quinolone 3‑Esters. Preserving the 4‑Oxoquinoline Structure To Retain Antimalarial Activity

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).