N-Aryl-7-hydroxy-5-oxo-2,3-dihydro-1H,5H-pyrido-[3,2,1-ij]quinoline-6-carboxamides. The Synthesis and Effects on Urinary Output

Abstract

Continuing a targeted search for new leading structures with diuretic action among tricyclic derivatives of hydroxyquinolines, which are of interest as potential inhibitors of aldosterone synthase, the synthesis of a series of the corresponding pyrido[3,2,1-ij]quinoline-6-carboxanilides was carried out by amidation of ethyl-7-hydroxy-5-oxo-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxylate with aniline, aminophenols and O-alkylsubstituted analogs with high yields and purity. The optimal conditions of this reaction are proposed; they make it possible to prevent partial destruction of the original heterocyclic ester and thereby avoid formation of specific impurities of 7-hydroxy-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one. To confirm the structure of all substances obtained, elemental analysis, nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry were used. Moreover, the peculiarities of their 1H and 13C-NMR spectra, as well as their mass spectrometric behavior under conditions of electron impact ionization, were discussed. The effect of pyrido[3,2,1-ij]quinoline-6-carboxanilides on the urinary function of the kidneys was studied in white rats of both genders by the standard method of oral administration at a dose of 10 mg/kg. Testing was conducted in comparison with hydrochlorothiazide, as well as with structurally close pyrrolo[3,2,1-ij] quinoline-5-carboxanilides studied earlier with the same substituents in the anilide fragments. It was found that addition of one methylene unit to the heterocycle partially hydrogenated and annelated with the quinolone core has a positive impact on biological properties—most of the substances studied exhibit a statistically significant diuretic effect exceeding the activity of not only hydrochlorothiazide, in some cases, but also the action of the structural analogs. The important structural and biological regularities, which are common with pyrroloquinolines and introduced by a chemical modification, were revealed. The importance of the presence in the structure of terminal amide fragments of tricyclic quinoline-3-carboxamides of a 4-methoxy-substituted aromatic ring was particularly marked. The expediency of further study of pyridoquinolines as promising diuretic agents has been shown.

The Study of the Structure—Diuretic Activity Relationship in a Series of New N-(Arylalkyl)-6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxamides

“…In addition, the analysis of the fragmentation ions that are formed during the primary fragmentation of molecular ions also provides the analytically important information about the components of the molecule under study (Scheme 2). It has been shown in the example of benzylamide 2a, which is typical for the whole group studied, that this process proceeds by the ketene type that is common for 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides and their tricyclic analogs [25,26], namely after breaking of the acyclic amide bond two characteristic fragments-the ion of tricyclic ketene 8 with m/z 227 and the ion of arylalkylamine 9, which is specific for each sample, are formed. provides the analytically important information about the components of the molecule under study (Scheme 2).…”

“…The transition to pyridoquinolines XI did not meet the expectations. Based on the tests conducted, it can be argued that, as a rule, the diuretic activity is somewhat reduced as a result of such a transformation, and the structure of the amide fragments affects the biological properties in the same way as in the pyroloquinolines VIII group [24,25]. At the same time, it has been found that bromination of the pyridoquinoline nucleus in position 9 (amides XII) leads to a significant increase in diuresis and, in principle, opens a new direction of "me-too" optimization of tricyclic 4-hydroxyquinoline-2-one diuretics [26].…”

QSAR analysis and molecular docking study of pyrrolo- and pyridoquinolinecarboxamides with diuretic activity

“…Two 6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1Hpyrrolo[3,2,1-ij]quinoline-5-carboxamides (Ia: R=2-COOH-C 6 H 4 ; Ib: R=CH 2 C 6 H 5 ) with the highest diuretic activity [20] were chosen as the ligands for docking study.…”

“…Having limited list of perspective structures, their laboratory synthesis would be greatly reduced in price. The proposed method [20,21] for synthesis of 6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1Hpyrrolo[3,2,1-ij]quinoline-5-carboxamides (I) and 7hydroxy-5-oxo-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxamides (II) opens up possibility to vary substituents on amide group for obtaining related compounds and completing the structure optimization of an identified lead compound in the future.…”

“…Water molecules, ions, and the ligand were removed from the PDB file ID: 1Z9Y. The visual analysis of complexes of substances in the active center of the carbonic anhydrase II (PDB ID: 1Z9Y) was performed using the Discovery Studio Visualizer program.Two 6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1Hpyrrolo[3,2,1-ij]quinoline-5-carboxamides (Ia: R=2-COOH-C 6 H 4 ; Ib: R=CH 2 C 6 H 5 ) with the highest diuretic activity[20] were chosen as the ligands for docking study.…”