5-HT3 Receptor antagonists. 2. 4-Hydroxy-4-quinolinecarboxylic acid derivatives

Abstract

A series of 4-hydroxy-3-quinolinecarboxylic acid derivatives (6) and 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid derivatives (7) were designed and synthesized as 5-HT3 receptor antagonists. Molecular modeling studies suggested that the 3-carbonyl moiety in 6 was almost coplanar to the plane of an aromatic ring, but in 7 there was a 30 degrees deviation. 4-Hydroxy substitution in quinoline derivatives enhanced affinity for the 5-HT3 receptors, and endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-4-hydroxy-3- quinolinecarboxamide (6f) exhibited the most potent activity in the Bezold-Jarisch (B-J) reflex test (ED50 = 0.1 micrograms/kg, iv) among quinoline derivatives 6. Although 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives (7a) exhibited higher affinity (e.g., 7d: Ki = 0.48 nM) for the 5-HT3 receptors than ondansetron (Ki = 7.6 nM) or granisetron (Ki = 2.1 nM), these amides showed less potent activity in the B-J reflex test than the reference compounds. Interestingly, the ester derivatives 7c, 7f, and 7h eliminated affinity for the 5-HT3 receptors. These unusual structure-activity relationships and the deviation of the 3-carbonyl moiety from the plane of an aromatic ring suggest that the active conformation of 7a might be different from the proposed one for the preceding 5-HT3 antagonists. Thus, 6f was chosen for further studies. No receptor binding for a variety of ligands was significantly antagonized by 6f. Comparing the ratios of the ED50 value in the B-J reflex test (rat, iv) with the LD50 value in acute lethal toxicity (mouse, iv), 6f was proved to have a 600-fold wider margin of safety than ondansetron. Compound 6f dose-dependently attenuated both the incidence and frequency of emetic episodes induced by cisplatin in the dog (ED50 = 14 micrograms/kg, iv) more potently than ondansetron (ED50 = 210 micrograms/kg, iv). Compound 6f (KF-20170) is now under further investigation as a drug for treating gastrointestinal disorder.

Discovery of Plasmodium vivaxN-Myristoyltransferase Inhibitors: Screening, Synthesis, and Structural Characterization of their Binding Mode

“…7 A number of potential substrates were tested, with Homo sapiens pp60 src (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) (GSNKSKPKDASQRRR-NH 2 ) being chosen as the most suitable substrate for the PvNMT assay, with apparent K m (K m app ) of 5.71 ± 0.6 μM in assay conditions. The compound collection was sourced by Medical Research Council Technology, largely from commercial suppliers.…”

Cloning and Structure-Function Analyses of Quinolone- and Acridone-producing Novel Type III Polyketide Synthases from Citrus microcarpa

“…droxytryptamine 3 receptor antagonists and as potential antimalarial drugs, respectively (7)(8)(9). The greatest abundance of these alkaloids is found in the Rutaceae plants, and N-methylanthranilic acid is thought to be a key intermediate in their biosynthesis (10 -12).…”

Studies on the chemical behavior of 3-(nitroacetyl)-1-ethyl-4-hydroxyquinolin-2(1H)-one towards some electrophilic and nucleophilic reagents

“…3-(1-Ethy1-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-3-oxopropanoic acid (1) This compound was prepared according to our published method. 11 6-Ethyl-4-hydroxy-3-nitropyrano[3,2-c]quinoline-2,5(6H) dione (3) A mixture of β-ketoacid 1 (0.55 g, 2 mmol) in concentrated nitric acid (5 mL) and concentrated sulfuric acid (5 mL) was stirred at room temperature for 2h, then left continuous stirring at ambient temperature.…”

“…[1][2][3][4][5][6] The biological importance of quinolinones stimulated an intensive research work for the synthesis of many members of this class of compounds. [7][8][9][10] In continuation of our previous reports on the synthesis of novel 4-hydroxyquinolin-2(1H)-ones starting from 3-(1-ethy1-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-3-oxopropanoic acid (1), 11 the present work aims to synthesize the 3-(nitroacetyl)-1-ethyl-4-hydroxyquinolin-2(1H)-one (4) and to study its reactivity towards a variety of chemical reagents.…”