Kojic amine - a novel .gamma.-aminobutyric acid analog

Abstract

A series of compounds containing the 3-hydroxy-4H-pyran-4-one nucleus has been synthesized and tested as potential skeletal muscle relaxants. Reduction of 2-(azidomethyl)-5-hydroxy-4H-pyran-4-one (4) with HBr in HOAc--phenol yielded 2-(aminomethyl)-5-hydroxy-4H-pyran-4-one (kojic amine, 3) in 81% yield. Reaction of 2-[(tosyloxy)-methyl]-5-(benzyloxy)-4H-pyran-4-one (5) with NH3 gave a 40% yield of the O-benzyl ether of kojic amine, which was N-acylated with a series of carbobenzyloxy-protected amino acids. Complete deprotection with HBr--HOAc gave the following amino acid amides of kojic amine: glycyl (23), alpha-alanyl (24), beta-alanyl (25), gamma-aminobutyryl (26), and glycylglycyl (27). Among the analogues of kojic amine prepared was a series of one-carbon homologues: 2-[(methylamino)methyl]-5-hydroxy-4H-pyran-4-one (7a), 2-(1-aminoethyl)-5-hydroxy-4H-pyran-4-one (8), 6-(aminomethyl)-3-hydroxy-2-methyl-4H-pyran-4-one (12), and 2-(2-aminoethyl)-5-hydroxy-4H-pyran-4-one (16). Kojic amine (3) has been found to possess certain of the properties to be expected in a gamma-aminobutyric acid mimetic agent, notably skeletal muscle relaxant activity. In the chronic spinal cat preparation, ED70 values for reduction of flexor spasms of 2.2 and 4.0 mg/kg by iv and po routes of administration, respectively, were observed for kojic amine, which was the most potent of the various hydroxypyrone derivatives investigated.

Pyrone derivatives and metals: From natural products to metal-based drugs

“…For example, the aliphatic alcohol can be oxidized with Jones reagent to the carboxylic acid [23] or can be converted into chlorokojic acid by reaction with thionylchloride. Chlorokojic acid can be reacted with different nucleophiles, such as azides [24], amines [25,26], thiolates [27], phenolates, etc. [28,29].…”

Synthesis and Evaluation of Anticonvulsant and Antimicrobial Activities of 3‐Hydroxy‐6‐methyl‐2‐substituted 4H‐Pyran‐4‐one Derivatives

“…Moreover, it is still not possible to get some types of epilepsy under control [1Ϫ4]. As GABA itself does not cross the blood-brain barrier, there is considerable interest in the development of systemically active GABA-mimetic agents [7]. GABA has been suggested to be a major inhibitory neurotransmitter in the central nervous system [6].…”

Balysum-2 inhibitis evoked activity of the pyramidal neurons in hippocampus

“…It is noteworthy that comenic acid has a similar structure as the kojic acid, whose derivative is a GABAA-agonist [8]. Comenic acid may directly interact with the GABAA-receptor-channel complex.…”