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• 646-07-1 4-Methylpentanoic acid 
• 78-77-3 Isobutyl bromide 
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Relevant academic research and scientific papers

3-Oxoisoxazole-2(3H)-carboxamides and isoxazol-3-yl carbamates: Resistance-breaking acetylcholinesterase inhibitors targeting the malaria mosquito, Anopheles gambiae

To identify potential selective and resistance-breaking mosquitocides against the African malaria vector Anopheles gambiae, we investigated the acetylcholinesterase (AChE) inhibitory and mosquitocidal properties of isoxazol-3-yl dimethylcarbamates (15), and the corresponding 3-oxoisoxazole-2(3H)-dimethylcarboxamide isomers (14). In both series, compounds were found with excellent contact toxicity to wild-type susceptible (G3) strain and multiply resistant (Akron) strain mosquitoes that carry the G119S resistance mutation of AChE. Compounds possessing good to excellent toxicity to Akron strain mosquitoes inhibit the G119S mutant of An. gambiae AChE (AgAChE) with ki values at least 10- to 600-fold higher than that of propoxur, a compound that does not kill Akron mosquitoes at the highest concentration tested. On average, inactivation of WT AgAChE by dimethylcarboxamides 14 was 10-20 fold faster than that of the corresponding isoxazol-3-yl dimethylcarbamates 15. X-ray crystallography of dimethylcarboxamide 14d provided insight into that reactivity, a finding that may explain the inhibitory power of structurally-related inhibitors of hormone-sensitive lipase. Finally, human/An. gambiae AChE inhibition selectivities of these compounds were low, suggesting the need for additional structural modification.

Excitatory amino-acid receptor agonists. Synthesis and pharmacology of analogues of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid.

We have previously proposed the existence of a lipophilic cavity of the 2-amino-3-(3 -hydroxy-5 -methylisoxazol-4-yl)propionic acid (AMPA) receptor recognition site capable of accommodating alkyl substituents of limited size in the 5-position of the isoxazole ring. In order to indirectly elucidate the approximate extent of this proposed cavity we have synthesized and pharmacologically characterized a number of AMPA analogues. For most of these AMPA analogues, a positive correlation between AMPA receptor affinity and agonist effect was observed. The only exception was demethyl-AMPA (8a), which showed relatively high AMPA receptor affinity (IC50, = 0.27 μM) but remarkably weak agonist potency (EC50 = 900 μM). Whereas the ethyl analogue of AMPA (Et-AMPA) (IC50 = 0.030 μM; EC50 = 2.3 μM) has previously been shown to be slightly more potent than AMPA (IC50 = 0.040 μM; EC50 = 3.5 μM), substitutions of a propyl or a butyl group for the methyl group of AMPA to give 8b IC50 = 0.090 μM; EC50 = 5.0 μM) or 8f (IC50 = 1.0 μM; EC50 = 32 μM), respectively, result in progressive loss of the AMPA agonist effect. Analogues containing larger groups, such as isopentyl (8e), 1-propylbutyl (8g), 2,2-dimethylpropyl (8h), or benzyl (14) groups, were very weak or totally inactive as AMPA receptor ligands.