Neuroprotective Effects of N‐Alkyl‐1,2,4‐oxadiazolidine‐3,5‐diones and Their Corresponding Synthetic Intermediates N‐Alkylhydroxylamines and N‐1‐Alkyl‐3‐carbonyl‐1‐hydroxyureas against in vitro Cerebral Ischemia

Abstract

Herein we report the synthesis and neuroprotective effects of new N-alkyl-1,2,4-oxadiazolidine-3,5-diones and their corresponding synthetic intermediates, N-alkylhydroxylamines and N-1-alkyl-3-carbonyl-1-hydroxyureas, in an in vitro model of ischemia. We found five analogues that protect HT22 cells from death in the concentration range of 1-5 muM. Because members of the MAP kinase family are known to be key players in nerve cell survival and death, we characterized the role of these kinases in the neuroprotective mechanisms of the newly synthesized analogues. The results indicate that these compounds provide neuroprotection through distinct mechanisms of action.

Chemical Modification of the Multitarget Neuroprotective Compound Fisetin

“…To induce ischemia in the HT22 cells we used iodoacetic acid (IAA), a well known, irreversible inhibitor of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (G3PDH) 14 . IAA has been used in a number of other studies to induce ischemia in nerve cells 15a–e and we have used it in several recent screens for neuroprotective molecules 16a,b . The changes following IAA treatment of neural cells are very similar to those seen in animal models of ischemic stroke 17 and include alterations in membrane potential 18 , breakdown of phospholipids 19 , loss of ATP 20a,b and an increase in reactive oxygen species (ROS) 21,19 .…”

One-Pot Anti-Markovnikov Hydroamination of Unactivated Alkenes by Hydrozirconation and Amination

“…The title compound was prepared via a modified literature procedure. − In a 50 mL flask, a solution of 3-phenylpropionaldehyde (1.98 mL, 15.0 mmol) in 10 mL of H 2 O was stirred, open to air. A solution of hydroxylamine hydrochloride (5.21 g, 75 mmol) in EtOH (10 mL) was added at room temperature, and the solution was cooled to 0 °C.…”

“…The title compound was prepared via a modified literature procedure . In a 100 mL round-bottom flask, a solution of 3-phenylpropionaldehyde (1.41 mL, 10.0 mmol) in 15 mL of H 2 O was stirred, open to the air.…”

Inhibition of long chain fatty acyl-CoA synthetase (ACSL) and ischemia reperfusion injury

“…Under other reaction conditions including the use of acetic acid as a catalyst in the reduction procedure resulted in a mixture of unidentifiable byproducts. 1,2,4-Oxadiazolidine-3,5-dione is a carboxylic acid bioisostere, 17 hence we synthesized compounds 11 and 12 from 9 and 10 , respectively, by the addition reactions with ethyl isocyanoformate followed by ring closure with NaOH. 17 …”

“…1,2,4-Oxadiazolidine-3,5-dione is a carboxylic acid bioisostere, 17 hence we synthesized compounds 11 and 12 from 9 and 10 , respectively, by the addition reactions with ethyl isocyanoformate followed by ring closure with NaOH. 17 …”