Phenothiazines as lipid peroxidation inhibitors and cytoprotective agents

Abstract

A series of phenothiazines was synthesized and evaluated as in vitro inhibitors of iron-dependent lipid peroxidation. The MIC (minimum tested concentration that gave greater than or equal to 50% inhibition) for 2-(10H-phenothiazin-2-yloxy)-N,N-dimethylethanolamine methanesulfonate (6) was 0.26 microM. Whereas methyl substitution at N-10 diminished activity nearly 100-fold, other structural modifications such as varying the amine group, the distance separating the amine substituent from the phenothiazine nucleus, and the linking group had little effect. Compound 6 was more effective than probucol, a known antioxidant, in blocking Cu2+ catalyzed oxidation of low-density lipoprotein (LDL) as measured by competitive scavenger receptor mediated degradation of 125I-labeled acetyl-LDL by mouse peritoneal macrophage cells in vitro. At a concentration of 5 microM, compound 6 also protected primary cultures of rat hippocampal neurons exposed to hydrogen peroxide (50 microM) when assessed 18 h later by fluorescein diacetate and propidium iodide uptake.

Protective Activity of Aromatic Amines and Imines against Oxidative Nerve Cell Death

“…It has already been shown that positively charged ammonium groups impede antioxidant action in derivatives of phenothiazine (Yu et al, 1992); nevertheless lipophilicity has to be considered with care, as far as drug design is concerned. Neuroprotective agents should be able to penetrate the blood-brain barrier effectively, but very lipophilic compounds with long alkyl chain membrane anchors are usually excluded from passively entering the brain (Seelig et al, 1994;Moosmann and Behl, 2000b).…”

A phenothiazine derivative reduces rat brain damage after global or focal ischemia.

“…The primary mechanism responsible for the cerebroprotective effect is unclear at the present time because multiple factors may influence the cascade of events leading to postischemic brain damage. However, the in vitro profile of 2-(10//-phenothiazin-2-yloxy)-AT,JV-dimethylethanamine hydrochloride 12 supports the possibility that antioxidant mechanisms may underly its ability to ameliorate brain damage when administered before and after a transient ischemic insult. Our study is therefore consistent with the hypothesis that oxidantmediated lipid peroxidation may be involved in the pathophysiology of postischemic brain injury.…”

“…Using a whole cell assay, we evaluated representative examples from that study as cytoprotective agents and found that they protected primary cultures of rat hippocampal neurons from hydrogen peroxide-induced toxicity. 12 Under these conditions, chlorpromazine was ineffective, which suggests that antioxidant capacity and in vitro cytoprotective efficacy may be related for this class of compounds.…”

“…9 - 11 We recently reported on the chemistry, electrochemistry, and structure-activity relation for a series of phenothiazines as in vitro inhibitors of iron-dependent lipid peroxidation. 12 Although chlorpromazine inhibits…”

Antioxidant Activity of Newly Synthesized 2,7‐Diazaphenothiazines

“…Although the phenothiazine structure, mainly represented by chlorpromazine, is considered to possess antioxidant properties [15][16][17][18][19], only few reports have studied the antioxidant activity of other phenothiazine derivatives [20,21]. Due to structural similarities as well as taking into consideration the involvement of reactive oxygen species (ROS) in pathological conditions such as inflammation, degenerative diseases, and aging, we considered it of interest to further investigate our newly synthesized 2,7-diazaphenothiazine derivatives for antioxidant activity.…”