Potential Antioxidant Activity of New Tetracyclic and Pentacyclic Nonlinear Phenothiazine Derivatives

Abstract

The global increase in oxidative stress related diseases such as cancer, cardiovascular, and inflammatory diseases caused by overwhelming level of free radicals in the body has encouraged the search for new antioxidant agents. Based on the ability of newly synthesized phenothiazine derivatives (6-chloro-11-azabenzo[a]phenothiazine-5-one and 6-[4-bromophenyl]-10-methyl-11-azabenzo[a]phenothiazine-5-one) to oxidize H2O2, a known free radical to sulfoxide, this study assessed the in vitro and in vivo antioxidant activity. The synthesized phenothiazine derivatives exhibited reducing power potential to convert Fe3+ to Fe2+ and high ability to scavenge H2O2 free radical in vitro. These activities were comparable to ascorbic acid, a standard antioxidant. The catalase activity significantly increased (p < 0.05) in groups 1 and 2 animals that received the phenothiazine derivatives compared to the controls (groups 3 and 4) suggesting the ability of the phenothiazine derivatives to scavenge H2O2 in vivo. The malondialdehyde level in groups 1 and 2 animals was lower than that in group 3 that received the reference compound (ascorbic acid) and group 4 that received the solvent suggesting the ability of the phenothiazine derivatives to prevent lipid membrane damage. AST and bilirubin levels were higher in group 2 animals which received 6-[4-bromophenyl]-10-methyl-11-azabenzo[a]phenothiazine-5-one compared to group 3, the positive control. The results suggest that phenothiazine derivatives, especially 6-chloro-11-azabenzo[a]phenothiazine-5-one, possess antioxidant activity though 6-[4-bromophenyl]-10-methyl-11-azabenzo[a]phenothiazine-5-one was slightly toxic. This activity may be due to the presence of electron donors such as sulfur as well as the richness of hydrogen in the additional benzene rings for substitution. Further study is needed to identify tolerable doses for possible therapeutic purposes.

Alteration of Gut Microbiota: New Strategy for Treating Autism Spectrum Disorder

“…Generally, the increase of toxic metabolism and decrease of protective metabolism are observed in gut dysbiosis ( Sivamaruthi et al, 2020 ). Several pieces of evidence have indicated that a lower abundance of protective bacteria plays critical roles in decreasing oxidative stress, cell detoxification, and excretion of heavy metal ( Engwa et al, 2016 ; Khatua et al, 2017 ).…”

Cancer and the Dopamine D2Receptor: A Pharmacological Perspective

“…Indeed, novel phenothiazine derivatives have been shown to have many potential anticancer activities aside from the established activities with respect to calmodulin, dopamine receptors, and other known psychiatrically relevant targets. These include antioxidant ability, inhibition of tubulin polymerization, and inhibition of farnesyl transferase (Prinz et al, 2011;Baciu-Atudosie et al, 2012;Engwa et al, 2016;Ghinet et al, 2016). We recognize how our hypothesis, which runs counter to a voluminous literature, could be interpreted, but we believe it would be useful if this generates controversy that leads to hypothesis-driven studies using orthogonal approaches and varying structural series of D 2 R antagonists.…”

Stress and cancer

“…In addition to neuroleptic effects (blocking D2 dopaminergic receptors in the central nervous system), they also exhibit antimicrobial, antiviral, antiprotozoal, antiprion, anthelmintic properties and -most importantly -anticancer properties. Their anticancer effect is mainly based on antiproliferative, antioxidant and immunomodulating effects [22,23,24]. Special attention should be paid to the study involving over 100,000 subjects, which showed that patients with schizophrenia, who were treated with neuroleptics, were less likely to develop cancer when compared to subjects who did not take antipsychotic medications [25].…”

“…Oprócz działania neuroleptycznego (blokującego receptory dopaminergiczne D2 w ośrodkowym układzie nerwowym) wykazują także właściwości przeciwbakteryjne, przeciwwirusowe, przeciwpierwotniakowe, przeciwprionowe, przeciwro-bacze… i co najważniejsze -przeciwnowotworowe. Ich działanie antyrakowe opiera się głównie na działaniu antyproliferacyjnym, antyoksydacyjnym i immunomodulującym [22,23,24]. Na szczególną uwagę zasługuje badanie obejmujące ponad 100 000 osób, w którym wykazano, że chorzy na schizofrenię, przyjmujący leki neuroleptyczne, chorowali rzadziej na nowotwory niż osoby, które nie zażywały neuroleptyków [25].…”