Phenothiazine (PTZ) is a heterocyclic pharmaceutical lead structure in medicinal chemistry, representing a major class of antipsychotic drugs that have an inhibitory effect against dopaminergic receptors, especially D2 receptor. Derivatives of PTZ have been extensively used to treat psychosis, including schizophrenia, violent, agitated, disturbed behaviour and bipolar disorder. While these medications are effective, side effects of PTZs include 1) the autonomic and cardiovascular systems, endocrinologic, metabolic, hematologic, hepatic, allergic/dermatologic, ophthalmologic, and anticholinergic effects; 2) the central nervous system, including extrapyramidal symptoms, tardive dyskinesia, neuroleptic malignant syndrome, seizure, and sedation; 3) the sexual and reproductive side effects, including sexual dysfunction, and teratogenicity. These side effects are primarily caused by the PTZs' non-selective blocking of receptors in the central nervous system, including dopamine (D1 and D2), muscarinic, histamine H1, and serotonergic 5-hydroxytryptamine (HT) 2 receptors. Clinical studies have shown that these side effects occur due to bioactive metabolites, which may significantly contribute to the toxicity in humans. Sulfoxide metabolites has been annotated to be responsible for cardiotoxic activity, and 7hydroxylated metabolite of the PTZs, form an electrophilic quinone imine intermediate, which is responsible for mechanisms of drug-induced idiosyncratic hepatotoxicity. PTZ analogues are classified into three groups, as shown in Table . . PTZ structure and their respective classifications (1-3) and bioactivities.