Antiviral activity of chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine towards RNA-viruses. A review

Abstract

In 2020 the whole world focused on antivirus drugs towards SARS-CoV-2. Most of the researchers focused on drugs used in other viral infections or malaria. We have not seen such mobilization towards one topic in this century. The whole situation makes clear that progress needs to be made in antiviral drug development. The first step to do it is to characterize the potential antiviral activity of new or already existed drugs on the market. Phenothiazines are antipsychotic agents used previously as antiseptics, anthelminthics, and antimalarials. Up to date, they are tested for a number of other disorders including the broad spectrum of viruses. The goal of this paper was to summarize the current literature on activity toward RNA-viruses of such drugs like chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine. We identified 49 papers, where the use of the phenothiazines for 23 viruses from different families were tested. Chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine possess anti-viral activity towards different types of viruses. These drugs inhibit clathrin-dependent endocytosis, cell-cell fusion, infection, replication of the virus, decrease viral invasion as well as suppress entry into the host cells. Additionally, since the drugs display activity at nontoxic concentrations they have therapeutic potential for some viruses, still, further research on animal and human subjects are needed in this field to verify cell base research.

Chemoinformatic Analysis of Psychotropic and Antihistaminic Drugs in the Light of Experimental Anti-SARS-CoV-2 Activities

“…Overall, the present analysis, together with other studies, 4,9,[66][67][68][69][70][71][72] supports our initial observation 2 and suggests that some psychiatric patients could have been protected by their pharmacological treatments. Along this line of reasoning, it should also be mentioned that these patients receive in general a cocktail of drugs (psychotropic and anti-histamine molecules) including several CAD compounds possibly working on different molecular mechanisms.…”

Head-to-Head Comparison of Sedation and Somnolence Among 37 Antipsychotics in Schizophrenia, Bipolar Disorder, Major Depression, Autism Spectrum Disorders, Delirium, and Repurposed in COVID-19, Infectious Diseases, and Oncology From the FAERS, 2004–2020

“…Zuclopenthixol, the neuroleptic with the strongest association with sedation and somnolence, has emerged as a compound that shows in vitro inhibition of the severe acute respiratory coronavirus 2 (SARS-CoV-2) pathogen which causes the novel coronavirus disease 2019 (COVID-19) (Bocci et al, 2020). A recent review article reported thioridazine, fluphenazine, perphenazine, chlorpromazine, prochlorperazine inhibits RNA viruses as these phenothiazines inhibit cell-cell fusion, viral replication, clathrin-dependent endocytosis, and entry into cells (Otręba et al, 2020). Dyall and colleagues, reported FIGURE 1 | Forest plots illustrating reporting odds-ratios (RORs) with 95% confidence intervals (CI) of sedation and somnolence among all thirty-seven typical an atypical antipsychotic compounds.…”

A Small Molecule Targeting Human MEK1/2 Enhances ERK and p38 Phosphorylation under Oxidative Stress or with Phenothiazines

“…Chlorpromazine, fluphenazine, and thioridazine are from the phenothiazine class of drugs with antipsychotic properties that are used in the treatment of schizophrenia and bipolar disorders [ 4 ]. Moreover, research from the last 15 years suggests that phenothiazines could play an important role in the treatment of other diseases: cancer as well as viral, bacterial, and fungal infections [ 5 , 6 , 7 , 8 ]. The anticancer activity of phenothiazines is related in part to reactive oxygen species (ROS) production, DNA fragmentation, and stimulation of apoptosis as well as inhibition of migration and invasiveness [ 5 , 8 , 9 , 10 ].…”