ABSTRACT
N-(4-chlorobenzyl)triflupromazinium chloride, a known antitubercular agent, has been found to also be active against HSV-1. A preliminary structure-activity relation has been explored to determine which groups are crucial to viral inhibition. Antiviral assessments such as GFP reduction, plaque reduction, treatment timing and wash-out studies have also been probed to determine a mode of action for QPD-1. Based on this preliminary data, it appears that QPD-1 is a reversible inhibitor, suspected to inhibit early stages of viral replication of HSV-1 at 50 µM, equipotent to acyclovir.
Subject(s)
Antiviral Agents/chemical synthesis , Herpesvirus 1, Human/drug effects , Phenothiazines/chemical synthesis , Promazine/chemistry , Quaternary Ammonium Compounds/chemical synthesis , Acyclovir/pharmacology , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Chlorocebus aethiops , Humans , Phenothiazines/chemistry , Phenothiazines/pharmacology , Promazine/chemical synthesis , Promazine/pharmacology , Quaternary Ammonium Compounds/chemistry , Quaternary Ammonium Compounds/pharmacology , Structure-Activity Relationship , Vero Cells , Virus Replication/drug effectsABSTRACT
Quaternized chlorpromazine, triflupromazine, and promethazine derivatives were synthesized and examined as antitubercular agents against both actively growing and non-replicating Mycobacterium tuberculosis H37Rv. Impressively, several compounds inhibited non-replicating M. tuberculosis at concentrations equal to or double their MICs against the actively growing strain. All active compounds were non-toxic toward Vero cells (IC50 > 128 microM). N-Allylchlorpromazinium bromide was only weakly antitubercular, but replacing allyl with benzyl or substituted benzyl improved potency. An electron-withdrawing substituent on the phenothiazine ring was also essential. Branching at the carbon chain decreased antitubercular activity. The optimum antitubercular structures possessed N-(4- or 3-chlorobenzyl) substitution on triflupromazine.
