title: Synthesis and antitubercular activity of quaternized promazine and promethazine derivatives.
abstract: 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.
authors.affiliation: Department of Chemistry, Salisbury University, Salisbury, MD 21801, USA.
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Bate
authors.forename: Jay H
authors.initials: JH
authors.lastname: Kalin
authors.forename: Eric M
authors.initials: EM
authors.lastname: Fooksman
authors.forename: Erica L
authors.initials: EL
authors.lastname: Amorose
authors.forename: Cristofer M
authors.initials: CM
authors.lastname: Price
authors.forename: Heather M
authors.initials: HM
authors.lastname: Williams
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rodig
authors.forename: Miguel O
authors.initials: MO
authors.lastname: Mitchell
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Cho
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Wang
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002746:Chlorpromazine / Q000138:chemical synthesis / Q000494:pharmacology; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011395:Promazine / Q000138:chemical synthesis / Q000494:pharmacology; D011398:Promethazine / Q000138:chemical synthesis / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014273:Triflupromazine / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D000644:Quaternary Ammonium Compounds; D011398:Promethazine; D011395:Promazine; D014273:Triflupromazine; D002746:Chlorpromazine