Synthesis and antitubercular activity of quaternized promazine and promethazine derivatives.
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.
Bate
Aaron B
AB
Department of Chemistry, Salisbury University, Salisbury, MD 21801, USA.
Kalin
Jay H
JH
Fooksman
Eric M
EM
Amorose
Erica L
EL
Price
Cristofer M
CM
Williams
Heather M
HM
Rodig
Michael J
MJ
Mitchell
Miguel O
MO
Cho
Sang Hyun
SH
Wang
Yuehong
Y
Franzblau
Scott G
SG
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
D000995:Antitubercular Agents; D000644:Quaternary Ammonium Compounds; D011398:Promethazine; D011395:Promazine; D014273:Triflupromazine; D002746:Chlorpromazine