1,4-diarylpiperazines and analogs as anti-tubercular agents: synthesis and biological evaluation.
Despite progress in modern chemotherapy to combat tuberculosis, the causative pathogen Mycobacterium tuberculosis (M.tb.) is far from eradicated. Bacillary resistance to anti-mycobacterial agents, bacillary persistence and human immunodeficiency virus (HIV) co-infection hamper current drug treatment to completely cure the infection, generating a constant demand for novel drug candidates to tackle these problems. A small library of novel heterocyclic compounds was screened in a rapid luminometric in vitro assay against the laboratory M.tb. strain H37Rv. A group of amidines was found to have the highest potency and was further evaluated for acute toxicity against C3A hepatocytes. Next, the most promising compounds were evaluated for activity against a multi-drug resistant clinical isolate. The group of amidines was also tested for their ability to kill intracellular M.tb. residing in mouse J774A.1 macrophages. Finally, we report on a correlation between the structural differences of the compounds and their anti-mycobacterial activity.
University of Mons-UMONS, Laboratory of Organic Chemistry, Mons, Belgium.
D
D
Forge
D
D
Cappoen
J
J
Laurent
D
D
Stanicki
A
A
Mayence
T L
TL
Huang
L
L
Verschaeve
K
K
Huygen
J J
JJ
Vanden Eynde
D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D015195:Drug Design; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D014376:Tuberculosis / Q000188:drug therapy
D000995:Antitubercular Agents; D010879:Piperazines