Biological evaluation of diazene derivatives as anti-tubercular compounds.
Despite efforts made in chemotherapeutic research in the past and present, Mycobacterium tuberculosis (M.tb), the etiological agent of tuberculosis, still causes more than a million deadly casualties each year, second only to HIV. The rapid generation and spread of drug resistant strains, a problem exacerbated by co-infection with HIV demands further efforts in the investigation of novel classes of anti-tubercular compounds. A library of eight substituted diazenecarboxamides, three carbamoyldiazenecarboxylates and four diazene-1,2-dicarboxamides was synthesized in a straightforward manner followed by a biological evaluation of the compounds. We observed minimal inhibitory concentrations below 10 μg/mL against the H37Rv lab strain of M.tb. Three compounds that showed a potency of 90% growth inhibition of M.tb at a concentration lower than 10 μg/mL were further evaluated and showed potency against other clinically relevant mycobacterial species such as Mycobacterium bovis, Mycobacterium avium and Mycobacterium ulcerans. The selected compounds were examined for acute cell toxicity on a murine macrophage like monocyte cell line J774 A.1 in which the cell viability was reduced by 50% at concentrations ranging from 7.4 μg/mL to 20.7 μg/mL. Neither of the three compounds showed signs of genotoxicity by VITOTOX or by Comet assay. The study was complemented by demonstration of the inhibition of intracellular replication of M.tb H37Rv inside J774 A.1 cells at 2 μg/mL concentration and the susceptibility of a MDR LAM-1 strain at concentrations between 5 and 1 μg/mL of the most active compound.
Scientific Service Immunology, O.D. Communicable & Infectious Diseases, Scientific Institute of Public Health (Site Ukkel), Engelandstraat 642, B-1180 Ukkel, Belgium.
Davie
D
Cappoen
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, SI-1000 Ljubljana, Slovenia.
Vita
V
Majce
Scientific Service Immunology, O.D. Communicable & Infectious Diseases, Scientific Institute of Public Health (Site Ukkel), Engelandstraat 642, B-1180 Ukkel, Belgium.
Cynthia
C
Uythethofken
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, SI-1000 Ljubljana, Slovenia.
Damijana
D
Urankar
Program Tuberculosis and Mycobacteria, O.D. Communicable & Infectious Diseases, Scientific Institute of Public Health (Site Ukkel), Engelandstraat 642, B-1180 Ukkel, Belgium.
Vanessa
V
Mathys
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, SI-1000 Ljubljana, Slovenia.
Marijan
M
Kočevar
Program Toxicology, O.D. Public Health and Surveillance, Scientific Institute of Public Health (Site Elsene), J. Wytsmanstraat 14, B-1050 Brussels, Belgium; Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.
Luc
L
Verschaeve
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, SI-1000 Ljubljana, Slovenia.
Slovenko
S
Polanc
Scientific Service Immunology, O.D. Communicable & Infectious Diseases, Scientific Institute of Public Health (Site Ukkel), Engelandstraat 642, B-1180 Ukkel, Belgium. Electronic address: kris.huygen@wiv-isp.be.
Kris
K
Huygen
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, SI-1000 Ljubljana, Slovenia. Electronic address: janez.kosmrlj@fkkt.uni-lj.si.
Janez
J
Košmrlj
D000995:Antitubercular Agents / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D007094:Imides / Q000494:pharmacology*
D000995:Antitubercular Agents; D007094:Imides; C038867:diazene
Acute toxicity; Antibiotics; Diazenes; Genotoxicity; Tuberculosis