Release of nitrite from the antitubercular nitroimidazoledrug PA-824 and analogues upon one-electron reduction in protic, non-aqueous solvent

Abstract

The one-electron reduction chemistry of the antituberculosis drug PA-824, together with a series of closely related compounds, has been investigated in irradiated anaerobic propan-2-ol solution. The protic solvent, of low dielectric constant, was chosen to mimic the environment of a water-restricting active site of a model protein, which is capable of reducing the compounds. Radiolytic reduction of the compounds containing electron donating substituents in the 2-position of the imidazole ring released nitrite, with compounds that are highly active against Mycobacterium tuberculosis exhibiting high yields of nitrite. The release of cytotoxic reactive nitrogen species through a one-electron pathway, by as yet unidentified proteins, may play a role in the activity of this class of compounds against TB. The described radiolytic quantification of nitrite release may have utility as a preliminary screening test for nitroaromatic candidate drugs against the disease.

Exploring the potential of endophytes from medicinal plants as sources of antimycobacterial compounds

“…On the other hand, M. tuberculosis is known to possess genomic plasticity (Domenech et al, 2001). Most cases of drug resistance in M. tuberculosis develop via mutations of the (Andries et al, 2005;Koul et al, 2008) Targeting ATP synthase, inhibition of proton pumping activity (Huitric et al, 2010) III, FDA-approved (accelerated programme) (Cohen, 2013) PA-824 TB Alliance Nitroimidazole 150-300 ng/ml (Stover et al, 2000) Prevention of cell wall mycolic acid biosynthesis Maroz et al, 2010;Manjunatha et al, 2006Manjunatha et al, , 2009 II (Jones, 2013) OPC 87863 (Delamanid) Otsuka Nitroimidazole 6-24 ng/ml (Matsumoto et al, 2006) Prevention of cell wall mycolic acid biosynthesis (Gler et al, 2012) III (Jones, 2013) SQ109 Sequella Ethylenediamine 200-780 ng/ml (Sacksteder et al, 2012) Inhibition of mycolic acid transport to the cell wall (Boshoff et al, 2004;Tahlan et al, 2012) II (Sacksteder et al, 2012) PNU-100480 (Sutezolid) Pfizer Oxazolidinone 120 ng/ml (Barbachyn et al, 1996) Targeting 23S rRNA, inhibition of bacterial protein synthesis (Patel et al, 2001) II (Jones, 2013) AZD5847 AstraZeneca Oxazolidinone -Undisclosed data--Undisclosed data-II (Jones, 2013) target genes, such as rpoB against rifampicin, rrs against kanamycin, and gyrA against the fluoroquinones. Multidrug resistance occurs via the accumulation of independent mutations in more than one of these genes (Rattan et al, 1998).…”

Antituberculosis therapy for 2012 and beyond

“…PA 824 is a pro-drug with a novel mechanism of action [40]. The active metabolite(s) probably attack M. tuberculosis , but not other mycobacteria, by inhibiting ketomycolic acid synthesis and protein synthesis, as well as possibly generating intracellular NO [35,41,42]. …”