The synthesis and evaluation of quinolinequinones as anti-mycobacterial agents.

A library of thirty-two quinolinequinones (QQs) with various amine substituents at the 6- and 7-positions were synthesised efficiently and in good yields for evaluation as potential anti-tuberculosis agents. Mycobacterium tuberculosis growth inhibition assays demonstrated that QQs bearing moderate length alkyl chains (i.e. heptylphenylamino- and octylamino-QQs), and aryl groups (i.e. phenylethylamino- and benzylamino-QQs) exhibited encouraging inhibitory activity, while QQ analogue 7-chloro-6-propargylamino-quinoline-5,8-dione (16b) had excellent inhibitory activity (MIC = 8 µM). The cLogP values and redox activities of the QQs were determined, and neither readout correlated with the anti-mycobacterial activities of the compounds. Notwithstanding, mode of action studies of 16b revealed that treatment of M. tuberculosis with this compound led to activation of NADH-dependent oxygen consumption suggesting a redox cycling mechanism. To this end, the promising anti-mycobacterial activity of several QQs and their ability to perturb oxygen management leading to an uncontrolled respiratory burst, as identified in this work and by others, demonstrates the merit of further optimising the anti-mycobacterial activity of this readily synthesised class of compound.

Synthesis and Investigation of Phthalazinones as Antitubercular Agents.

A series of 2- and 7-substituted phthalazinones was synthesised and their potential as anti-tubercular drugs assessed via Mycobacterium tuberculosis (mc2 6230) growth inhibition assays. All phthalazinones tested showed growth inhibitory activity (MIC <100 µm), and those compounds containing lipophilic and electron-withdrawing groups generally exhibited better anti-tubercular activity. Several lead compounds were identified, including 7-((2-amino-6-(4-fluorophenyl)pyrimidin-4-yl)amino)-2-heptylphthalazin-1(2H)-one (MIC=1.6 µm), 4-tertbutylphthalazin-2(1H)-one (MIC=3 µm), and 7-nitro-phthalazin-1(2H)-one (MIC=3 µm). Mode of action studies indicated that selected pyrimidinyl-phthalazinones may interfere with NADH oxidation, however, the mode of action of the lead compound is independent of this enzyme. MIC=minimum inhibitory concentration.

Evaluation of anti α-d-Glcp-(1→4)-α-d-Glcp (GAGA4) IgM antibodies as a biomarker for multiple sclerosis.

The correct diagnosis of multiple sclerosis (MS) remains challenging due to the complex pathophysiological and clinical characteristics of the disease. Consequently, there has been immense interest in finding a non-invasive diagnostic test for MS. Recent studies found that serum anti-α-d-Glcp-(1→4)-α-d-Glcp (GAGA4) IgM antibodies were upregulated in MS patients, and this finding led to the development of a commercial diagnostic test (gMS® Dx test), although the test has poor selectivity and has not been independently validated. Herein, we developed an enzyme-linked immunosorbent assay (ELISA) to evaluate the use and reliability of several anti-glucose IgM antibodies, including those against GAGA4, as diagnostic biomarkers for MS. In contrast to previous studies, our results show that serum anti-GAGA4 IgM antibody levels are not significantly higher in MS patients, which could potentially explain the poor selectivity of the commercial test.