Abstract
The emergence of multi-drug resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis creates the urgency for new anti-tuberculosis drugs to improve the efficiency of current tuberculosis treatment. In the search for a new potential tuberculosis drug, we synthesized an isoindole based chemical library and screened a potential candidate with significant anti-tuberculosis activity. The compound named 2-hydroxy-4-(4-nitro-1,3-dioxoisoindolin-2-yl) benzoic acid (IDD-B40) showed strong activity against all the tested drug-susceptible and drug-resistant strains of M. tuberculosis, with the 50% minimum inhibitory concentrations (MIC50) of 0.39 μg/ml both in culture broth and inside Raw 264.7 cells. Also, IDD-B40, in combination with rifampicin, exhibited a direct synergistic effect against both XDR and H37Rv M. tuberculosis. Besides, IDD-B40 showed a better post-antibiotic effect (PAE) than did some first-line drugs and showed no significant cytotoxicity to any cell line tested, with a selectivity index of ≥ 128. Although IDD-B40 showed a result similar to isoniazid in the preliminary mycolic acid inhibition assay, it did not exhibit any effect against other mycolic acid-producing nontuberculous mycobacterial strains (NTM), and different non-mycobacterial pathogenic strains, so further studies are required to confirm the mode of action of IDD-B40. Considering its results against M. tuberculosis, IDD-B40 is a potential anti-tuberculosis drug candidate. However, further studies are required to evaluate its potential in vivo effect and therapeutic potential.
Highlights
Tuberculosis is one of the oldest and most highly contagious diseases caused by Mycobacterium tuberculosis (M. tuberculosis)
After an extensive screening test, we found a promising isoindoledione based compound, 2-Hydroxy-4-(4-nitro-1,3-dioxoisoindolin-2-yl) benzoic acid (IDD-B40), that has an intense activity against M. tuberculosis
The results indicated that IDD-B40 did not have any significant cytotoxicity up to a concentration of 100 μg/ml and it was safe for further evaluation as the lowest selectivity index, 128.2, among all tested cell lines (Fig. 4 and Supplementary Table S3) was higher than the recommended minimum acceptable limit, 1016
Summary
Tuberculosis is one of the oldest and most highly contagious diseases caused by Mycobacterium tuberculosis (M. tuberculosis). First-line drugs are still the primary treatment of choice for drug-susceptible M. tuberculosis infection[2,3]. These drugs are facing significant compliance challenges because of the long duration of therapy and associated toxicities[4]. A total of 25 indole derivatives were synthesized at Korea Chemical Bank of Korea Research Institute of Chemical Technology, Korea and initially tested for in vitro anti-tubercular activity against M. tuberculosis H37Rv and H37Ra. After an extensive screening test, we found a promising isoindoledione based compound, 2-Hydroxy-4-(4-nitro-1,3-dioxoisoindolin-2-yl) benzoic acid (IDD-B40), that has an intense activity against M. tuberculosis. We selected it for further studies to find out whether it might have characteristics suitable as a potential anti-tuberculosis drug
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