C-1 Substituted isoquinolines potentiate the antimycobacterial activity of rifampicin and ethambutol (original) (raw)
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8‐Hydroxyquinolines are bactericidal against Mycobacterium tuberculosis
Drug Development Research, 2019
There is an urgent need for new treatments effective against Mycobacterium tuberculosis, the causative agent of tuberculosis. The 8-hydroxyquinoline series is a privileged scaffold with anticancer, antifungal, and antibacterial activities. We conducted a structure-activity relationship study of the series regarding its antitubercular activity using 26 analogs. The 8-hydroxyquinolines showed good activity against M. tuberculosis, with minimum inhibitory concentrations (MIC90) of <5 μM for some analogs. Small substitutions at C5 resulted in the most potent activity. Substitutions at C2 generally decreased potency, although a sub-family of 2-styryl-substituted analogs retained activity. Representative compounds demonstrated bactericidal activity against replicating M. tuberculosis with >4 log kill at 10× MIC over 14 days. The majority of the compounds demonstrated cytotoxicity (IC 50 of <100 μM). Further development of this series as antitubercular agents should address the cytotoxicity liability. However, the 8-hydroxyquinoline series represents a useful tool for chemical genomics to identify novel targets in M. tuberculosis.
Bioorganic & Medicinal Chemistry Letters, 2020
A series of 4-aminoquinoline-isoindoline-dione-isoniazid triads were synthesized and assessed for their anti-mycobacterial activities and cytotoxicity. Most of the synthesized compounds exhibited promising activities against the mc26230 strain of M. tuberculosis with MIC in the range of 3.125-12.5 µg/mL and were non-cytotoxic against Vero cells. The conjugates lacking either isoniazid or quinoline core in their structural framework failed to inhibit the growth of M. tuberculosis; thus, further strengthening the proposed design of triads in the present study.
Substituted 4-methylquinolines as a new class of anti-tuberculosis agents
2003
We report synthesis and anti-tuberculosis activities of a series of novel ring-substituted quinolines. The most effective compound of the series 3d (MIC= 6.25 μg/mL, Mycobacterium tuberculosis H37Rv strain) was synthesized in one step; thus is an attractive lead molecule for anti-tuberculosis drug development. The results of this study represent the discovery of ring-substituted 4-methylquinolines as new class of potential anti-tuberculosis agents.
Bioorganic & Medicinal Chemistry, 2009
We herein describe the synthesis and antimycobacterial activity of a series of 27 different derivatives of 3-benzyl-6-bromo-2-methoxy-quinolines and amides of 2-[(6-bromo-2-methoxy-quinolin-3-yl)-phenyl-methyl]-malonic acid monomethyl ester. The antimycobacterial activity of these compounds was evaluated in vitro against Mycobacterium tuberculosis H37Rv for nine consecutive days upon a fixed concentration (6.25 μg/mL) at day one in Bactec assay and compared to untreated TB cell culture as well as one with isoniazide treated counterpart, under identical experimental conditions. The compounds 3, 8, 17 and 18 have shown 92–100% growth inhibition of mycobacterial activity, with minimum inhibitory concentration (MIC) of 6.25 μg/mL. Based on our molecular modelling and docking studies on well-known diarylquinoline antitubercular drug R207910, the presence of phenyl, naphthyl and halogen moieties seem critical. Comparison of docking studies on different stereoisomers of R207910 as well as compounds from our data set, suggests importance of electrostatic interactions. Further structural analysis of docking studies on our compounds suggests attractive starting point to find new lead compounds with potential improvements.Synthesis and biological evaluation of quinoline based compounds against Mycobacterium tuberculosis H37Rv.
TMC207: the first compound of a new class of potent anti-tuberculosis drugs
Future Microbiology, 2010
Disease caused by Mycobacterium tuberculosis continues as a global epidemic: over 2 billion people harbor latent TB infection, and more than 9 million new TB cases, of whom 500,000 are multidrug-resistant (MDR), and nearly 2 million deaths are estimated to occur each year. New drugs are required to shorten treatment duration of drug-sensitive TB and for the treatment of MDR-TB. TMC207 is a first-in-class diarylquinoline compound with a novel mechanism of action, the inhibition of bacterial ATP synthase, and potent activity against drug-sensitive and drug-resistant TB. It has bactericidal and sterilizing activity against M. tuberculosis and other mycobacterial species, but little activity against other bacteria. In a Phase II efficacy study conducted in patients with MDR-TB taking TMC207 plus a standard background regimen, the drug appeared to be safe and well tolerated, and showed significant efficacy after 2 months of treatment with conversion rates of sputum culture of 48% (vs 9% ...
Mycobacterium tuberculosis Gyrase Inhibitors as a New Class of Antitubercular Drugs
Antimicrobial Agents and Chemotherapy, 2015
One way to speed up the TB drug discovery process is to search for antitubercular activity among compound series that already possess some of the key properties needed in anti-infective drug discovery, such as whole-cell activity and oral absorption. Here, we present MGIs, a new series of Mycobacterium tuberculosis gyrase inhibitors, which stem from the long-term efforts GSK has dedicated to the discovery and development of novel bacterial topoisomerase inhibitors (NBTIs). The compounds identified were found to be devoid of fluoroquinolone (FQ) cross-resistance and seem to operate through a mechanism similar to that of the previously described NBTI GSK antibacterial drug candidate. The remarkable in vitro and in vivo antitubercular profiles showed by the hits has prompted us to further advance the MGI project to full lead optimization.
Synthesis and antituberculosis activity of novel mefloquine-isoxazole carboxylic esters as prodrugs
Bioorganic & Medicinal Chemistry Letters, 2010
a b s t r a c t 5-(2,8-Bis(trifluoromethyl)quinolin-4-yloxymethyl)isoxazole-3-carboxylic acid ethyl ester (compound 3) was reported to have excellent antituberculosis activity against both replicating and non-replicating Mycobacterium tuberculosis, with a minimum inhibitory concentration (MIC) of 0.9 lM and 12.2 lM, respectively. In this study, the antituberculosis activity of compound 3 was further investigated. Its activity appeared to be very specific for organisms of the M. tuberculosis complex and it effected significant reductions of bacterial numbers in infected macrophages with an EC 90 of 4.1 lM. More importantly, the increased in vitro antituberculosis activity of the corresponding acid (compound 4) at pH 6.0 suggested that it may be active in vivo in an acidic environment produced as a consequence of inflammation in the lungs of TB patients. The fact that various ester bioisosteres of compound 3 lost anti-TB activity further suggested that the ester compound 3 may function as a prodrug. The detailed structure-activity relationships (SARs) from this study should facilitate our ultimate goal of improving the anti-TB potency of this isoxazole ester series.