Tetrahydroisoquinolines affect the whole-cell phenotype of Mycobacterium tuberculosis by inhibiting the ATP-dependent MurE ligase (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.
Arabian Journal of Chemistry, 2019
The multicomponent syntheses of 2,4-di-aryl-quinolines and analogous polycyclic derivatives as anti-tuberculosis agents were described. They were prepared via Beyer and Friedla¨nder methods under microwave irradiation in short reaction times and good yields. Several homogeneous and heterogeneous acid catalysts were compared for preparing 2,4-di-arylquinolines and among them trifluoroacetic acid (TFA) reached the higher yields. Two derivatives exhibited activity against Mycobacterium tuberculosis H37Rv (Mtb), underwent additional testing and were considered lead compounds. The synthesis of a series of polycyclic analogous led to six new active compounds and a Quantitative Structure Activity Relationship study (QSAR) study was established.
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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 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.
C-1 Substituted isoquinolines potentiate the antimycobacterial activity of rifampicin and ethambutol
Frontiers in Antibiotics
IntroductionThe emergence of extensively drug-resistant strains of Mycobacterium tuberculosis threatens decades of progress in the treatment of a disease which remains one of the leading infectious causes of death worldwide. The development of novel antimycobacterial compounds is therefore essential to reinforce the existing antitubercular drug discovery pipeline. There is also interest in new compounds which can synergize with existing antitubercular drugs and can be deployed as part of a combination therapy. This strategy could serve to delay the emergence of resistance to first-line anti-tuberculosis drugs and increase their efficacy against resistant strains of tuberculosis. Previous research has established that several C-1 substituted tetrahydroisoquinolines have antimycobacterial activity. Here we sought to expand our understanding of their antimycobacterial structure activity relationships and their potential to act as adjunct therapies alongside existing antitubercular drug...
Biological evaluation of novel substituted chloroquinolines targeting mycobacterial ATP synthase
International Journal of Antimicrobial Agents, 2012
The ATP synthase of Mycobacterium tuberculosis is a validated drug target against which a diarylquinoline drug is under clinical trials. The enzyme is crucial for the viability both of actively replicating and non-replicating/dormant M. tuberculosis. Enzyme levels drop drastically as the bacilli enter dormancy and hence an inhibitor would make the dormant bacilli even more vulnerable. In this study, a set of 18 novel substituted chloroquinolines were screened against Mycobacterium smegmatis ATP synthase; 6 compounds with the ...
2-Carboxyquinoxalines Kill Mycobacterium tuberculosis through Noncovalent Inhibition of DprE1
ACS Chemical Biology, 2015
Phenotypic screening of a quinoxaline library against replicating Mycobacterium 33 tuberculosis led to the identification of lead compound Ty38c (3-((4-methoxybenzyl)amino)-6-34 (trifluoromethyl)quinoxaline-2-carboxylic acid). With an MIC 99 and MBC of 3.1 µM, Ty38c is 35 bactericidal and active against intracellular bacteria. To investigate its mechanism of action we 36 isolated mutants resistant to Ty38c and sequenced their genomes. Mutations were found in 37 rv3405c, coding for the transcriptional repressor of the divergently expressed rv3406 gene. 38 Biochemical studies clearly showed that Rv3406 decarboxylates Ty38c into its inactive keto 39 metabolite. The actual target was then identified by isolating Ty38c-resistant mutants of an M. 40 tuberculosis strain lacking rv3406. Here, mutations were found in dprE1, encoding the 41 decaprenylphosphoryl-D-ribose oxidase DprE1, essential for biogenesis of the mycobacterial cell 42 wall. Genetics, biochemical validation, and X-ray crystallography revealed Ty38c to be a non-43 covalent, non-competitive DprE1 inhibitor. Structure-activity relationship studies generated a 44 family of DprE1 inhibitors with a range of IC 50 s and bactericidal activity. Co-crystal structures 45 Page 3 of 35 ACS Paragon Plus Environment ACS Chemical Biology 3 of DprE1 in complex with eight different quinoxaline analogs provided a high-resolution 46 interaction map of the active site of this extremely vulnerable target in M. tuberculosis. 48 biochemical assays and X-ray crystallography. Furthermore, the synthesis and structure activity 69 relationship studies of analogs of Ty38c provide valuable information regarding this novel DprE1 inhibitor scaffold. 71 72 RESULTS AND DISCUSSION 73 A phenotypic screen identifies a tuberculocidal quinoxaline scaffold 74 Single point screening of a library containing 266 quinoxaline analogs against M. tuberculosis 75 H37Rv using the resazurin reduction assay revealed five compounds with MIC <15 µM. In 76 order to focus on non-nitroaromatic scaffolds, with potentially novel mechanisms of action, we 77 selected a 2-carboxyquinoxaline cluster with 3 compounds: Ty38c, Ty21c (the ethyl ester of 78 Ty38c) and Ty36c (Table 1). Ty38c and Ty21c killed intracellular H37Rv in a macrophage 79 model with IC 50 s of 2.5 and 6.1 µM, respectively. Both compounds were inactive against the 80 non-replicating ss18b M. tuberculosis strain (MIC 99 >100 µM), suggesting that they inhibit a 81 function essential for growth. Ty38c and Ty21c presented selectivity indexes (TD 50 /MIC 99) of 12 82 and 15, respectively, based on their HepG2 cytotoxicity (Table 1). Ty38c was confirmed to be 83 bactericidal with an MBC equal to its MIC 99 of 3.1 µM (1.2 µg/ml). Cidality was also directly 84 visualized using microfluidics-based time-lapse microscopy of M. tuberculosis expressing GFP 9. 85 Exposure of H37Rv to 5 µM Ty38c caused a dramatic reduction in the growth rate of individual 86 bacteria (Fig. 1, Movie Supplementary Movie 1), although some cells continued to divide 87 without elongation. Cell lysis occurred after a certain lag (25-30 h), and most of the cells lysed 88 over the 7-day exposure period. 89 90 Rv3406 is responsible for primary resistance of M. tuberculosis to Ty38c 91 Page 5 of 35 ACS Paragon Plus Environment ACS Chemical Biology 131 KG as a substrate. Subsequent kinetic analysis showed that Ty38c presents a 14-fold lower k cat 132 value and a 17-fold higher K m value as compared to α-KG (Table 2), indicating that Rv3406 133 metabolizes Ty38c significantly less efficiently than α-KG in the assay conditions. We isolated 134 and purified the reaction products from the reaction mixture, and through NMR and mass 135 spectrometry, the main metabolite was identified as a keto derivative of Ty38c (QN113), 136 resulting from oxidative decarboxylation by Rv3406 (Fig. 2B). In parallel, we independently 137
Synthesis and 3D-QSAR Analysis of 2-Chloroquinoline Derivatives as H 37 RV MTB Inhibitors
Chemical Biology & Drug Design, 2013
Frequency of tuberculosis is progressively increasing worldwide. New emerging strains of bacilli that are emerging are resistant to the currently available drugs which make this issue more alarming. In this regard, a series of substituted quinolinyl chalcones, quinolinyl pyrimidines, and pyridines were synthesized and evaluated for their antitubercular activity in vitro against Mycobacterium tuberculosis H 37 RV. To establish the role of the 2-chloroquinoline nucleus as a pharmacophoric group and study its influence on the antimycobacterial activity, a 3D-QSAR study based on CoMFA and CoMSIA was undertaken on this set of 2-chloroquinoline derivatives. Statistically significant models that are able to well correlate the antimycobacterial activity with the chemical structures of the 2-chloroquinolines have been developed. The contour maps resulting from the best CoMFA and CoMSIA models were used to identify the structural features relevant to the biological activity in this series of analogs. Further analysis of these interaction-field contour maps also showed a high level of internal consistency. The information obtained from the field 3-D contour maps may be fruitfully utilized in the design of more potent 2-chloroquinoline-based analogs as potential antitubercular candidates.