Design, synthesis and antibacterial properties of pyrimido[4,5-b]indol-8-amine inhibitors of DNA gyrase

McGarry, D.H.; Cooper, Ian; Walker, Rolf; Warrilow, Catherine E.; Pichowicz, Mark; Ratcliffe, Andrew J.; Salisbury, Anne‐Marie; Savage, Victoria J.; Moyo, Emmanuel; Maclean, John; Smith, Andrew C.; Charrier, Cédric; Stokes, Neil R.; Lindsay, David M.; Kerr, William J.

doi:10.1016/j.bmcl.2018.05.049

Cited by 17 publications

(20 citation statements)

References 16 publications

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“…Therefore, we suggest that, consistent with other similar compounds, Redx03863 and Redx04739 could be ATPase inhibitors. 15,17,18 We directly tested Redx03863 and Redx04739 in gyrase ATPase reactions and found that both compounds inhibit the ATPase reaction of M. tuberculosis gyrase with high efficiency, like that of novobiocin (Figure 3), with IC 50 values of 200 nM. As the gyrase concentration used in the ATPase assays was 200 nM it is not feasible to determine IC 50 values that are lower than this.…”

Section: Inhibition Of Dna Gyrasementioning

confidence: 99%

“…More recently, these compounds have been further developed to create the current series with increased specificity against mycobacteria. 18 Additionally, it has been shown that these compounds inhibit the supercoiling and ATPase reactions of M. tuberculosis gyrase without inhibiting human topoisomerase II, and maintain activity against a panel of relevant M. tuberculosis clinical isolates resistant to other commonly used drugs. 18 In this paper we have extended this work using two compounds ( Figure 1) and show that they are effective inhibitors of M. tuberculosis gyrase and inhibit the growth of Mycobacterium smegmatis.…”

Section: Introductionmentioning

confidence: 99%

“…18 Additionally, it has been shown that these compounds inhibit the supercoiling and ATPase reactions of M. tuberculosis gyrase without inhibiting human topoisomerase II, and maintain activity against a panel of relevant M. tuberculosis clinical isolates resistant to other commonly used drugs. 18 In this paper we have extended this work using two compounds ( Figure 1) and show that they are effective inhibitors of M. tuberculosis gyrase and inhibit the growth of Mycobacterium smegmatis. In addition, we present crystal structures of the GyrB N-terminal ATPase sub-domain from Mycobacterium thermoresistibile bound to one of these compounds (Redx03863) and also to novobiocin, demonstrating that this novel compound class inhibits via a binding pocket and resistance mechanism different from that of novobiocin.…”

Section: Introductionmentioning

confidence: 99%

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Structural and mechanistic analysis of ATPase inhibitors targeting mycobacterial DNA gyrase

Henderson

Stevenson

Malone

et al. 2020

Journal of Antimicrobial Chemotherapy

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Objectives To evaluate the efficacy of two novel compounds against mycobacteria and determine the molecular basis of their action on DNA gyrase using structural and mechanistic approaches. Methods Redx03863 and Redx04739 were tested in antibacterial assays, and also against their target, DNA gyrase, using DNA supercoiling and ATPase assays. X-ray crystallography was used to determine the structure of the gyrase B protein ATPase sub-domain from Mycobacterium smegmatis complexed with the aminocoumarin drug novobiocin, and structures of the same domain from Mycobacterium thermoresistibile complexed with novobiocin, and also with Redx03863. Results Both compounds, Redx03863 and Redx04739, were active against selected Gram-positive and Gram-negative species, with Redx03863 being the more potent, and Redx04739 showing selectivity against M. smegmatis. Both compounds were potent inhibitors of the supercoiling and ATPase reactions of DNA gyrase, but did not appreciably affect the ATP-independent relaxation reaction. The structure of Redx03863 bound to the gyrase B protein ATPase sub-domain from M. thermoresistibile shows that it binds at a site adjacent to the ATP- and novobiocin-binding sites. We found that most of the mutations that we made in the Redx03863-binding pocket, based on the structure, rendered gyrase inactive. Conclusions Redx03863 and Redx04739 inhibit gyrase by preventing the binding of ATP. The fact that the Redx03863-binding pocket is distinct from that of novobiocin, coupled with the lack of activity of resistant mutants, suggests that such compounds could have potential to be further exploited as antibiotics.

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Section: Inhibition Of Dna Gyrasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structural and mechanistic analysis of ATPase inhibitors targeting mycobacterial DNA gyrase

Henderson

Stevenson

Malone

et al. 2020

Journal of Antimicrobial Chemotherapy

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“…Several studies revealed that the solubility of active pharmaceutical ingredients can be increased by the preparation of nanoparticles and by optimization of physicochemical properties [9,10,11]. Besides, indole and thiophene derivatives have wide range of pharmacological activity including anticancer, antimicrobial and antiinflammatory [12,13,14,15,16,17,18,19].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Bioactivity Evaluation of Indole-Thiophene polymer with Molecular Docking Studies

Baseer¹,

Abdrabou²,

Zarie³

et al. 2020

Egypt. J. Chem.

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Emulsion polymerization of 2-amino-4-(1-benzyl-1H-indol-3-yl) thiophene-3-carbonitrile (ABITC) using ammonium persulfate (APS) afforded two isomers of (PABITC) with high molecular weight. Chemical structure and morphology of the synthesized polymers were investigated by IR, 1HNMR, SEM, and GPC. Nano-capsulation of ABITC, PABITC, and PABITC/Doxorubicin by polyethylene glycol (PEG) was achieved by the nanoprecipitation method. The anti-proliferative activity of the PABITC and nano-capsulation against HepG2, Huh7, and A549 cancer cell lines were investigated using MTT assay. The result obtained indicates that the encapsulation of ABITC inside PEG-NP led to an improvement in their anti-proliferative activity against cancer cell lines compared to ABITC. The PABITC revealed moderate anti-proliferative activity against tested cells and their encapsulation form with PEG-NP revealed no significant change in the activity. Furthermore, the anti-proliferative activity of PABITC-NP was improved after Doxorubicin (DOX) encapsulation against tested cells compared to PABITC -PEG-NP. In addition, PABITC exhibited potent antibacterial activity against tested microbes comparing to ABITC and amikacin. Moreover, the binding mode of the ABITC beside two repeated units inside the active site of the DNA gyrase B chain (PDB ID: 1KIJ) as promising bacterial target and CDK2 enzyme (PDB ID: 1PYE)] as promising cancer target was studied using molecular docking technique.

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“…The action of topoisomerases is to change the spatial structure of DNA by catenation and decatenation of duplex DNA rings, relaxation of supercoiled DNA, and in the use of DNA topoisomerase II introduction of negative supercoils into DNA in an energy-dependent reaction [3]. Therefore, bacterial DNA topoisomerase II has drawn much attention as a selected target for finding potent antibacterial agents [4,5,6]. For example, a lot of synthetic quinolone antibacterial agents have been marketed and are now widely used for the treatment of bacterial infectious diseases [7,8].…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Triazole-Containing Pyrazole Ester Derivatives as Potential Antibacterial Agents

et al. 2019

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To develop new antibacterial agents, a series of novel triazole-containing pyrazole ester derivatives were designed and synthesized and their biological activities were evaluated as potential topoisomerase II inhibitors. Compound 4d exhibited the most potent antibacterial activity with Minimum inhibitory concentration (MIC) alues of 4 µg/mL, 2 µg/mL, 4 µg/mL, and 0.5 µg/mL against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, and Salmonella gallinarum, respectively. The in vivo enzyme inhibition assay 4d displayed the most potent topoisomerase II (IC50 = 13.5 µg/mL) and topoisomerase IV (IC50 = 24.2 µg/mL) inhibitory activity. Molecular docking was performed to position compound 4d into the topoisomerase II active site to determine the probable binding conformation. In summary, compound 4d may serve as potential topoisomerase II inhibitor.

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Design, synthesis and antibacterial properties of pyrimido[4,5-b]indol-8-amine inhibitors of DNA gyrase

Cited by 17 publications

References 16 publications

Structural and mechanistic analysis of ATPase inhibitors targeting mycobacterial DNA gyrase

Structural and mechanistic analysis of ATPase inhibitors targeting mycobacterial DNA gyrase

Synthesis and Bioactivity Evaluation of Indole-Thiophene polymer with Molecular Docking Studies

Discovery of Novel Triazole-Containing Pyrazole Ester Derivatives as Potential Antibacterial Agents

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