Incorporation of triphenylphosphonium functionality improves the inhibitory properties of phenothiazine derivatives in Mycobacterium tuberculosis

Dunn, Elyse; Roxburgh, Marina; Larsen, Lesley; Smith, Robin A.J.; McLellan, Alexander D.; Heikal, Adam; Murphy, Michael P.; Cook, Gregory M.

doi:10.1016/j.bmc.2014.07.050

Cited by 35 publications

(41 citation statements)

References 62 publications

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“…7,8 Tellingly, conjugation of the membrane targeting triphenylphosphonium (TPP) moiety to antimycobacterial phenothiazines led to significant improvements in activity, likely due to enhanced localization within the mycobacterial membrane. 9 Relatably, grafting TPP onto an inactive indole scaffold resulted in mycobactericidal cationic amphiphilic TPP indoles that rapidly depolarized the membrane of M. bovis BCG. 11 1-Octylindolyl Mannich bases embedded with a cationic amphiphilic motif were similarly mycobactericidal and additionally, more potent and selective than the TPP indoles.…”

Section: Introductionmentioning

confidence: 99%

Indolyl Azaspiroketal Mannich Bases Are Potent Antimycobacterial Agents with Selective Membrane Permeabilizing Effects and in Vivo Activity

Nyantakyi

Gopal

et al. 2018

J. Med. Chem.

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The inclusion of an azaspiroketal Mannich base in the membrane targeting anti-tubercular 6- methoxy-1-n-octyl-1H-indole scaffold resulted in analogs with improved selectivity and submicromolar activity against Mycobacterium tuberculosis H37Rv. The potency enhancing properties of the spiro-ring fused motif was affirmed by SAR and validated in a mouse model of tuberculosis. As expected for membrane inserting agents, the indolyl azaspiroketal Mannich bases perturbed phospholipid vesicles, permeabilized bacterial cells and induced the mycobacterial cell envelope stress reporter promoter piniBAC. Surprisingly, their membrane disruptive effects did not appear to be associated with bacterial membrane depolarization. This profile was not uniquely associated with azaspiroketal Mannich bases but was characteristic of indolyl Mannich bases as a class. Whereas resistant mycobacteria could not be isolated for a less potent indolyl Mannich base, the more potent azaspiroketal analog displayed low spontaneous resistance mutation frequency of 10−8/CFU. This may indicate involvement of an additional envelope-related target in its mechanism of action.

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Section: Introductionmentioning

confidence: 99%

Indolyl Azaspiroketal Mannich Bases Are Potent Antimycobacterial Agents with Selective Membrane Permeabilizing Effects and in Vivo Activity

Nyantakyi

Gopal

et al. 2018

J. Med. Chem.

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“…In notable pathogenic microorganisms NDH-2 is essential for growth, even in some organisms that contain both complex I and NDH-2 such as Mycobacterium tuberculosis 7. Together with the presence of NDH-1 in mammalian species, this has rendered NDH-2 an attractive drug target891011.…”

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confidence: 99%

The mechanism of catalysis by type-II NADH:quinone oxidoreductases

Blaza

Bridges

Aragão

et al. 2017

Sci Rep

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Type II NADH:quinone oxidoreductase (NDH-2) is central to the respiratory chains of many organisms. It is not present in mammals so may be exploited as an antimicrobial drug target or used as a substitute for dysfunctional respiratory complex I in neuromuscular disorders. NDH-2 is a single-subunit monotopic membrane protein with just a flavin cofactor, yet no consensus exists on its mechanism. Here, we use steady-state and pre-steady-state kinetics combined with mutagenesis and structural studies to determine the mechanism of NDH-2 from Caldalkalibacillus thermarum. We show that the two substrate reactions occur independently, at different sites, and regardless of the occupancy of the partner site. We conclude that the reaction pathway is determined stochastically, by the substrate/product concentrations and dissociation constants, and can follow either a ping-pong or ternary mechanism. This mechanistic versatility provides a unified explanation for all extant data and a new foundation for the development of therapeutic strategies.

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“…To better explain the anti‐tubercular activity of the phthalazinones, investigations into the ability of the compounds to affect respiratory NDH‐II‐dependent NADH oxidation were undertaken. Here, the rates of NADH oxidation in the absence and presence of inhibitors were measured using inverted membrane vesicles (IMVs) from M. smegmatis . The addition of several phthalazinones to IMVs oxidising NADH showed a trend whereby the rates of NADH oxidation were enhanced compared to the basal rate (Figure ), particularly pyrimidinyl‐phthalazinones 46 , 49 and 50 .…”

Section: Resultsmentioning

confidence: 99%

“…Here, the rates of NADH oxidation in the absence and presence of inhibitors were measured using inverted membrane vesicles (IMVs)from M. smegmatis. [43,44] The addition of several phthalazinones to IMVs oxidising NADH showeda trend whereby the rates of NADH oxidation weree nhanced compared to the basal rate ( Figure 5), particularly pyrimidinylphthalazinones 46, 49 and 50.T hese data suggest that these compounds might activate NDH-IIa ctivity probably via ar edox cycling mechanism. [21,27] Conversely,m anyp hthalazinonesa ppearedt oc ause al ower rate of NADH oxidation, notably phenyl-phthalazinone 16,h eptyl-phthalazinone 23,a nd nitroheptyl-phthalazinone 31,w hich could be ar esult of NDH-IIi nhibition( direct or indirect).…”

Section: Scheme3synthesis Of the Amino Phthalazinonesmentioning

confidence: 92%

Synthesis and Investigation of Phthalazinones as Antitubercular Agents

Santoso

Cheung

Hards

et al. 2019

Chemistry An Asian Journal

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A series of 2‐ and 7‐substituted phthalazinones was synthesised and their potential as anti‐tubercular drugs assessed via Mycobacterium tuberculosis (mc26230) 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.

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Incorporation of triphenylphosphonium functionality improves the inhibitory properties of phenothiazine derivatives in Mycobacterium tuberculosis

Cited by 35 publications

References 62 publications

Indolyl Azaspiroketal Mannich Bases Are Potent Antimycobacterial Agents with Selective Membrane Permeabilizing Effects and in Vivo Activity

Indolyl Azaspiroketal Mannich Bases Are Potent Antimycobacterial Agents with Selective Membrane Permeabilizing Effects and in Vivo Activity

The mechanism of catalysis by type-II NADH:quinone oxidoreductases

Synthesis and Investigation of Phthalazinones as Antitubercular Agents

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