2014
DOI: 10.1016/j.bmc.2014.07.050
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Incorporation of triphenylphosphonium functionality improves the inhibitory properties of phenothiazine derivatives in Mycobacterium tuberculosis

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Cited by 35 publications
(41 citation statements)
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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%
“…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%
“…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.…”
mentioning
confidence: 99%
“…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%