An evaluation of Minor Groove Binders as anti- Trypanosoma brucei brucei therapeutics

Scott, Fraser J.; Khalaf, Abedawn I.; Giordani, Federica; Wong, Pui Ee; Duffy, Sandra; Barrett, Michael P.; Avery, Vicky M.; Suckling, Colin J.

doi:10.1016/j.ejmech.2016.03.064

Cited by 27 publications

(35 citation statements)

References 19 publications

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“…The intrinsic fluorescence of some S-MGBs makes it possible to investigate their intracellular distribution in trypanosomes following incubation. As previously shown for T. b. brucei(21), experiments with the highly fluorescent 9 confirmed internalisation in T. congolense(Fig. 3a).…”

supporting

confidence: 83%

Novel Minor Groove Binders Cure Animal African Trypanosomiasis in an in Vivo Mouse Model

et al. 2019

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supporting

confidence: 83%

Novel Minor Groove Binders Cure Animal African Trypanosomiasis in an in Vivo Mouse Model

et al. 2019

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“…By manipulating these variables potent antibacterial compounds have been discovered, one of which has completed phase 1 clinical trials, 17 and other compounds have been shown to be active against Trypanosoma both in cell-based studies and in mouse models of disease and leishmaniasis (unpublished results). 18,19 A potential benefit of targeting DNA is that it is to be expected that several binding sites will be occupied by S-MGBs leading to multiple mechanisms of action, which in turn could mitigate risks of rapid development of resistance. A counter balancing risk is that the ubiquity of DNA makes species selectivity critical.…”

Section: Ar T Ic Le In Fomentioning

confidence: 99%

“…For example, the clogD7.4 values for the set range between -3.28 and 6.97 (Table 1). 19 Compound inhibitory activity was determined in IC50 dose response format against Pf3D7 (chloroquine sensitive) and PfDd2 (chloroquine resistant) stains using a previously described high content imaging assay. 22 In addition, compounds were simultaneously tested for general cytotoxicity against HEK293 cells using an AlamarBlue based assay which measures cell metabolic activity.…”

Section: Ar T Ic Le In Fomentioning

confidence: 99%

Selective anti-malarial minor groove binders

Scott

Khalaf

Duffy

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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A set of 31 DNA minor groove binders (MGBs) with diverse structural features relating to both physical chemical properties and DNA binding sequence preference has been evaluated as potential drugs to treat Plasmodium falciparum infections using a chloroquine sensitive strain (3D7) and a chloroquine resistant strain (Dd2) in comparison with human embryonic kidney (HEK) cells as an indicator of mammalian cell toxicity. MGBs with an alkene link between the two N-terminal building blocks were demonstrated to be most active with IC50 values in the range 30-500nM and therapeutic ratios in the range 10->500. Many active compounds contained a C-alkylthiazole building block. Active compounds with logD7.4 values of approximately 3 or 7 were identified. Importantly the MGBs tested were essentially equally effective against both chloroquine sensitive and resistant strains. The results show that suitably designed MGBs have the potential for development into clinical candidates for antimalarial drugs effective against resistant strains of Plasmodia.

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“…46 This compound was built from Nmethylpyrrole amino acid amides and has an amidine end group (Scheme 1). Also, we modified a number of the fragments of the original structure.…”

Section: Scheme 6 Synthesis Of C-isopropyl-substituted Thiazole Amidmentioning

confidence: 99%

DNA Minor Groove Binders-Inspired by Nature

Khalaf¹,

Al-kadhimi²,

Ali³

2016

ACSi

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The synthesis and biological activity of a variety of analogues to the naturally occurring antibacterial and antifungal Distamycin A were explored by a number of authors. These compounds were subject to a large array of assays. Some of these compounds showed high activity against a range of Gram-positive, Gram-negative bacteria as well as fungi. To explore the anti-parasitic activity of this class of compounds, specific modifications had to be made. A number of these compounds proved to be active against Trypanosoma brucei. The binding of a number of these compounds to short sequences of DNA were also examined using footprinting assays as well as NMR spectroscopy. Computer modelling was employed on selected compounds to understand the way these compounds bind to specific DNA sequences. A large number of variations were made to the standard structure of Distamycin. These changes involved the replacement of the pyrrole moieties as well as the head and tail groups with a number of heterocyclic compounds. Some of these minor groove binders (MGBs) were also investigated for their capability for the treatment of cancer and in particular lung cancer.

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An evaluation of Minor Groove Binders as anti- Trypanosoma brucei brucei therapeutics

Cited by 27 publications

References 19 publications

Novel Minor Groove Binders Cure Animal African Trypanosomiasis in an in Vivo Mouse Model

Novel Minor Groove Binders Cure Animal African Trypanosomiasis in an in Vivo Mouse Model

Selective anti-malarial minor groove binders

DNA Minor Groove Binders-Inspired by Nature

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