Development of Simplified Heterocyclic Acetogenin Analogues as Potent and Selective <i>Trypanosoma brucei</i> Inhibitors

Florence, Gordon J.; Fraser, Andrew L.; Gould, Eoin R.; King, Elizabeth F.; Menzies, Stefanie K.; Morris, Joanne C.; Thomson, Marie I.; Tulloch, L.B.; Zacharova, Marija K.; Smith, Terry

doi:10.1002/cmdc.201600210

Cited by 12 publications

(12 citation statements)

References 30 publications

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“…Simplified furoxan‐based acetogenin analogue 60 , incorporating two chiral tetrahydropyran (THP) scaffolds, was synthesized in one step from the corresponding diastereomeric oxime 61 (Scheme ). Hybrid 60 displayed high anti‐ T. brucei activity while being 5.6‐fold more selective over HeLa cells …”

Section: Synthesis No‐donor Properties and Pharmacological Activitmentioning

confidence: 99%

“… Synthesis of simplified furoxan acetogenin analogue . Reagents and conditions : a) t BuOCl, CH 2 Cl 2 , then TEA, −78 °C→RT, 61 %.…”

Section: Synthesis No‐donor Properties and Pharmacological Activitmentioning

confidence: 99%

“…Hybrid 60 displayed high anti-T. brucei activity while being 5.6-fold more selectiveo ver HeLa cells. [45] The furoxan scaffold incorporated in the structure of the naturally occurring flavonoid chrysin (5,7-dihydroxyflavone) by meanso fc ondensationo fhydroxymethyl derivative 49 directly with chrysin or via ap henol bridge resulted in the formation of hybrids 62 and 63 a,b (Scheme 23). All designed hybridss ignificantly promotedg lucose consumption in HepG2 cells, with the effect being strongert han with the parent chrysin, which is explained by the synergistic role of the NO-donor furoxan moiety.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Hybridization Tools in the Development of Furoxan‐Based NO‐Donor Prodrugs

Ферштат

Махова

2017

ChemMedChem

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The molecular hybridization of different compounds with known pharmacological activity is a particularly prominent approach for the design of potential drugs with improved pharmacokinetic profiles. Much attention over the last decade has been focused on the synthesis of hybrid structures with a nitric oxide (NO)-donor framework, as NO is a ubiquitous and crucial regulator of cellular metabolism, affecting various physiological and pathophysiological processes. 1,2,5-Oxadiazole 2-oxides (furoxans), which are capable of exogenous NO release in the presence of thiol cofactors, are an important class of prospective NO donors. As such, a wide range of hybrid compounds that combine a furoxan ring with various pharmacologically active structures have been created. This review focuses on recent results in the synthesis and pharmacological activity of furoxan-based hybrids. Special attention is given to chemo- and regioselective methods used in the preparation of these hybrid structures, and the role of synergistic effects on their pharmacological activity, associated with the furoxan fragment.

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Section: Synthesis No‐donor Properties and Pharmacological Activitmentioning

confidence: 99%

“… Synthesis of simplified furoxan acetogenin analogue . Reagents and conditions : a) t BuOCl, CH 2 Cl 2 , then TEA, −78 °C→RT, 61 %.…”

Section: Synthesis No‐donor Properties and Pharmacological Activitmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular Hybridization Tools in the Development of Furoxan‐Based NO‐Donor Prodrugs

Ферштат

Махова

2017

ChemMedChem

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“…The determination of the EC 50 of the compounds using Alamar Blue was completed as previously described. [42,43] Briefly,D MSO solutions of the compounds were added to the media and at wofold serial dilution done across a9 6-well plate in quadruplicate (12point serial dilution). Cells were counted using aC ASY Cell Counter and seeded at cell densities given below.A fter three days, 10 mL Alamar Blue (12.5 mg resazurin salt in 100 mL PBS) was added to Bloodstream-form T. brucei brucei strain 427 were grown in HMI-9 media supplemented with 10 %f etal bovine serum and 2.5 mgmL À1 G418 at 37 8Cw ith 5% v/v CO 2 and seeded at 1 10 3 cells per well.…”

Section: Cell Culture and Cytotoxicity Assaysmentioning

confidence: 99%

Structure‐Based Design of a Eukaryote‐Selective Antiprotozoal Fluorinated Aminoglycoside

et al. 2018

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Aminoglycosides (AG) are antibiotics that lower the accuracy of protein synthesis by targeting a highly conserved RNA helix of the ribosomal A-site. The discovery of AGs that selectively target the eukaryotic ribosome, but lack activity in prokaryotes, are promising as antiprotozoals for the treatment of neglected tropical diseases, and as therapies to read-through point-mutation genetic diseases. However, a single nucleobase change A1408G in the eukaryotic A-site leads to negligible affinity for most AGs. Herein we report the synthesis of 6'-fluorosisomicin, the first 6'-fluorinated aminoglycoside, which specifically interacts with the protozoal cytoplasmic rRNA A-site, but not the bacterial A-site, as evidenced by X-ray co-crystal structures. The respective dispositions of 6'-fluorosisomicin within the bacterial and protozoal A-sites reveal that the fluorine atom acts only as a hydrogen-bond acceptor to favorably interact with G1408 of the protozoal A-site. Unlike aminoglycosides containing a 6'-ammonium group, 6'-fluorosisomicin cannot participate in the hydrogen-bonding pattern that characterizes stable pseudo-base-pairs with A1408 of the bacterial A-sites. Based on these structural observations it may be possible to shift the biological activity of aminoglycosides to act preferentially as antiprotozoal agents. These findings expand the repertoire of small molecules targeting the eukaryotic ribosome and demonstrate the usefulness of fluorine as a design element.

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“…We have since described a series of bis‐tetrahydropyran 1,4‐triazole analogues based on the chamuvarinin polyether core and assembled from a pool of readily accessible chiral tetrahydropyran (THP) building blocks linked by different heterocyclic spacers including 1,4‐triazoles of type 2 (Figure ). Many of these simplified analogues displayed low micromolar trypanocidal activities but more significantly excellent selectivities relative to mammalian cell lines …”

Section: Introductionmentioning

confidence: 99%

Structure‐Based Design, Synthesis and Biological Evaluation of Bis‐Tetrahydropyran Furan Acetogenin Mimics Targeting the Trypanosomatid F1 Component of ATP Synthase

et al. 2019

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The protozoan parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are responsible for the severely debilitating neglected Tropical diseases of African sleeping sickness, Chagas disease and leishmaniasis, respectively. As part of our ongoing programme exploring the potential of simplified analogues of the acetogenin chamuvarinin we identified the T. brucei FoF1‐ATP synthase as a target of our earlier triazole analogue series. Using computational docking studies, we hypothesised that the central triazole heterocyclic spacer could be substituted for a central 2,5‐substituted furan moiety, thus diversifying the chemical framework for the generation of compounds with greater potency and/or selectivity. Here we report the design, docking, synthesis and biological evaluation of new series of trypanocidal compounds and demonstrate their on‐target inhibitory effects. Furthermore, the synthesis of furans by the modular coupling of alkyne‐ and aldehyde‐THPs to bis‐THP 1,4‐alkyne diols followed by ruthenium/xantphos‐catalysed heterocyclisation described here represents the most complex use of this method of heterocyclisation to date.

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Development of Simplified Heterocyclic Acetogenin Analogues as Potent and Selective Trypanosoma brucei Inhibitors

Cited by 12 publications

References 30 publications

Molecular Hybridization Tools in the Development of Furoxan‐Based NO‐Donor Prodrugs

Molecular Hybridization Tools in the Development of Furoxan‐Based NO‐Donor Prodrugs

Structure‐Based Design of a Eukaryote‐Selective Antiprotozoal Fluorinated Aminoglycoside

Structure‐Based Design, Synthesis and Biological Evaluation of Bis‐Tetrahydropyran Furan Acetogenin Mimics Targeting the Trypanosomatid F1 Component of ATP Synthase

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