Structure-Guided Lead Optimization of Triazolopyrimidine-Ring Substituents Identifies Potent <i>Plasmodium falciparum</i> Dihydroorotate Dehydrogenase Inhibitors with Clinical Candidate Potential

Coteron, Jose M.; Marco, María; Esquivias, Jorge; Deng, Xingming; White, Karen L.; White, John; Koltun, Maria; Mazouni, Farah El; Kokkonda, Sreekanth; Katneni, Kasiram; Bhamidipati, Ravi Kanth; Shackleford, David M.; Angulo-Barturen, Íñigo; Ferrer, Santiago; Jiménez-Dı́az, Marı́a Belén; Gamo, Francisco Javier; Goldsmith, Elizabeth J.; Charman, William N.; Bathurst, Ian C.; Floyd, David M.; Matthews, David J.; Burrows, Jeremy N.; Rathod, Pradipsinh K.; Charman, Susan A.; Phillips, Margaret A.

doi:10.1021/jm200592f

Cited by 260 publications

(348 citation statements)

References 43 publications

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“…Key hydrogen-bond contacts used by the triazolopyrimidines and other chemical series are the amino acid residues Arg-265 and His-185, highlighted in Figure 4A. Two inhibitor classes have been crystallised with PfDHODH to date: the aforementioned triazolopyrimidines (PDB ID 3SFK) [59] and the thiophene-2-carboxamides (PDB ID 3O8A) [60], The structures reveal that the inhibitor binding pocket is directly adjacent to the FMN cofactor (shown in red in Fig. 4A) which can be divided into two portions: (i) the space immediately next to the FMN which is generally fully occupied by structurally-diverse PfDHODH inhibitors (i.e.…”

Section: Dhodh -Targeting Pyrimidine Biosynthesis Using Structure-basmentioning

confidence: 99%

New Opportunities in the Structure-based Design of Anti-Protozoan Agents

Gordon¹,

Fishwick²,

McPhillie

2016

CTMC

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Abstract:Since the recent renaissance of phenotypic screening in the field of protozoan drug discovery, is there still an opportunity for the structure-based design of new anti-protozoan agents? Target-based approaches should be used in parallel to phenotypic screening to strengthen the pipeline of anti-protozoan agents. We give an overview of the protozoan drug discovery landscape highlighting four protein targets of interest: cytochrome bc1, dihydroorotate dehydrogenase, dihydrofolate reductase and calcium-dependent protein kinase 1. We discuss recent structure-based design efforts to inhibit these targets, reviewing their crystal structures and their ability to accommodate potent and selective compounds. Finally, we discuss future opportunities to apply structure-based methods to promising molecular targets within protozoan parasites discovered using chemical genomics.

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Section: Dhodh -Targeting Pyrimidine Biosynthesis Using Structure-basmentioning

confidence: 99%

New Opportunities in the Structure-based Design of Anti-Protozoan Agents

Gordon¹,

Fishwick²,

McPhillie

2016

CTMC

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“…The compounds above were subsequently optimised and a number of novel derivatives having the structure below where synthesised and tested for their ability to inhibit P. falciparum and P. berghei DHODH [122]. The compounds having R = CF 2 CH 3 were found to display the highest inhibitory potency and the DHODH/CF 3 -triazolopyrimidine complex was successfully crystallised confirming that the CF 3 group (and therefore the SF 5 group too) occupy a narrow and hydrophobic pocket of the enzyme.…”

Section: Figurementioning

confidence: 99%

Synthetic chemistry and biological activity of pentafluorosulphanyl (SF5) organic molecules

Zanda

Altomonte

2012

Journal of Fluorine Chemistry

196

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The pentafluorosulfanyl group (SF5) is a highly stable chemical function which has been attracting a great deal of interest owing to its peculiar chemical, structural, physicochemical and biological properties. Progress in the area of SF5-compounds has been somewhat hindered by the lack of straightforward lab-scale synthetic methods for introducing the SF5-group into organic molecules. However, recent synthetic progress, the availability of some SF5-building blocks from commercial suppliers and the discovery of interesting properties of SF5-substituted molecules in materials science, biology and drug discovery are giving new momentum to research in this fascinating area of fluorine chemistry. Synthesis, reactivity and biological properties of SF5-substituted organic molecules are herein reviewed with an emphasis on the work published after year 2000. Object *Cover Letter or Page containing Author DetailsAll of the referees' suggestions have been accepted, with the only exception of Referee's 2 point 5 "Reactions of ArylSF5 systems should be divided into sections …electrophilc substitutions, nucleophilic substitutions, reactions of diazo systems,…" because in that section the chemistry is inherently heterogeneous and we feel that such a subclassification would be very challenging to achieve and would make less homogeneous the discussion of the topic. Molecolare, via Mancinelli 7, 20131 Milano, Italy Synthesis, reactivity and biological properties of SF 5 -substituted organic molecules are reviewed in this article, with an emphasis on the work published in the last decade. *Graphical Abstract -Synopsis Highlights We review the synthesis of SF 5 -compounds, with an emphasis on work published after year 2000.  We review the reactivity of SF 5 -substituted organic molecules.  We review the biological properties of SF 5 -substituted drug candidates. Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK; e-mail: m.zanda@abdn.ac.uk b C.N.R.-Istituto di Chimica del Riconoscimento Molecolare, via Mancinelli 7, 20131 Milano, Italy AbstractThe pentafluorosulfanyl group (SF 5 ) is a highly stable chemical function which has been attracting a great deal of interest owing to its peculiar chemical, structural, physicochemical and biological properties. Progress in the area of SF 5 -compounds has been somewhat hindered by the lack of straightforward lab-scale synthetic methods for introducing the SF 5 -group into organic molecules. However, recent synthetic progress, the availability of some SF 5 -building blocks from commercial suppliers and the discovery of interesting properties of SF 5 -substituted molecules in materials science, biology and drug discovery are giving new momentum to research in this fascinating area of fluorine chemistry. Synthesis, reactivity and biological properties of SF 5 -substituted organic molecules are herein reviewed with an emphasis on the work published after year 2000.

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“…see Refs. [7][8][9][10][11][12]. The challenge to develop selective agents with targeted approaches has been a formidable obstacle to overcome in bringing such agents to the clinic.…”

mentioning

confidence: 99%

“…Although elements of cell division have been and continue to be probed for antimalarial potential, including DNA replication (10,11,15,16) and microtubule assembly and function (17)(18)(19), specific mitotic targets have not been validated in Plasmodium heretofore. The essential and conserved roles of mitotic enzymes in all eukaryotes argue for the directed development of this class of novel antimalarial candidates.…”

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confidence: 99%

Small Molecule Screen for Candidate Antimalarials Targeting Plasmodium Kinesin-5

Liu

Richard

Kim

et al. 2014

Journal of Biological Chemistry

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Background:The genome of the major malaria parasites encodes a single Kinesin-5 homolog. Results: MMV666693 is a selective allosteric inhibitor of Plasmodium Kinesin-5. Conclusion: Plasmodium Kinesin-5 is druggable and susceptible to allosteric inhibition. Significance: This is the first demonstration of allosteric control of a non-human Kinesin-5 by a small chemical and opens the door to new antimalarials.

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Structure-Guided Lead Optimization of Triazolopyrimidine-Ring Substituents Identifies Potent Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors with Clinical Candidate Potential

Cited by 260 publications

References 43 publications

New Opportunities in the Structure-based Design of Anti-Protozoan Agents

New Opportunities in the Structure-based Design of Anti-Protozoan Agents

Synthetic chemistry and biological activity of pentafluorosulphanyl (SF5) organic molecules

Small Molecule Screen for Candidate Antimalarials Targeting Plasmodium Kinesin-5

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