Synthesis of brequinar analogue inhibitors of malaria parasite dihydroorotate dehydrogenase

Boa, Andrew N.; Canavan, Shane P; Hirst, Paul R.; Ramsey, Christopher; Stead, Andrew M W; McConkey, Glenn A.

doi:10.1016/j.bmc.2005.01.017

Cited by 75 publications

(36 citation statements)

References 22 publications

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“…This flexibility is likely to underlie the finding that multiple inhibitor series have been reported for PfDHODH that sample diverse chemical space (17,18,(21)(22)(23)(24). Although the triazolopyrimidine derivatives interact with the Pfnaphthyl pocket, other identified inhibitors are likely to bind to the PfA77 phenyl pocket, explaining how the enzyme can accommodate these wide ranging scaffolds.…”

Section: Discussionmentioning

confidence: 99%

“…This has led to a substantial effort to target PfDHODH for drug discovery programs and to the identification of diverse scaffolds showing species-selective inhibition of the enzyme (17,18,(21)(22)(23)(24). The prior structure of PfDHODH complexed to A77 1726 (14), a hDHODH-specific inhibitor with poor affinity for PfDHODH (19), neither explains the ability of PfDHODH to bind the array of identified inhibitors nor provides an understanding of the developing SAR for the triazolopyrimidine-based inhibitor series.…”

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confidence: 99%

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Structural Plasticity of Malaria Dihydroorotate Dehydrogenase Allows Selective Binding of Diverse Chemical Scaffolds

Deng

Gujjar

Mazouni

et al. 2009

Journal of Biological Chemistry

116

214

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Malaria remains a major global health burden and current drug therapies are compromised by resistance. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) was validated as a new drug target through the identification of potent and selective triazolopyrimidine-based DHODH inhibitors with anti-malarial activity in vivo. Here we report x-ray structure determination of PfDHODH bound to three inhibitors from this series, representing the first of the enzyme bound to malaria specific inhibitors. We demonstrate that conformational flexibility results in an unexpected binding mode identifying a new hydrophobic pocket on the enzyme. Importantly this plasticity allows PfDHODH to bind inhibitors from different chemical classes and to accommodate inhibitor modifications during lead optimization, increasing the value of PfDHODH as a drug target. A second discovery, based on small molecule crystallography, is that the triazolopyrimidines populate a resonance form that promotes charge separation. These intrinsic dipoles allow formation of energetically favorable H-bond interactions with the enzyme. The importance of delocalization to binding affinity was supported by site-directed mutagenesis and the demonstration that triazolopyrimidine analogs that lack this intrinsic dipole are inactive. Finally, the PfDHODH-triazolopyrimidine bound structures provide considerable new insight into speciesselective inhibitor binding in this enzyme family. Together, these studies will directly impact efforts to exploit PfDHODH for the development of anti-malarial chemotherapy.The human malaria parasite is endemic in 87 countries putting 2.5 billion people in the poorest nations of the tropics at risk for the disease (1, 2). Despite intensive efforts to control malaria through combination drug therapy and insect control programs, malaria remains one of the largest global health problems. The most severe form of the disease is caused by Plasmodium falciparum, which kills 1-2 million people yearly, primarily children and pregnant woman. Effective vaccines have not been developed, and chemotherapy remains the mainstay of both treatment and prevention of the disease. Unfortunately widespread drug resistance to almost every known antimalarial agent has compromised the effectiveness of malaria control programs (3). The introduction of artemisinin combination chemotherapy has provided new treatment options to combat drug-resistant parasites (4). However, recent reports by the World Health Organization suggest that resistance to artemisinin is developing along the Thai-Cambodian border, underscoring the need for a continual pipeline of new drug development to combat this disease.The malaria parasite relies exclusively on de novo pyrimidine biosynthesis to supply precursors for DNA and RNA biosynthesis (5, 6). In contrast, the human host cells contain the enzymatic machinery for both de novo pyrimidine biosynthesis and for salvage of preformed pyrimidine bases and nucleosides. The lack of a redundant mechanism to acquire pyrimidines in malaria...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Structural Plasticity of Malaria Dihydroorotate Dehydrogenase Allows Selective Binding of Diverse Chemical Scaffolds

Deng

Gujjar

Mazouni

et al. 2009

Journal of Biological Chemistry

116

214

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“…The quinoline ring occurs in various natural products and represents a key motif in medicinal chemistry [9][10][11][12], and its derivatives, quinoline-4-carboxylic acids, are a group of compounds associated with different biological activities, such asantiviral [13], anti-inflammatory [14], antimicrobial [15], anti-atherothrombosis [16], antiemetic [17], anxiolytic [18], antimalarial and antileishmanial [19]. Although quinoline-4-carboxylic acid derivatives exhibit various bioactivities, the research of new quinoline-4-carboxylic acid-based antibacterial drugs has developed slowly.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Antibacterial Evaluation of Some New 2-Phenyl-quinoline-4-carboxylic Acid Derivatives

et al. 2016

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A series of new 2-phenyl-quinoline-4-carboxylic acid derivatives was synthesized starting from aniline, 2-nitrobenzaldehyde, pyruvic acid followed by Doebner reaction, amidation, reduction, acylation and amination. All of the newly-synthesized compounds were characterized by 1 H-NMR, 13 C-NMR and HRMS. The antibacterial activities of these compounds against Gram-negative (Escherichia coli, Pseudomonas aeruginosa) and Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis), as well as one strain of methicillin-resistant Staphylococcus aureus (MRSA) bacteria were evaluated by the agar diffusion method (zone of inhibition) and a broth dilution method (minimum inhibitory concentration (MIC)), and their structure-activity relationships were obtained and discussed. The results revealed that some compounds displayed good antibacterial activity against Staphylococcus aureus, and Compounds 5a 4 and 5a 7 showed the best inhibition with an MIC value of 64 µg/mL against Staphylococcus aureus and with an MIC value of 128 µg/mL against Escherichia coli, respectively. The results of the MTT assay illustrated the low cytotoxicity of Compound 5a 4 .

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“…The efficacy of BQR against graft rejection has been investigated extensively in preclinical models (47)(48)(49), and LFM has been proposed as an off-label immunosuppressive therapy in bone marrow (11) and renal (50) transplantation. In addition, DHODH inhibitors have been explored as treatments of other diseases, including malaria, autoimmune and inflammatory dis- eases, cancer, rheumatoid arthritis, and psoriasis (51)(52)(53)(54)(55). Given the bifunctional antiviral and immunosuppressive effects of BQR and LFM, these regimens may hold the potential to treat HEVinfected organ recipients.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between Nucleotide Synthesis Pathways with Cellular Immunity in Constraining Hepatitis E Virus Replication

Wang¹,

Wang²,

Xu³

et al. 2016

Journal of Hepatology

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Synthesis of brequinar analogue inhibitors of malaria parasite dihydroorotate dehydrogenase

Cited by 75 publications

References 22 publications

Structural Plasticity of Malaria Dihydroorotate Dehydrogenase Allows Selective Binding of Diverse Chemical Scaffolds

Structural Plasticity of Malaria Dihydroorotate Dehydrogenase Allows Selective Binding of Diverse Chemical Scaffolds

Design, Synthesis and Antibacterial Evaluation of Some New 2-Phenyl-quinoline-4-carboxylic Acid Derivatives

Crosstalk between Nucleotide Synthesis Pathways with Cellular Immunity in Constraining Hepatitis E Virus Replication

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