Hydroxyazole scaffold-based Plasmodium falciparum dihydroorotate dehydrogenase inhibitors: Synthesis, biological evaluation and X-ray structural studies

Pippione, Agnese Chiara; Sainas, Stefano; Goyal, Parveen; Fritzson, Ingela; Cassiano, Gustavo Capatti; Giraudo, Alessandro; Giorgis, Marta; Tavella, Tatyana Almeida; Bagnati, Renzo; Rolando, Barbara; Caing-Carlsson, Rhawnie; Costa, Fábio Trindade Maranhão; Andrade, Carolina Horta; Al-Karadaghi, Salam; Boschi, Donatella; Friemann, Rosmarie; Lolli, Marco Lucio

doi:10.1016/j.ejmech.2018.11.044

Cited by 25 publications

(19 citation statements)

References 41 publications

(53 reference statements)

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“…A dedicated synthetic scheme was applied for the synthesis of compound 4 ; the hydroxyl group of 18 was O-protected with a Boc group to afford 40 . 39 By use of lithium hexamethyldisilylazide on 40 , the pyrazolo[1,5- a ]pyridine moiety was selectively deprotonated on the 7 position. Subsequently, quenching the lithium salt of 40 with hexachloroethane, which was used as an electrophile source of Cl + , afforded compound 41 in a good yield.…”

Section: Chemistrymentioning

confidence: 99%

Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5-a]pyridine Scaffold: SAR of the Biphenyl Moiety

et al. 2021

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The connection with acute myelogenous leukemia (AML) of dihydroorotate dehydrogenase ( h DHODH), a key enzyme in pyrimidine biosynthesis, has attracted significant interest from pharma as a possible AML therapeutic target. We recently discovered compound 1 , a potent h DHODH inhibitor (IC 50 = 1.2 nM), able to induce myeloid differentiation in AML cell lines (THP1) in the low nM range (EC 50 = 32.8 nM) superior to brequinar’s phase I/II clinical trial (EC 50 = 265 nM). Herein, we investigate the 1 drug-like properties observing good metabolic stability and no toxic profile when administered at doses of 10 and 25 mg/kg every 3 days for 5 weeks (Balb/c mice). Moreover, in order to identify a backup compound, we investigate the SAR of this class of compounds. Inside the series, 17 is characterized by higher potency in inducing myeloid differentiation (EC 50 = 17.3 nM), strong proapoptotic properties (EC 50 = 20.2 nM), and low cytotoxicity toward non-AML cells (EC 30 (Jurkat) > 100 μM).

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Section: Chemistrymentioning

confidence: 99%

Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5-a]pyridine Scaffold: SAR of the Biphenyl Moiety

et al. 2021

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“…We retrieved all the crystallographic structures from the Protein Data Bank (PDB) (Berman et al, 2000). In doing so, we considered the PDB IDs 2BJU (Prade et al, 2005), 6I55 (Pippione et al, 2019), 1ME3 (Huang et al, 2003), and 4KY4 (Zaware et al, 2013) for the proteins plasmepsin 2 (P. falciparum), dihydroorotate dehydrogenase (P. falciparum), cruzipain (T. cruzi), and dihydrofolate reductase (T. gondii), respectively. These PDB files contained the aforementioned proteins complexed with their corresponding reference ligands.…”

Section: Molecular Dockingmentioning

confidence: 99%

QSAR Modeling for Multi-Target Drug Discovery: Designing Simultaneous Inhibitors of Proteins in Diverse Pathogenic Parasites

et al. 2021

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Parasitic diseases remain as unresolved health issues worldwide. While for some parasites the treatments involve drug combinations with serious side effects, for others, chemical therapies are inefficient due to the emergence of drug resistance. This urges the search for novel antiparasitic agents able to act through multiple mechanisms of action. Here, we report the first multi-target model based on quantitative structure-activity relationships and a multilayer perceptron neural network (mt-QSAR-MLP) to virtually design and predict versatile inhibitors of proteins involved in the survival and/or infectivity of different pathogenic parasites. The mt-QSAR-MLP model exhibited high accuracy (>80%) in both training and test sets for the classification/prediction of protein inhibitors. Several fragments were directly extracted from the physicochemical and structural interpretations of the molecular descriptors in the mt-QSAR-MLP model. Such interpretations enabled the generation of four molecules that were predicted as multi-target inhibitors against at least three of the five parasitic proteins reported here with two of the molecules being predicted to inhibit all the proteins. Docking calculations converged with the mt-QSAR-MLP model regarding the multi-target profile of the designed molecules. The designed molecules exhibited drug-like properties, complying with Lipinski’s rule of five, as well as Ghose’s filter and Veber’s guidelines.

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“…Pippione et al, developed two new hydroxylated-azole-based scaffolds that show micromolar activity against PfDHODH and P. falciparum-infected erythrocytes, as well as good selectivity versus the human form of the enzyme and mammalian cells [55]. These compounds are interesting both because of the original design approach (the scaffold-hopping strategy was used) [132], and because they are new chemical entities in the field of PfDHODH inhibition.…”

Section: Plasmodiamentioning

confidence: 99%

Dihydroorotate dehydrogenase inhibitors in anti-infective drug research

Boschi

Pippione

Sainas

et al. 2019

European Journal of Medicinal Chemistry

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Pyrimidines are essential for the cell survival and proliferation of living parasitic organisms, such as Helicobacter pylori, Plasmodium falciparum and Schistosoma mansoni, that are able to impact upon human health. Pyrimidine building blocks, in human cells, are synthesised via both de novo biosynthesis and salvage pathways, the latter of which is an effective way of recycling pre-existing nucleotides. As many parasitic organisms lack pyrimidine salvage pathways for pyrimidine nucleotides, blocking de novo biosynthesis is seen as an effective therapeutic means to selectively target the parasite without effecting the human host. Dihydroorotate dehydrogenase (DHODH), which is involved in the de novo biosynthesis of pyrimidines, is a validated target for anti-infective drug research. Recent advances in the DHODH microorganism field are discussed herein, as is the potential for the development of DHODH-targeted therapeutics.

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Hydroxyazole scaffold-based Plasmodium falciparum dihydroorotate dehydrogenase inhibitors: Synthesis, biological evaluation and X-ray structural studies

Cited by 25 publications

References 41 publications

Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5-a]pyridine Scaffold: SAR of the Biphenyl Moiety

Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5-a]pyridine Scaffold: SAR of the Biphenyl Moiety

QSAR Modeling for Multi-Target Drug Discovery: Designing Simultaneous Inhibitors of Proteins in Diverse Pathogenic Parasites

Dihydroorotate dehydrogenase inhibitors in anti-infective drug research

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