Characterization of Competitive Inhibitors of <i>Plasmodium falciparum</i> cGMP‐Dependent Protein Kinase**

Eck, Tyler; Souza, Márcia Regina de; Delvillar, Melvin; Ashraf, Kutub; Bheemanaboina, Rammohan R. Yadav; Chakrasali, R. T.; Kreiss, Tamara; Siekierka, John; Rotella, David P.; Bhanot, Purnima; Goodey, Nina M.

doi:10.1002/cbic.202100704

Cited by 3 publications

(17 citation statements)

References 29 publications

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“…Compounds were tested in the PbLuc-HepG2 model as previously described. 23 Briefly, HepG2 cells were cultured at 7 °C, 5% CO 2 in Dulbecco's Modified Eagle Medium (DMEM) supplemented with L-glutamine (Gibco), 10% heat-inactivated fetal bovine serum (FBS) (v/v) (Sigma-Aldrich), and 1% penicillin-streptomycin (Thermo Fisher Scientific). Cells (3 × 10 4 cells per well) were seeded in 96-well microplates (flat bottom, uClear, white; Greiner Bio-one, ref# 655098) for 24 h after which test compounds at the appropriate concentrations, DMSO (0.4%).…”

Section: Tert-butyl (3s4s)-4-[5-(4-fluorophenyl)-4-(pyridin-4-yl)-1h-...mentioning

confidence: 99%

“…Growth inhibition assays were performed as previously described. 23 Parasites were grown in RPMI 1640 medium (Sigma-Aldrich, St. Louis, MO, U.S.A.) supplemented with 5 mg/mL Albumax (Gibco), 50 μg/mL hypoxanthine (Sigma-Aldrich), 2 mg/mL Na 2 CO 3 (Sigma-Aldrich), 25 mM HEPES, and 50 μg/mL gentamicin (Gibco). The asexual blood stage growth assay was initiated with cultures with >80% ring stage parasites.…”

Section: Tert-butyl (3s4s)-4-[5-(4-fluorophenyl)-4-(pyridin-4-yl)-1h-...mentioning

confidence: 99%

“…A second purification by silica gel chromatography (8% MeOH/CHCl 3 with 0.25% NH 3 ) afforded 5-(4-fluorophenyl)-2-(1-methylpiperidin-4-yl)-4-(pyridin-4yl)-1H-pyrrole-3-carbonitrile (23-fb) (52 mg, 54% yield, 97% purity by LC-MS) as a crystalline yellow solid. 1 (23). Compound 23-fb was dissolved in a 1:1 mixture of CH 2 Cl 2 /MeOH.…”

Section: Synthesis Of Final Compound 23 Following the Route Outlined ...mentioning

confidence: 99%

“…Activity against sporozoites was determined using HepG2 infection of luciferase-expressing P. berghei (PbLuc). 23 Cellular specificity of compounds for PfPKG was determined by testing against P. falciparum expressing a "gatekeeper" mutant of PfPKG (T 618 Q). 15 The longer side chain of Gln compared to Thr prevents access of compounds into their binding pocket, blocking inhibition of PfPKG and hence decreasing compound activity against "gatekeeper" mutant parasites relative to WT.…”

Section: ■ Introductionmentioning

confidence: 99%

“…In order to obtain a preliminary assessment of safety, compounds were assayed for cytotoxicity against HepG2 cells. 23 Compounds 38 and 39 were shown to have significantly improved cellular activity although their in vitro potencies against PfPKG are similar to 1. Importantly, the in vivo specificity of these compounds for PfPKG was improved since their EC 50 values against T 618 Q parasites were >20-fold higher than against 3D7.…”

Section: ■ Introductionmentioning

confidence: 99%

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Structure–Activity Relationship of a Pyrrole Based Series of PfPKG Inhibitors as Anti-Malarials

Gilleran,

Ashraf,

Delvillar

et al. 2024

J. Med. Chem.

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Controlling malaria requires new drugs against Plasmodium falciparum. The P. falciparum cGMP-dependent protein kinase (PfPKG) is a validated target whose inhibitors could block multiple steps of the parasite's life cycle. We defined the structure− activity relationship (SAR) of a pyrrole series for PfPKG inhibition. Key pharmacophores were modified to enable full exploration of chemical diversity and to gain knowledge about an ideal core scaffold. In vitro potency against recombinant PfPKG and human PKG were used to determine compound selectivity for the parasite enzyme. P. berghei sporozoites and P. falciparum asexual blood stages were used to assay multistage antiparasitic activity. Cellular specificity of compounds was evaluated using transgenic parasites expressing PfPKG carrying a substituted "gatekeeper" residue. The structure of PfPKG bound to an inhibitor was solved, and modeling using this structure together with computational tools was utilized to understand SAR and establish a rational strategy for subsequent lead optimization.

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Section: Tert-butyl (3s4s)-4-[5-(4-fluorophenyl)-4-(pyridin-4-yl)-1h-...mentioning

confidence: 99%

Section: Tert-butyl (3s4s)-4-[5-(4-fluorophenyl)-4-(pyridin-4-yl)-1h-...mentioning

confidence: 99%

Section: Synthesis Of Final Compound 23 Following the Route Outlined ...mentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Structure–Activity Relationship of a Pyrrole Based Series of PfPKG Inhibitors as Anti-Malarials

Gilleran,

Ashraf,

Delvillar

et al. 2024

J. Med. Chem.

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Screening Carica Papaya Compounds as an Antimalarial Agent: In Silico Study

2023

TJNPR

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In the plasmodium synthesis process, the chain cleavage leads to a lack of energy required for metabolism, which ultimately leads to its death. This study aims to identify potential candidate compounds from C. papaya, which can be further explored in the search for new antimalarial drugs. Material and Methods MaterialsThe materials used in this study include a Lenovo laptop with 4GB RAM, an Intel Core i3 processor, and software such as Windows 10 operating system, Pyrx, Biovia (Discovery Studio 2021 client), PDB (Protein Data Bank used for searching for plasmodium proteins), and secondary metabolites obtained from papaya leaves, which were downloaded from Pubchem website in the PDB format. Preparation of Ligand CompoundsTo obtain the structure of a compound, the Pubchem program on the website pubchem.ncbi.nlm.nih.gov can be used. 8 This website provides information, including Simplified Molecular Input Life Entry System (SMILE). The downloaded compound structure should be in 3D format with SDF. After obtaining the SMILES from the C. papaya compound can be copied and pasted into the PASS Test. The PASS test can be performed on the way2drug.com website by entering the SMILES in the provided box and clicking the "Get prediction" button to view the prediction results. To see the predicted biological activity of a compound, click on the "Pa>0.7" button. A pre-ADMET test can also be performed on the https://PkCSM.com/ website by entering the SMILES in the box and clicking the black pre-ADMEt button. Preparation of Proteins Related to MalariaTo prepare the malaria protein for docking, the protein is obtained from the PDB database through the website www.rcsb.org. When selecting the protein, it is essential to consider the resolution limit of 1-3, with a lower limit preferred to avoid missing residues.

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Marinoquinolinas como uma nova classe de compostos antiplasmodiais

Santos Barbosa

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Characterization of Competitive Inhibitors of Plasmodium falciparum cGMP‐Dependent Protein Kinase**

Cited by 3 publications

References 29 publications

Structure–Activity Relationship of a Pyrrole Based Series of PfPKG Inhibitors as Anti-Malarials

Structure–Activity Relationship of a Pyrrole Based Series of PfPKG Inhibitors as Anti-Malarials

Screening Carica Papaya Compounds as an Antimalarial Agent: In Silico Study

Marinoquinolinas como uma nova classe de compostos antiplasmodiais

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