Chemical probes of a trisubstituted pyrrole to identify its protein target(s) in Plasmodium sporozoites

Towle, Tyrell R.; Chang, Isabel; Kerns, Robert J.; Bhanot, Purnima

doi:10.1016/j.bmcl.2013.01.010

Cited by 9 publications

(6 citation statements)

References 7 publications

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“…Compound 1 and 3MBP-PP1 were prepared according to literature procedures (Biftu et al, 2005;Lourido et al, 2010;Towle, Chang, Kerns, & Bhanot, 2013).…”

Section: Compound Synthesismentioning

confidence: 99%

Analysis of Ca ² ⁺ mediated signaling regulating Toxoplasma infectivity reveals complex relationships between key molecules

Stewart

Whitehead

Nijagal

et al. 2017

Cellular Microbiology

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Host cell invasion, exit and parasite dissemination is critical to the pathogenesis of apicomplexan parasites such as Toxoplasma gondii and Plasmodium spp. These processes are regulated by intracellular Ca signaling although the temporal dynamics of Ca fluxes and down-stream second messenger pathways are poorly understood. Here, we use a genetically encoded biosensor, GFP-Calmodulin-M13-6 (GCaMP6), to capture Ca flux in live Toxoplasma and investigate the role of Ca signaling in egress and motility. Our analysis determines how environmental cues and signal activation influence intracellular Ca flux, allowing placement of effector molecules within this pathway. Importantly, we have identified key interrelationships between cGMP and Ca signaling that are required for activation of egress and motility. Furthermore, we extend this analysis to show that the Ca Dependent Protein Kinases-TgCDPK1 and TgCDPK3-play a role in signal quenching before egress. This work highlights the interrelationships of second messenger pathways of Toxoplasma in space and time, which is likely required for pathogenesis of all apicomplexan species.

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“…Compound 1 and 3MBP-PP1 were prepared according to literature procedures (Biftu et al, 2005;Lourido et al, 2010;Towle, Chang, Kerns, & Bhanot, 2013).…”

Section: Compound Synthesismentioning

confidence: 99%

Analysis of Ca ² ⁺ mediated signaling regulating Toxoplasma infectivity reveals complex relationships between key molecules

Stewart

Whitehead

Nijagal

et al. 2017

Cellular Microbiology

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“…[143] The compound 89 shows good antimalarial activity against Plasmodium berghei sporozoites and human hepatoma cell line HepG2 with the IC 50 value of 10 μM. [144] The compound 90 and 91 shows promising antimalarial activity against W2(CQÀ R) strain of P. falciparum with the IC 50 value of 49.6 � 5.2 nM (90), 59.0 � 16.6 nM (91A) and 65.8 � 12.7 nM (91B). The most lipophilic substances, were most effective against the W2 (CQÀ R) strain of P. falciparum.…”

Section: Antimalarial Activitymentioning

confidence: 99%

Pyrrole: A Decisive Scaffold for the Development of Therapeutic Agents and Structure‐Activity Relationship

Ganesh,

Raj,

Aruchamy

et al. 2023

ChemMedChem

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An overview of pyrroles as distinct scaffolds with therapeutic potential and the significance of pyrrole derivatives for drug development are provided in this article. It lists instances of naturally occurring pyrrole‐containing compounds and describes the sources of pyrroles in nature, including plants and microbes. It also explains the many conventional and modern synthetic methods used to produce pyrroles. The key topics are the biological characteristics, pharmacological behavior, and functional alterations displayed by pyrrole derivatives. It also details how pyrroles are used to treat infectious diseases. It describes infectious disorders resistant to standard treatments and discusses the function of compounds containing pyrroles in combating infectious diseases. Furthermore, the review covers the uses of pyrrole derivatives in treating non‐infectious diseases and resistance mechanisms in non‐infectious illnesses like cancer, diabetes, and Alzheimer's and Parkinson's diseases. The important discoveries and probable avenues for pyrrole research are finally summarized, along with their significance for medicinal chemists and drug development. A reference from the last two decades is included in this review.

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“…The aqueous phase was extracted with EtOAc (3 x) and the combined organic phase was dried over sodium sulfate and concentrated to give crude 31 (1.3 g) which was taken onto the next step without any purification. (32). Compound 32fb was dissolved in a 1:1 mixture of CH 2 Cl 2 /MeOH.…”

Section: -(5-(4-fluorophenyl)-2-(1-methylpiperidin-4-yl)-4-(pyridin-4...mentioning

confidence: 99%

“…R 2 − In Vitro SAR Trend. In the investigation of position R 2 , addition of anything hydrophilic on the pyrrole ring, such as the carboxamide (26), ethyl ester (32), secondary alcohol (27), and dimethylamine (28) resulted in poor activity (Tables 2 and 3). However, interestingly, nitrile substitution seemed to give a boost in activity, perhaps indicating a limited tolerance for smaller groups at this position.…”

Section: ■ Introductionmentioning

confidence: 99%

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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Chemical probes of a trisubstituted pyrrole to identify its protein target(s) in Plasmodium sporozoites

Cited by 9 publications

References 7 publications

Analysis of Ca ² ⁺ mediated signaling regulating Toxoplasma infectivity reveals complex relationships between key molecules

Analysis of Ca ² ⁺ mediated signaling regulating Toxoplasma infectivity reveals complex relationships between key molecules

Pyrrole: A Decisive Scaffold for the Development of Therapeutic Agents and Structure‐Activity Relationship

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

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Chemical probes of a trisubstituted pyrrole to identify its protein target(s) in Plasmodium sporozoites

Cited by 9 publications

References 7 publications

Analysis of Ca 2 + mediated signaling regulating Toxoplasma infectivity reveals complex relationships between key molecules

Analysis of Ca 2 + mediated signaling regulating Toxoplasma infectivity reveals complex relationships between key molecules

Pyrrole: A Decisive Scaffold for the Development of Therapeutic Agents and Structure‐Activity Relationship

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

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Analysis of Ca ² ⁺ mediated signaling regulating Toxoplasma infectivity reveals complex relationships between key molecules

Analysis of Ca ² ⁺ mediated signaling regulating Toxoplasma infectivity reveals complex relationships between key molecules