Synthesis and SAR of 2,3-diarylpyrrole inhibitors of parasite cGMP-dependent protein kinase as novel anticoccidial agents

Biftu, Tesfaye; Feng, Danqing; Ponpipom, Mitree M.; Girotra, N. N.; Liang, Gui-Bai; Qian, Xiaoxia; Bugianesi, Rossana; Simeone, Joseph P.; Chang, Linda; Gurnett, Anne; Liberator, Paul; Dulski, Paula M.; Leavitt, Penny; Crumley, Tami; Misura, Andrew S.; Murphy, Terence Patrick; Rattray, Sandra; Samaras, Samantha; Tamas, Tamas; Mathew, John; Brown, C. M.; Thompson, Don; Schmatz, Dennis M.; Fisher, Michael H.; Wyvratt, Matthew J.

doi:10.1016/j.bmcl.2005.04.060

Cited by 50 publications

(30 citation statements)

References 6 publications

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“…Furthermore, compound 212 also displayed the ability to influence the development of T. gondii by altering host cell transcription . SAR extension of this series identified 213 and 214 as compounds with encouraging activity against E. tenella culture and PKG, while MMV688509 ( 215 ) was reported as a synthetic intermediate in the synthesis of various analogues in this class . Compound 212 has also been shown to inhibit infection of mammalian hepatocytes by P. falciparum and growth of Babesia bovis and L. major …”

Section: Cryptosporidiosis and Toxoplasmosismentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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The Pathogen Box is a 400‐strong collection of drug‐like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition to malaria and tuberculosis. This library represents an ensemble of numerous successful drug discovery programmes from around the globe, aimed at providing a powerful resource to stimulate open source drug discovery for diseases threatening the most vulnerable communities in the world. This review seeks to provide an in‐depth analysis of the literature pertaining to the compounds in the Pathogen Box, including structure–activity relationship highlights, mechanisms of action, related compounds with reported activity against different diseases, and, where appropriate, discussion on the known and putative targets of compounds, thereby providing context and increasing the accessibility of the Pathogen Box to the drug discovery community.

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Section: Cryptosporidiosis and Toxoplasmosismentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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“…It was also derived from a PKG inhibitor program in Eimeria tenella where several core heterocycles and substitution patterns were investigated and in vivo efficacy was shown. 73 One of these compounds, compound 15 ( Figure 7 ), was further evaluated against Plasmodia . 74 Compound 15 showed an IC 50 of 3.5 nM against recombinant Pf PKG, similar to the native strain.…”

Section: Agcmentioning

confidence: 99%

Plasmodial Kinase Inhibitors: License to Cure?

et al. 2018

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Advances in the genetics, function, and stage-specificity of Plasmodium kinases has driven robust efforts to identify targets for the design of antimalarial therapies. Reverse genomics following phenotypic screening against Plasmodia or related parasites has uncovered vulnerable kinase targets including PI4K, PKG, and GSK-3, an approach bolstered by access to human disease-directed kinase libraries. Alternatively, screening compound libraries against Plasmodium kinases has successfully led to inhibitors with antiplasmodial activity. As with other therapeutic areas, optimizing compound ADMET and PK properties in parallel with target inhibitory potency and whole cell activity becomes paramount toward advancing compounds as clinical candidates. These and other considerations will be discussed in the context of progress achieved toward deriving important, novel mode-of-action kinase-inhibiting antimalarial medicines.

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“…In addition to their known activity against p38 MAPKs, the tri-substituted pyrroles have previously been shown to have anti-parasitic activity against Apicomplexan parasites both in vitro and in vivo . However, the molecular target in these organisms was determined not to be a p38 MAPK homologue, but a parasite protein kinase G (PKG) homologue (Biftu et al, 2005). Similarity modeling of the PKG catalytic site using the crystal structure of mammalian p38α MAPK demonstrated that these tri-substituted compounds exploit a hydrophobic binding pocket that overlaps the ATP binding site, analogous to known p38 MAPK inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Human p38 mitogen-activated protein kinase inhibitor drugs inhibit Plasmodium falciparum replication

Brumlik

Nkhoma

Kious

et al. 2011

Experimental Parasitology

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We recently demonstrated that human p38 mitogen-activated protein kinase (MAPK) inhibitors reduced in vitro and in vivo replication of the protozoan parasites Toxoplasma gondii and Encephalitozoon cuniculi. In this study, we assessed the efficacy of five p38 MAPK inhibitors to block the replication of Plasmodium falciparum in human erythrocytes cultured ex vivo and demonstrate that the pyridinylimidazole RWJ67657 and the pyrrolobenzimidazole RWJ68198 reduced Plasmodium falciparum replication, yielded trophozoites that were greatly diminished in size at 24 h, and that these two agents interfered with stage differentiation. Interestingly, the chloroquine-resistant strain W2 was significantly more sensitive to these drugs than was the chloroquine-sensitive strain HB3. These results suggest that pyridinylimidazoles and pyrrolobenzimidazoles designed to inhibit human p38 MAPK activation can be developed to treat malaria.

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Synthesis and SAR of 2,3-diarylpyrrole inhibitors of parasite cGMP-dependent protein kinase as novel anticoccidial agents

Cited by 50 publications

References 6 publications

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Plasmodial Kinase Inhibitors: License to Cure?

Human p38 mitogen-activated protein kinase inhibitor drugs inhibit Plasmodium falciparum replication

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