Antiplasmodial dihetarylthioethers target the coenzyme A synthesis pathway in Plasmodium falciparum erythrocytic stages.
Thomas Weidner,Leonardo Lucantoni,Abed Nasereddin,Lutz Preu,Peter G. Jones,Ron Dzikowski,Vicky M. Avery,Conrad Kunick +7 more
TLDR
The class of antiplasmodial bishetarylthioethers reported here has been shown to interfere with plas modial coenzyme A synthesis, a mechanism of action not yet exploited for registered anti-malarial drugs.Abstract:
Malaria is a widespread infectious disease that threatens a large proportion of the population in tropical and subtropical areas. Given the emerging resistance against the current standard anti-malaria chemotherapeutics, the development of alternative drugs is urgently needed. New anti-malarials representing chemotypes unrelated to currently used drugs have an increased potential for displaying novel mechanisms of action and thus exhibit low risk of cross-resistance against established drugs. Phenotypic screening of a small library (32 kinase-inhibitor analogs) against Plasmodium falciparum NF54-luc asexual erythrocytic stage parasites identified a diarylthioether structurally unrelated to registered drugs. Hit expansion led to a series in which the most potent congener displayed nanomolar antiparasitic activity (IC50 = 39 nM, 3D7 strain). Structure–activity relationship analysis revealed a thieno[2,3-d]pyrimidine on one side of the thioether linkage as a prerequisite for antiplasmodial activity. Within the series, the oxazole derivative KuWei173 showed high potency (IC50 = 75 nM; 3D7 strain), good solubility in aqueous solvents (1.33 mM), and >100-fold selectivity toward human cell lines. Rescue experiments identified inhibition of the plasmodial coenzyme A synthesis as a possible mode of action for this compound class. The class of antiplasmodial bishetarylthioethers reported here has been shown to interfere with plasmodial coenzyme A synthesis, a mechanism of action not yet exploited for registered anti-malarial drugs. The oxazole congener KuWei173 displays double-digit nanomolar antiplasmodial activity, selectivity against human cell lines, high drug likeness, and thus represents a promising chemical starting point for further drug development.read more
Citations
More filters
Journal ArticleDOI
Fueling Open Innovation for Malaria Transmission-Blocking Drugs: Hundreds of Molecules Targeting Early Parasite Mosquito Stages.
Michael J. Delves,Michael J. Delves,M. Jose Lafuente-Monasterio,Leanna M. Upton,Andrea Ruecker,Andrea Ruecker,Andrea Ruecker,Didier Leroy,Francisco-Javier Gamo,Robert E. Sinden +9 more
TL;DR: The P. berghei ookinete development assay is an excellent high throughput assay for efficiently identifying antimalarial molecules targeting early mosquito stage parasite development and identified distinct, but partially overlapping subsets of transmission-blocking molecules.
Journal ArticleDOI
Structure-activity relationships in a series of antiplasmodial thieno[2,3-b]pyridines.
Andreas Masch,Abed Nasereddin,Arne Alder,Megan J. Bird,Sandra I. Schweda,Lutz Preu,Christian Doerig,Christian Doerig,Ron Dzikowski,Tim W. Gilberger,Conrad Kunick +10 more
TL;DR: The attachment of alkylamino side chains leads to the improvement of antiplasmodial activity and aqueous solubility of selective PfGSK-inhibitors belonging to the class of 4-phenylthieno[2,3-b]pyridines, which shows axial chirality, a feature of high impact for biological activity.
Journal ArticleDOI
Developments in drug design strategies for bromodomain protein inhibitors to target Plasmodium falciparum parasites
Hanh H. T. Nguyen,Hanh H. T. Nguyen,Lee M. Yeoh,Scott A. Chisholm,Michael F. Duffy,Michael F. Duffy +5 more
TL;DR: A key task for the field is to generate parasite assays to validate the hit compounds’ specificity for PfBDPs, which could prove to be promising targets for novel antimalarials, which are urgently required to address increasing drug resistance.
Journal ArticleDOI
Characterization of Plasmodium falciparum Pantothenate Kinase and Identification of Its Inhibitors From Natural Products.
Arif Nurkanto,Ghulam Jeelani,Herbert J. Santos,Yulia Rahmawati,Mihoko Mori,Yumi Nakamura,Kana Goto,Yoko Saikawa,Takeshi Annoura,Yuzuru Tozawa,Takaya Sakura,Daniel Ken Inaoka,Kazuro Shiomi,Tomoyoshi Nozaki +13 more
TL;DR: In this article, the first and rate-limiting reaction in the CoA biosynthetic pathway is catalyzed by two putative pantothenate kinases (PfPanK1 and 2) in this parasite.
Journal ArticleDOI
A novel heteromeric pantothenate kinase complex in apicomplexan parasites.
TL;DR: In this article, the PanKs in two pathogenic apicomplexan parasites, Plasmodium falciparum and Toxoplasma gondii, were investigated.
References
More filters
Journal ArticleDOI
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
TL;DR: Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described in this article, where the rule of 5 is used to predict poor absorption or permeability when there are more than 5 H-bond donors, 10 Hbond acceptors, and the calculated Log P (CLogP) is greater than 5 (or MlogP > 415).
Journal ArticleDOI
Artemisinin Resistance in Plasmodium falciparum Malaria
Arjen M. Dondorp,François Nosten,Poravuth Yi,Debashish Das,Aung Phae Phyo,Joel Tarning,Khin Maung Lwin,Frédéric Ariey,Warunee Hanpithakpong,Sue J. Lee,Pascal Ringwald,Kamolrat Silamut,Mallika Imwong,Kesinee Chotivanich,Pharath Lim,Trent Herdman,Sen Sam An,Shunmay Yeung,Pratap Singhasivanon,Nicholas P. J. Day,Niklas Lindegardh,Duong Socheat,Nicholas J. White +22 more
TL;DR: The overall median clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours in Wang Pha (P<0.001) in each of the two locations as discussed by the authors.
Journal ArticleDOI
Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of Drug transport properties
TL;DR: The method, termed topological PSA (TPSA), provides results which are practically identical with the 3D PSA, while the computation speed is 2-3 orders of magnitude faster and may be used for fast bioavailability screening of virtual libraries having millions of molecules.
Journal ArticleDOI
Thousands of chemical starting points for antimalarial lead identification
Francisco-Javier Gamo,Laura M. Sanz,J. Vidal,Cristina de Cozar,Emilio Alvarez,J.L. Lavandera,Dana E. Vanderwall,Darren V. S. Green,Vinod Kumar,Samiul Hasan,James R. Brown,Catherine E. Peishoff,Lon R. Cardon,Jose F. Garcia-Bustos +13 more
TL;DR: Chemical structures and associated data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host–pathogen interaction related targets.
Journal ArticleDOI
Prediction of Physicochemical Parameters by Atomic Contributions
TL;DR: A new atom type classification system for use in atom-based calculation of partition coefficient (log P) and molar refractivity (MR) designed in part to address published concerns of previous atomic methods is presented.
Related Papers (5)
A novel approach for the discovery of chemically diverse anti-malarial compounds targeting the Plasmodium falciparum Coenzyme A synthesis pathway
Sabine Fletcher,Vicky M. Avery +1 more
QSAR-driven design and discovery of novel compounds with antiplasmodial and transmission blocking activities
Cyclopropyl Carboxamides, a Chemically Novel Class of Antimalarial Agents Identified in a Phenotypic Screen
Laura M. Sanz,M. Belen Jiménez-Díaz,Benigno Crespo,Cristina De-Cozar,M. Jesus Almela,Iñigo Angulo-Barturen,Pablo Castañeda,Javier Ibáñez,Esther Fernández,Santiago Ferrer,Esperanza Herreros,Sonia Lozano,María Santos Martínez,Lourdes Rueda,Jeremy N. Burrows,Jose F. Garcia-Bustos,Francisco-Javier Gamo +16 more