Publications by authors named "Kerstin Gagaring"

18 Publications

  • Page 1 of 1

Antimalarial Peptide and Polyketide Natural Products from the Fijian Marine Cyanobacterium .

Mar Drugs 2020 03 18;18(3). Epub 2020 Mar 18.

School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA.

A new cyclic peptide, kakeromamide B (), and previously described cytotoxic cyanobacterial natural products ulongamide A (), lyngbyabellin A (), 18-lyngbyaloside C (), and lyngbyaloside () were identified from an antimalarial extract of the Fijian marine cyanobacterium . Compounds and exhibited moderate activity against blood-stages with EC values of 0.89 and 0.99 µM, respectively, whereas was more potent with an EC value of 0.15 nM, respectively. Compounds , , and displayed moderate liver-stage antimalarial activity against liver schizonts with EC values of 1.1, 0.71, and 0.45 µM, respectively. The threading-based computational method FINDSITE predicted the binding of and to potentially druggable proteins of , prompting formulation of hypotheses about possible mechanisms of action. Kakeromamide B () was predicted to bind to several actin-like proteins and a sortilin protein suggesting possible interference with parasite invasion of host cells. When 1 was tested in a mammalian actin polymerization assay, it stimulated actin polymerization in a dose-dependent manner, suggesting that 1 does, in fact, interact with actin.
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http://dx.doi.org/10.3390/md18030167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142784PMC
March 2020

Probing the Open Global Health Chemical Diversity Library for Multistage-Active Starting Points for Next-Generation Antimalarials.

ACS Infect Dis 2020 04 4;6(4):613-628. Epub 2020 Mar 4.

School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.

Most phenotypic screens aiming to discover new antimalarial chemotypes begin with low cost, high-throughput tests against the asexual blood stage (ABS) of the malaria parasite life cycle. Compounds active against the ABS are then sequentially tested in more difficult assays that predict whether a compound has other beneficial attributes. Although applying this strategy to new chemical libraries may yield new leads, repeated iterations may lead to diminishing returns and the rediscovery of chemotypes hitting well-known targets. Here, we adopted a different strategy to find starting points, testing ∼70,000 open source small molecules from the Global Health Chemical Diversity Library for activity against the liver stage, mature sexual stage, and asexual blood stage malaria parasites in parallel. In addition, instead of using an asexual assay that measures accumulated parasite DNA in the presence of compound (SYBR green), a real time luciferase-dependent parasite viability assay was used that distinguishes slow-acting (delayed death) from fast-acting compounds. Among 382 scaffolds with the activity confirmed by dose response (<10 μM), we discovered 68 novel delayed-death, 84 liver stage, and 68 stage V gametocyte inhibitors as well. Although 89% of the evaluated compounds had activity in only a single life cycle stage, we discovered six potent (half-maximal inhibitory concentration of <1 μM) multistage scaffolds, including a novel cytochrome bc1 chemotype. Our data further show the luciferase-based assays have higher sensitivity. Chemoinformatic analysis of positive and negative compounds identified scaffold families with a strong enrichment for activity against specific or multiple stages.
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http://dx.doi.org/10.1021/acsinfecdis.9b00482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155171PMC
April 2020

Peyssonnosides A-B, Unusual Diterpene Glycosides with a Sterically Encumbered Cyclopropane Motif: Structure Elucidation Using an Integrated Spectroscopic and Computational Workflow.

J Org Chem 2019 07 18;84(13):8531-8541. Epub 2019 Jun 18.

Parker H. Petit Institute for Bioengineering and Bioscience , Georgia Institute of Technology , Atlanta , Georgia 30332 , United States.

Two sulfated diterpene glycosides featuring a highly substituted and sterically encumbered cyclopropane ring have been isolated from the marine red alga Peyssonnelia sp. Combination of a wide array of 2D NMR spectroscopic experiments, in a systematic structure elucidation workflow, revealed that peyssonnosides A-B (1-2) represent a new class of diterpene glycosides with a tetracyclo [7.5.0.0.0] tetradecane architecture. A salient feature of this workflow is the unique application of quantitative interproton distances obtained from the rotating frame Overhauser effect spectroscopy (ROESY) NMR experiment, wherein the β-d-glucose moiety of 1 was used as an internal probe to unequivocally determine the absolute configuration, which was also supported by optical rotatory dispersion (ORD). Peyssonnoside A (1) exhibited promising activity against liver stage Plasmodium berghei and moderate antimethicillin-resistant Staphylococcus aureus (MRSA) activity, with no cytotoxicity against human keratinocytes. Additionally, 1 showed strong growth inhibition of the marine fungus Dendryphiella salina indicating an antifungal ecological role in its natural environment. The high natural abundance and novel carbon skeleton of 1 suggests a rare terpene cyclase machinery, exemplifying the chemical diversity in this phylogenetically distinct marine red alga.
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http://dx.doi.org/10.1021/acs.joc.9b00884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614789PMC
July 2019

Discovery of short-course antiwolbachial quinazolines for elimination of filarial worm infections.

Sci Transl Med 2019 05;11(491)

Research Foundation in Tropical Diseases and the Environment, Buea, Cameroon.

Parasitic filarial nematodes cause debilitating infections in people in resource-limited countries. A clinically validated approach to eliminating worms uses a 4- to 6-week course of doxycycline that targets , a bacterial endosymbiont required for worm viability and reproduction. However, the prolonged length of therapy and contraindication in children and pregnant women have slowed adoption of this treatment. Here, we describe discovery and optimization of quinazolines CBR417 and CBR490 that, with a single dose, achieve >99% elimination of in the in vivo filarial infection model. The efficacious quinazoline series was identified by pairing a primary cell-based high-content imaging screen with an orthogonal ex vivo validation assay to rapidly quantify elimination in filarial ovaries. We screened 300,368 small molecules in the primary assay and identified 288 potent and selective hits. Of 134 primary hits tested, only 23.9% were active in the worm-based validation assay, 8 of which contained a quinazoline heterocycle core. Medicinal chemistry optimization generated quinazolines with excellent pharmacokinetic profiles in mice. Potent antiwolbachial activity was confirmed in , , and in vivo preclinical models of filarial disease and in vitro selectivity against (a safety concern in endemic areas). The favorable efficacy and in vitro safety profiles of CBR490 and CBR417 further support these as clinical candidates for treatment of filarial infections.
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http://dx.doi.org/10.1126/scitranslmed.aav3523DOI Listing
May 2019

Modular, stereocontrolled C-H/C-C activation of alkyl carboxylic acids.

Proc Natl Acad Sci U S A 2019 04 17;116(18):8721-8727. Epub 2019 Apr 17.

Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;

The union of two powerful transformations, directed C-H activation and decarboxylative cross-coupling, for the enantioselective synthesis of vicinally functionalized alkyl, carbocyclic, and heterocyclic compounds is described. Starting from simple carboxylic acid building blocks, this modular sequence exploits the residual directing group to access more than 50 scaffolds that would be otherwise extremely difficult to prepare. The tactical use of these two transformations accomplishes a formal vicinal difunctionalization of carbon centers in a way that is modular and thus, amenable to rapid diversity incorporation. A simplification of routes to known preclinical drug candidates is presented along with the rapid diversification of an antimalarial compound series.
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http://dx.doi.org/10.1073/pnas.1903048116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500144PMC
April 2019

Antibacterial Oligomeric Polyphenols from the Green Alga Cladophora socialis.

J Org Chem 2019 05 3;84(9):5035-5045. Epub 2019 Apr 3.

Aquatic Chemical Ecology Center , Georgia Institute of Technology , Atlanta , Georgia 30332 , United States.

A series of oligomeric phenols including the known natural product 3,4,3',4'-tetrahydroxy-1,1'-biphenyl (3), the previously synthesized 2,3,8,9-tetrahydroxybenzo[ c]chromen-6-one (4), and eight new related natural products, cladophorols B-I (5-12), were isolated from the Fijian green alga Cladophora socialis and identified by a combination of NMR spectroscopy, mass spectrometric analysis, and computational modeling using DFT calculations. J-resolved spectroscopy and line width reduction by picric acid addition aided in resolving the heavily overlapped aromatic signals. A panel of Gram-positive and Gram-negative pathogens used to evaluate pharmacological potential led to the determination that cladophorol C (6) exhibits potent antibiotic activity selective toward methicillin-resistant Staphylococcus aureus (MRSA) with an MIC of 1.4 μg/mL. Cladophorols B (5) and D-H (7-11) had more modest but also selective antibiotic potency. Activities of cladophorols A-I (4-12) were also assessed against the asexual blood stages of Plasmodium falciparum and revealed cladophorols A (4) and B (5) to have modest activity with EC values of 0.7 and 1.9 μg/mL, respectively.
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http://dx.doi.org/10.1021/acs.joc.8b03218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503470PMC
May 2019

Open-source discovery of chemical leads for next-generation chemoprotective antimalarials.

Science 2018 12;362(6419)

Center for Tropical and Emerging Global Diseases, University of Georgia, 500 D. W. Brooks Drive, Athens, GA 30602, USA.

To discover leads for next-generation chemoprotective antimalarial drugs, we tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing spp. parasites (681 compounds showed a half-maximal inhibitory concentration of less than 1 micromolar). Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity distinguished compound classes that are likely to provide symptomatic relief by reducing asexual blood-stage parasitemia from those which are likely to only prevent malaria. Target identification by using functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unidentified mechanisms of action.
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http://dx.doi.org/10.1126/science.aat9446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516198PMC
December 2018

High-Throughput Luciferase-Based Assay for the Discovery of Therapeutics That Prevent Malaria.

ACS Infect Dis 2016 Apr 10;2(4):281-293. Epub 2016 Feb 10.

School of Medicine, Department of Pediatrics, Pharmacology & Drug Discovery, University of California, San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.

In order to identify the most attractive starting points for drugs that can be used to prevent malaria, a diverse chemical space comprising tens of thousands to millions of small molecules may need to be examined. Achieving this throughput necessitates the development of efficient ultra-high-throughput screening methods. Here, we report the development and evaluation of a luciferase-based phenotypic screen of malaria exoerythrocytic-stage parasites optimized for a 1536-well format. This assay uses the exoerythrocytic stage of the rodent malaria parasite, , and a human hepatoma cell line. We use this assay to evaluate several biased and unbiased compound libraries, including two small sets of molecules (400 and 89 compounds, respectively) with known activity against malaria erythrocytic-stage parasites and a set of 9886 diversity-oriented synthesis (DOS)-derived compounds. Of the compounds screened, we obtain hit rates of 12-13 and 0.6% in preselected and naïve libraries, respectively, and identify 52 compounds with exoerythrocytic-stage activity less than 1 μM and having minimal host cell toxicity. Our data demonstrate the ability of this method to identify compounds known to have causal prophylactic activity in both human and animal models of malaria, as well as novel compounds, including some exclusively active against parasite exoerythrocytic stages.
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http://dx.doi.org/10.1021/acsinfecdis.5b00143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4890880PMC
April 2016

Mutations in the P-type cation-transporter ATPase 4, PfATP4, mediate resistance to both aminopyrazole and spiroindolone antimalarials.

ACS Chem Biol 2015 Feb 5;10(2):413-20. Epub 2014 Nov 5.

Division of Pharmacology and Drug Discovery, Department of Pediatrics, ‡Division of Infectious Diseases, Department of Medicine, University of California San Diego School of Medicine , La Jolla, California 92093, United States.

Aminopyrazoles are a new class of antimalarial compounds identified in a cellular antiparasitic screen with potent activity against Plasmodium falciparum asexual and sexual stage parasites. To investigate their unknown mechanism of action and thus identify their target, we cultured parasites in the presence of a representative member of the aminopyrazole series, GNF-Pf4492, to select for resistance. Whole genome sequencing of three resistant lines showed that each had acquired independent mutations in a P-type cation-transporter ATPase, PfATP4 (PF3D7_1211900), a protein implicated as the novel Plasmodium spp. target of another, structurally unrelated, class of antimalarials called the spiroindolones and characterized as an important sodium transporter of the cell. Similarly to the spiroindolones, GNF-Pf4492 blocks parasite transmission to mosquitoes and disrupts intracellular sodium homeostasis. Our data demonstrate that PfATP4 plays a critical role in cellular processes, can be inhibited by two distinct antimalarial pharmacophores, and supports the recent observations that PfATP4 is a critical antimalarial target.
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http://dx.doi.org/10.1021/cb500616xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340351PMC
February 2015

Lead optimization of imidazopyrazines: a new class of antimalarial with activity on Plasmodium liver stages.

ACS Med Chem Lett 2014 Aug 6;5(8):947-50. Epub 2014 Jul 6.

Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.

Imidazopyridine 1 was identified from a phenotypic screen against P. falciparum (Pf) blood stages and subsequently optimized for activity on liver-stage schizonts of the rodent parasite P. yoelii (Py) as well as hypnozoites of the simian parasite P. cynomolgi (Pc). We applied these various assays to the cell-based lead optimization of the imidazopyrazines, exemplified by 3 (KAI407), and show that optimized compounds within the series with improved pharmacokinetic properties achieve causal prophylactic activity in vivo and may have the potential to target the dormant stages of P. vivax malaria.
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http://dx.doi.org/10.1021/ml500244mDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137381PMC
August 2014

KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission.

Antimicrob Agents Chemother 2014 Sep 9;58(9):5060-7. Epub 2014 Jun 9.

Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.

Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have activity in the prevention and treatment of blood stage infection in a mouse model of malaria. Consistent with the previously reported activity profile of this series, the clinical candidate KAF156 shows blood schizonticidal activity with 50% inhibitory concentrations of 6 to 17.4 nM against P. falciparum drug-sensitive and drug-resistant strains, as well as potent therapeutic activity in a mouse models of malaria with 50, 90, and 99% effective doses of 0.6, 0.9, and 1.4 mg/kg, respectively. When administered prophylactically in a sporozoite challenge mouse model, KAF156 is completely protective as a single oral dose of 10 mg/kg. Finally, KAF156 displays potent Plasmodium transmission blocking activities both in vitro and in vivo. Collectively, our data suggest that KAF156, currently under evaluation in clinical trials, has the potential to treat, prevent, and block the transmission of malaria.
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http://dx.doi.org/10.1128/AAC.02727-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135840PMC
September 2014

KAI407, a potent non-8-aminoquinoline compound that kills Plasmodium cynomolgi early dormant liver stage parasites in vitro.

Antimicrob Agents Chemother 2014 23;58(3):1586-95. Epub 2013 Dec 23.

Biomedical Primate Research Centre, Department of Parasitology, Rijswijk, The Netherlands.

Preventing relapses of Plasmodium vivax malaria through a radical cure depends on use of the 8-aminoquinoline primaquine, which is associated with safety and compliance issues. For future malaria eradication strategies, new, safer radical curative compounds that efficiently kill dormant liver stages (hypnozoites) will be essential. A new compound with potential radical cure activity was identified using a low-throughput assay of in vitro-cultured hypnozoite forms of Plasmodium cynomolgi (an excellent and accessible model for Plasmodium vivax). In this assay, primary rhesus hepatocytes are infected with P. cynomolgi sporozoites, and exoerythrocytic development is monitored in the presence of compounds. Liver stage cultures are fixed after 6 days and stained with anti-Hsp70 antibodies, and the relative proportions of small (hypnozoite) and large (schizont) forms relative to the untreated controls are determined. This assay was used to screen a series of 18 known antimalarials and 14 new non-8-aminoquinolines (preselected for blood and/or liver stage activity) in three-point 10-fold dilutions (0.1, 1, and 10 μM final concentrations). A novel compound, designated KAI407 showed an activity profile similar to that of primaquine (PQ), efficiently killing the earliest stages of the parasites that become either primary hepatic schizonts or hypnozoites (50% inhibitory concentration [IC50] for hypnozoites, KAI407, 0.69 μM, and PQ, 0.84 μM; for developing liver stages, KAI407, 0.64 μM, and PQ, 0.37 μM). When given as causal prophylaxis, a single oral dose of 100 mg/kg of body weight prevented blood stage parasitemia in mice. From these results, we conclude that KAI407 may represent a new compound class for P. vivax malaria prophylaxis and potentially a radical cure.
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http://dx.doi.org/10.1128/AAC.01927-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3957848PMC
October 2014

Indolcarboxamide is a preclinical candidate for treating multidrug-resistant tuberculosis.

Sci Transl Med 2013 Dec;5(214):214ra168

Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.

New chemotherapeutic compounds against multidrug-resistant Mycobacterium tuberculosis (Mtb) are urgently needed to combat drug resistance in tuberculosis (TB). We have identified and characterized the indolcarboxamides as a new class of antitubercular bactericidal agent. Genetic and lipid profiling studies identified the likely molecular target of indolcarboxamides as MmpL3, a transporter of trehalose monomycolate that is essential for mycobacterial cell wall biosynthesis. Two lead candidates, NITD-304 and NITD-349, showed potent activity against both drug-sensitive and multidrug-resistant clinical isolates of Mtb. Promising pharmacokinetic profiles of both compounds after oral dosing in several species enabled further evaluation for efficacy and safety. NITD-304 and NITD-349 were efficacious in treating both acute and chronic Mtb infections in mouse efficacy models. Furthermore, dosing of NITD-304 and NITD-349 for 2 weeks in exploratory rat toxicology studies revealed a promising safety margin. Finally, neither compound inhibited the activity of major cytochrome P-450 enzymes or the hERG (human ether-a-go-go related gene) channel. These results suggest that NITD-304 and NITD-349 should undergo further development as a potential treatment for multidrug-resistant TB.
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http://dx.doi.org/10.1126/scitranslmed.3007355DOI Listing
December 2013

Targeting Plasmodium PI(4)K to eliminate malaria.

Nature 2013 Dec 27;504(7479):248-253. Epub 2013 Nov 27.

Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research (ASTAR), Biopolis, Singapore.

Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.
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http://dx.doi.org/10.1038/nature12782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940870PMC
December 2013

Imidazolopiperazines: lead optimization of the second-generation antimalarial agents.

J Med Chem 2012 May 23;55(9):4244-73. Epub 2012 Apr 23.

Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.

On the basis of the initial success of optimization of a novel series of imidazolopiperazines, a second generation of compounds involving changes in the core piperazine ring was synthesized to improve antimalarial properties. These changes were carried out to further improve the potency and metabolic stability of the compounds by leveraging the outcome of a set of in vitro metabolic identification studies. The optimized 8,8-dimethyl imidazolopiperazine analogues exhibited improved potency, in vitro metabolic stability profile and, as a result, enhanced oral exposure in vivo in mice. The optimized compounds were found to be more efficacious than the current antimalarials in a malaria mouse model. They exhibit moderate oral exposure in rat pharmacokinetic studies to achieve sufficient multiples of the oral exposure at the efficacious dose in toxicology studies.
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http://dx.doi.org/10.1021/jm300041eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350218PMC
May 2012

Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery.

Science 2011 Dec 17;334(6061):1372-7. Epub 2011 Nov 17.

Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA.

Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 milligrams/kilogram) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.
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http://dx.doi.org/10.1126/science.1211936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3473092PMC
December 2011

Imidazolopiperazines: hit to lead optimization of new antimalarial agents.

J Med Chem 2011 Jul 23;54(14):5116-30. Epub 2011 Jun 23.

Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.

Starting from a hit series from a GNF compound library collection and based on a cell-based proliferation assay of Plasmodium falciparum, a novel imidazolopiperazine scaffold was optimized. SAR for this series of compounds is discussed, focusing on optimization of cellular potency against wild-type and drug resistant parasites and improvement of physiochemical and pharmacokinetic properties. The lead compounds in this series showed good potencies in vitro and decent oral exposure levels in vivo. In a Plasmodium berghei mouse infection model, one lead compound lowered the parasitemia level by 99.4% after administration of 100 mg/kg single oral dose and prolonged mice survival by an average of 17.0 days. The lead compounds were also well-tolerated in the preliminary in vitro toxicity studies and represents an interesting lead for drug development.
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http://dx.doi.org/10.1021/jm2003359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950218PMC
July 2011

Identification of inhibitors for putative malaria drug targets among novel antimalarial compounds.

Mol Biochem Parasitol 2011 Jan 15;175(1):21-9. Epub 2010 Sep 15.

University of Washington, Seattle, WA, USA.

The efficacy of most marketed antimalarial drugs has been compromised by evolution of parasite resistance, underscoring an urgent need to find new drugs with new mechanisms of action. We have taken a high-throughput approach toward identifying novel antimalarial chemical inhibitors of prioritized drug targets for Plasmodium falciparum, excluding targets which are inhibited by currently used drugs. A screen of commercially available libraries identified 5655 low molecular weight compounds that inhibit growth of P. falciparum cultures with EC(50) values below 1.25μM. These compounds were then tested in 384- or 1536-well biochemical assays for activity against nine Plasmodium enzymes: adenylosuccinate synthetase (AdSS), choline kinase (CK), deoxyuridine triphosphate nucleotidohydrolase (dUTPase), glutamate dehydrogenase (GDH), guanylate kinase (GK), N-myristoyltransferase (NMT), orotidine 5'-monophosphate decarboxylase (OMPDC), farnesyl pyrophosphate synthase (FPPS) and S-adenosylhomocysteine hydrolase (SAHH). These enzymes were selected using TDRtargets.org, and are believed to have excellent potential as drug targets based on criteria such as their likely essentiality, druggability, and amenability to high-throughput biochemical screening. Six of these targets were inhibited by one or more of the antimalarial scaffolds and may have potential use in drug development, further target validation studies and exploration of P. falciparum biochemistry and biology.
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http://dx.doi.org/10.1016/j.molbiopara.2010.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108854PMC
January 2011