A5050752664- Malaria Research and Control
- Synthesis and Catalytic Reactions
- Mosquito-borne diseases and control
- Computational Drug Discovery Methods
- HIV/AIDS drug development and treatment
- Drug Transport and Resistance Mechanisms
- Microbial Natural Products and Biosynthesis
- Catalytic C–H Functionalization Methods
- Biochemical and Molecular Research
- Trypanosoma species research and implications
- Seaweed-derived Bioactive Compounds
- Synthetic Organic Chemistry Methods
- Phenothiazines and Benzothiazines Synthesis and Activities
- Marine Sponges and Natural Products
- Molecular spectroscopy and chirality
- Asymmetric Hydrogenation and Catalysis
- Synthesis and biological activity
- Tuberculosis Research and Epidemiology
- Liver Disease Diagnosis and Treatment
- Parasitic Diseases Research and Treatment
- Cancer therapeutics and mechanisms
- Quinazolinone synthesis and applications
- Drug-Induced Hepatotoxicity and Protection
- Plant biochemistry and biosynthesis
- Mycobacterium research and diagnosis
California Institute for Biomedical Research
2019-2020
Scripps Research Institute
2019-2020
Scripps Institution of Oceanography
2019
Scripps (United States)
2019
Genomics Institute of the Novartis Research Foundation
2010-2018
Novartis (Switzerland)
2013
Boston Biomedical Research Institute
2011
Swiss Tropical and Public Health Institute
2011
Novartis (Singapore)
2011
University of Basel
2011
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 set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) identified chemical scaffolds potent forms. From this screen, we an imidazolopiperazine...
Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of parasite life cycle. We previously reported discovery a class compounds in imidazolopiperazine series that prevention and treatment blood stage infection mouse model malaria. Consistent profile this series, clinical candidate KAF156 shows schizonticidal 50% inhibitory concentrations 6 to 17.4 nM P. falciparum drug-sensitive drug-resistant strains,...
New chemotherapeutic compounds against multidrug-resistant Mycobacterium tuberculosis (Mtb) are urgently needed to combat drug resistance in (TB). We have identified and characterized the indolcarboxamides as a new class of antitubercular bactericidal agent. Genetic lipid profiling studies likely molecular target MmpL3, transporter trehalose monomycolate that is essential for mycobacterial cell wall biosynthesis. Two lead candidates, NITD-304 NITD-349, showed potent activity both...
To discover leads for next-generation chemoprotective antimalarial drugs, we tested more than 500,000 compounds their ability to inhibit liver-stage development of luciferase-expressing Plasmodium spp. parasites (681 showed a half-maximal inhibitory concentration less 1 micromolar). Cluster analysis identified potent and previously unreported scaffold families as well other series associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific...
In order to identify the most attractive starting points for drugs that can be used prevent malaria, a diverse chemical space comprising tens of thousands millions small molecules may need examined. Achieving this throughput necessitates development efficient ultra-high-throughput screening methods. Here, we report and evaluation luciferase-based phenotypic screen malaria exoerythrocytic-stage parasites optimized 1536-well format. This assay uses exoerythrocytic stage rodent parasite,...
Starting from a hit series GNF compound library collection and based on cell-based proliferation assay of Plasmodium falciparum, novel imidazolopiperazine scaffold was optimized. SAR for this compounds is discussed, focusing optimization cellular potency against wild-type drug resistant parasites improvement physiochemical pharmacokinetic properties. The lead in showed good potencies vitro decent oral exposure levels vivo. In berghei mouse infection model, one lowered the parasitemia level...
Aminopyrazoles are a new class of antimalarial compounds identified in cellular antiparasitic screen with potent activity against Plasmodium falciparum asexual and sexual stage parasites. To investigate their unknown mechanism action thus identify target, we cultured parasites the presence representative member aminopyrazole series, GNF-Pf4492, to select for resistance. Whole genome sequencing three resistant lines showed that each had acquired independent mutations P-type cation-transporter...
On the basis of initial success optimization a novel series imidazolopiperazines, second generation compounds involving changes in core piperazine ring was synthesized to improve antimalarial properties. These were carried out further potency and metabolic stability by leveraging outcome set vitro identification studies. The optimized 8,8-dimethyl imidazolopiperazine analogues exhibited improved potency, profile and, as result, enhanced oral exposure vivo mice. found be more efficacious than...
Preventing relapses of Plasmodium vivax malaria through a radical cure depends on use the 8-aminoquinoline primaquine, which is associated with safety and compliance issues. For future eradication strategies, new, safer curative compounds that efficiently kill dormant liver stages (hypnozoites) will be essential. A new compound potential activity was identified using low-throughput assay in vitro-cultured hypnozoite forms cynomolgi (an excellent accessible model for vivax). In this assay,...
Significance The combination of two newly emerging methods for chemical synthesis enables access to molecular space that was previously challenging or impossible access. Thus, a C–H activation ubiquitous carboxylic acids followed by their decarboxylative functionalization provides modular difunctionalized carbon frameworks with distinctly controlled stereochemistry. Application this strategy simplify the medicinally important entities and discover potent antimalarial compounds is described.
A new cyclic peptide, kakeromamide B (
This study identifies oral, highly efficacious antiwolbachial compounds to cure filarial infections in mice.
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 wide array 2D NMR spectroscopic experiments, in systematic structure elucidation workflow, revealed that peyssonnosides A-B (1-2) represent new class with tetracyclo [7.5.0.01,10.05,9] tetradecane architecture. A salient feature this workflow is unique application quantitative interproton distances obtained...
Most phenotypic screens aiming to discover new antimalarial chemotypes begin with low cost, high-throughput tests against the asexual blood stage (ABS) of malaria parasite life cycle. Compounds active ABS are then sequentially tested in more difficult assays that predict whether a compound has other beneficial attributes. Although applying this strategy chemical libraries may yield leads, repeated iterations lead diminishing returns and rediscovery hitting well-known targets. Here, we...
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 yoelii (Py) as well hypnozoites simian cynomolgi (Pc). We applied these various assays to cell-based lead optimization imidazopyrazines, exemplified by 3 (KAI407), show that compounds within series with improved pharmacokinetic properties achieve causal prophylactic in vivo may have potential target dormant...
A series of oligomeric phenols including the known natural product 3,4,3′,4′-tetrahydroxy-1,1′-biphenyl (3), previously synthesized 2,3,8,9-tetrahydroxybenzo[c]chromen-6-one (4), and eight new related products, cladophorols B–I (5–12), were isolated from Fijian green alga Cladophora socialis identified by a combination NMR spectroscopy, mass spectrometric analysis, computational modeling using DFT calculations. J-resolved spectroscopy line width reduction picric acid addition aided in...
The union of two powerful transformations, directed C–H activation and decarboxylative cross-coupling, for the enantioselective synthesis vicinally functionalized alkyl, carbocyclic, heterocyclic compounds is described. Starting from simple carboxylic acid building blocks, this modular sequence exploits residual directing group to access more than 50 scaffolds that would be otherwise extremely difficult prepare. tactical use these transformations accomplishes a formal vicinal...
<div> <p>The union of two powerful transformations, directed C–H activation and decarboxylative cross-coupling, for the enantioselective synthesis vicinally functionalized alkyl, carbocyclic, heterocyclic compounds is described. Starting from simple carboxylic acid building blocks, this modular sequence exploits residual directing group to access more than 50 scaffolds that would be otherwise extremely difficult prepare. The tactical use these transformations accomplishes a...