A5006614252- Malaria Research and Control
- Synthesis and Catalytic Reactions
- Antibiotic Resistance in Bacteria
- Cancer therapeutics and mechanisms
- HIV/AIDS drug development and treatment
- Chemical Synthesis and Analysis
- Synthetic Organic Chemistry Methods
- Pneumocystis jirovecii pneumonia detection and treatment
- Asymmetric Synthesis and Catalysis
- Carbohydrate Chemistry and Synthesis
- Bioactive Compounds and Antitumor Agents
- Computational Drug Discovery Methods
- Synthesis and biological activity
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Pharmacological Effects of Natural Compounds
- Research on Leishmaniasis Studies
- Trypanosoma species research and implications
- Enzyme Catalysis and Immobilization
- Phenothiazines and Benzothiazines Synthesis and Activities
- Crystallography and molecular interactions
- Peroxisome Proliferator-Activated Receptors
- Advanced Synthetic Organic Chemistry
- Retinoids in leukemia and cellular processes
- Tuberculosis Research and Epidemiology
Vertex Pharmaceuticals (United States)
2012-2024
Agouron Institute
2011
Pfizer (United States)
2007-2008
Harvard University
2006-2007
Ardent Sound (United States)
2003-2004
Johns Hopkins University
1998-2000
Shanghai Institute of Organic Chemistry
1999
Johns Hopkins Medicine
1998
Compound 3 is a potent aminobenzimidazole urea with broad-spectrum Gram-positive antibacterial activity resulting from dual inhibition of bacterial gyrase (GyrB) and topoisomerase IV (ParE), it demonstrates efficacy in rodent models infection. Preclinical vitro vivo studies showed that compound covalently labels liver proteins, presumably via formation reactive metabolite, hence presented potential safety liability. The moiety was identified as being potentially responsible for metabolite...
Nine C-10 non-acetal derivatives of the natural trioxane artemisinin (1) were prepared as dimers using some novel chemistry. As designed, each dimer was stable chemically. Olefinic 7 and saturated 8−13 all showed good to excellent antimalarial antiproliferative activities in vitro. Dimers 8, 10, 12 especially potent selective at inhibiting growth human cancer cell lines NCI vitro 60-cell line assay.
The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat variety of autoimmune disorders, including multiple sclerosis, due its role in immune modulation and microglial activation. By minimizing the number hydrogen bond donors while targeting previously uncovered selectivity pocket adjacent ATP binding site PI3Kγ, we discovered series azaisoindolinones selective, brain penetrant inhibitors PI3Kγ. This ultimately led discovery 16, an orally...
Over 20 new, cyclic, peroxy ketals have been prepared via a two-step protocol starting with readily available aryl methyl ketones. Structure−activity correlations using in vitro antimalarial data as guide for optimization of potency led to the design and synthesis seven new peroxides that IC50 values 31−85 nM (artemisinin = 8.4 nM). Some SAR generalizations are discussed.
A series of new sulfide and sulfone 1,2,4-trioxanes was prepared in only a few steps from commercial reactants. The trioxanes were found to have higher vitro antimalarial potencies than the sulfides, with 12β-arylsulfone 1β being 13 14 as potent complex natural trioxane artemisinin (2). tentative chemical mechanism is proposed account for great difference activity 12α- vs. 12β-sulfide trioxanes.
An enantioselective synthetic route to the enediyne antibiotic N1999A2 (1) is described, proceeding in 21 steps (0.4% yield, 77% average yield per step) from (R)-(+)-glycidol. The involves convergent assembly of three components: a (1-iodovinyl) stannane (2), 1,5-hexadiyne-3,4-diol derivative (3), and substituted naphthoic acid (4). Important transformations sequence include palladium-catalyzed coupling 2 3, an intramolecular oxidative cyclization terminal bisacetylene, transannular anionic...
Benzimidazole 1 is the lead compound resulting from an antibacterial program targeting dual inhibitors of bacterial DNA gyrase and topoisomerase IV. With goal improving key drug-like properties, namely, solubility formulability 1, effort to identify prodrugs was undertaken. This has led discovery a phosphate ester prodrug 2. rapidly cleaved parent drug molecule upon both oral intravenous administration. The achieved equivalent exposure compared dosing in multiple species. 2 improved aqueous...
The peroxide bond in artemisinin trioxane lactone (1) withstood exposure to lithiothiazole and lithiobenzothiazole; nucleophilic addition of these powerful organometallic reagents only the carbonyl group was observed. Likewise, aldehyde 5 reacted with organolithium, Grignard, phosphorus ylide nucleophiles exclusively via addition. Also, ketone 7b phenyllithium These chemoselective lactone, aldehyde, reactions produced a series new, enantiomerically pure, C-10 non-acetal derivatives natural...
A series of trioxanes featuring sulfide, sulfone, and sulfonamide substituents in diverse positions has been prepared. Structure–activity relationship (SAR) generalizations highlight two major factors controlling the antimalarial potency these new chemical entities: (1) proximity sulfur-containing substituent to crucial peroxide bond (2) oxidation state substituent. Generally, sulfones are more antimalarially potent than corresponding sulfides.
To facilitate a drug discovery project, we needed to develop robust asymmetric synthesis of (2S,5S)-5-substituted-azepane-2-carboxylate derivatives. Two key requirements for the were flexibility elaboration at C5 and suitability large scale preparation. this end have successfully developed scalable these derivatives that starts with known hydroxy-ketone 8. The step features an oxidative cleavage aza-bicyclo[3.2.2]nonene 14, which simultaneously generates C2 substituents in stereoselective manner.
The desymmetrization of a prochiral 6-oxaspiro[3.3]heptane-2-carboxylic acid derivative via biocatalytic ketoreductase-mediated reduction has provided access to both enantiomers in high ee. axially chiral alcohol was converted the corresponding ester alcohol, amino acid, and building blocks while enantiopurity maintained.
Accumulation of very long chain fatty acids (VLCFAs) due to defects in ATP binding cassette protein D1 (ABCD1) is thought underlie the pathologies observed adrenoleukodystrophy (ALD). Pursuing a substrate reduction approach based on inhibition elongation acid 1 enzyme (ELOVL1), we explored series thiazole amides that evolved into compound 27─a highly potent, central nervous system (CNS)-penetrant with favorable vivo pharmacokinetics. Compound 27 selectively inhibits ELOVL1, reducing C26:0...
In our efforts to identify novel small molecule inhibitors for the treatment of adrenoleukodystrophy (ALD), we conducted a high-throughput radiometric screen elongation very long chain fatty acid 1 (ELOVL1) enzyme. We developed series highly potent, central nervous system (CNS)-penetrant pyrimidine ether-based compounds with favorable pharmacokinetics culminating in compound 22. Compound 22 is selective inhibitor ELOVL1, reducing C26:0 VLCFA synthesis ALD patient fibroblasts and lymphocytes...
Cyclic peroxy ketal (I), prepared using the Snider photoenolizationoxygenation procedure, has been found to have measurable antimalarial activity.Upon reaction with ferrous ions, peroxide (1) is converted mainly into hydroxylated epoxy ketone (6), and a mechanism involving several intermediates including high-valent iron-0x0 species proposed account for this chemical transformation.Approximately 300 million people worldwide currently suffer from malaria, each year 1-2 million,
Phosphoinositide 3-kinase (PI3Kγ) is a drug target that has been implicated in the treatment of range diseases. We have developed synthesis novel PI3Kγ inhibitor containing 1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one scaffold. The key step involved ruthenium-catalyzed [2 + 2 2] cyclotrimerization reaction between diyne and an alkoxycarbonyl isocyanate, previously unreported coupling partner such reaction.
Selective access to both cis- and trans-isomers of α-substituted 3-hydroxycyclobutane-1-carboxylic esters has been demonstrated using ketoreductase (KRED) enzymes. Two stereocomplementary KREDs were identified from a commercial panel that are highly selective for small α-substituents when the ester group was para-methoxybenzyl. Probing substrate scope these two enzymes revealed selectivity declined rapidly with increasing steric bulk α-substituent. For methyl substrates larger...