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1.  A Simple Litmus Test for Aldehyde Oxidase Metabolism of Heteroarenes 
Journal of Medicinal Chemistry  2014;57(4):1616-1620.
The bioavailability of aromatic azaheterocyclic drugs can be affected by the activity of aldehyde oxidase (AO). Susceptibility to AO metabolism is difficult to predict computationally and can be complicated in vivo by differences between species. Here we report the use of bis(((difluoromethyl)sulfinyl)oxy)zinc (DFMS) as a source of CF2H radical for a rapid and inexpensive chemical “litmus test” for the early identification of heteroaromatic drug candidates that have a high probability of metabolism by AO.
PMCID: PMC3983350  PMID: 24472070
2.  Targeting Staphylococcus aureus Quorum Sensing with Nonpeptidic Small Molecule Inhibitors 
Journal of Medicinal Chemistry  2014;57(6):2813-2819.
A series of 3-oxo-C12-HSL, tetramic acid, and tetronic acid analogues were synthesized to gain insights into the structural requirements for quorum sensing inhibition in Staphylococcus aureus. Compounds active against agr were noncompetitive inhibitors of the autoinducing peptide (AIP) activated AgrC receptor, by altering the activation efficacy of the cognate AIP-1. They appeared to act as negative allosteric modulators and are exemplified by 3-tetradecanoyltetronic acid 17, which reduced nasal cell colonization and arthritis in a murine infection model.
PMCID: PMC4010551  PMID: 24592914
3.  Targeting Low-Druggability Bromodomains: Fragment Based Screening and Inhibitor Design against the BAZ2B Bromodomain 
Journal of Medicinal Chemistry  2013;56(24):10183-10187.
Bromodomains are epigenetic reader domains that have recently become popular targets. In contrast to BET bromodomains, which have proven druggable, bromodomains from other regions of the phylogenetic tree have shallower pockets. We describe successful targeting of the challenging BAZ2B bromodomain using biophysical fragment screening and structure-based optimization of high ligand-efficiency fragments into a novel series of low-micromolar inhibitors. Our results provide attractive leads for development of BAZ2B chemical probes and indicate the whole family may be tractable.
PMCID: PMC3905694  PMID: 24304323
4.  Identification and Characterization of Small Molecule Inhibitors of a Class I Histone Deacetylase from Plasmodium falciparum 
Journal of Medicinal Chemistry  2009;52(8):2185-2187.
A library of approximately 2000 small molecules biased toward inhibition of histone deacetylases was assayed for antimalarial activity in a high-throughput P. falciparum viability assay. Active compounds were cross-analyzed for induction of histone hyperacetylation in a human myeloma cell line to identify HDAC inhibitors with selectivity for P. falciparum over the human host. To verify on-target selectivity, pfHDAC-1 was expressed and purified and a biochemical assay for pfHDAC-1 activity was established.
PMCID: PMC2669731  PMID: 19317450
5.  Inhibition of Protein Kinase C-Driven Nuclear Factor-κB Activation: Synthesis, Structure−Activity Relationship, and Pharmacological Profiling of Pathway Specific Benzimidazole Probe Molecules 
Journal of Medicinal Chemistry  2010;53(12):4793-4797.
A unique series of biologically active chemical probes that selectively inhibit NF-κB activation induced by protein kinase C (PKC) pathway activators have been identified through a cell-based phenotypic reporter gene assay. These 2-aminobenzimidazoles represent initial chemical tools to be used in gaining further understanding on the cellular mechanisms driven by B and T cell antigen receptors. Starting from the founding member of this chemical series 1a (notated in PubChem as CID-2858522), we report the chemical synthesis, SAR studies, and pharmacological profiling of this pathway-selective inhibitor of NF-κB activation.
PMCID: PMC2887059  PMID: 20481485
6.  Novel Lipophilic Acetohydroxamic Acid Derivatives Based on Conformationally Constrained Spiro Carbocyclic 2,6-Diketopiperazine Scaffolds with Potent Trypanocidal Activity 
Journal of Medicinal Chemistry  2011;54(14):5250-5254.
We describe novel acetohydroxamic acid derivatives with potent activity against cultured bloodstream-form Trypanosoma brucei and selectivity indices of >1000. These analogues were derived from conformationally constrained, lipophilic, spiro carbocyclic 2,6-diketopiperazine (2,6-DKP) scaffolds by attaching acetohydroxamic acid moieties to the imidic nitrogen. Optimal activity was achieved by placing benzyl groups adjacent to the basic nitrogen of the 2,6-DKP core. S-Enantiomer 7d was the most active derivative against T. brucei (IC50 = 6.8 nM) and T. cruzi (IC50 = 0.21 μM).
PMCID: PMC3140774  PMID: 21542562
7.  Trisubstituted Imidazoles as Mycobacterium tuberculosis Glutamine Synthetase Inhibitors† 
Journal of Medicinal Chemistry  2012;55(6):2894-2898.
Mycobacterium tuberculosis glutamine synthetase (MtGS) is a promising target for antituberculosis drug discovery. In a recent high-throughput screening study we identified several classes of MtGS inhibitors targeting the ATP-binding site. We now explore one of these classes, the 2-tert-butyl-4,5-diarylimidazoles, and present the design, synthesis, and X-ray crystallographic studies leading to the identification of MtGS inhibitors with submicromolar IC50 values and promising antituberculosis MIC values.
PMCID: PMC3381009  PMID: 22369127
8.  Discovery of Novel and Ligand-Efficient Inhibitors of Plasmodium falciparum and Plasmodium vivaxN-Myristoyltransferase 
Journal of Medicinal Chemistry  2012;56(1):371-375.
N-Myristoyltransferase (NMT) is an attractive antiprotozoan drug target. A lead-hopping approach was utilized in the design and synthesis of novel benzo[b]thiophene-containing inhibitors of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) NMT. These inhibitors are selective against Homo sapiens NMT1 (HsNMT), have excellent ligand efficiency (LE), and display antiparasitic activity in vitro. The binding mode of this series was determined by crystallography and shows a novel binding mode for the benzothiophene ring.
PMCID: PMC3601602  PMID: 23170970
9.  Toward Biophysical Probes for the 5-HT3 Receptor: Structure−Activity Relationship Study of Granisetron Derivatives 
Journal of Medicinal Chemistry  2010;53(5):2324-2328.
This report describes the synthesis and biological characterization of novel granisetron derivatives that are antagonists of the human serotonin (5-HT3A) receptor. Some of these substituted granisetron derivatives showed low nanomolar binding affinity and allowed the identification of positions on the granisetron core that might be used as attachment points for biophysical tags. A BODIPY fluorophore was appended to one such position and specifically bound to 5-HT3A receptors in mammalian cells.
PMCID: PMC4166935  PMID: 20146481
10.  Structure-Guided Design and Optimization of Small Molecules Targeting the Protein–Protein Interaction between the von Hippel–Lindau (VHL) E3 Ubiquitin Ligase and the Hypoxia Inducible Factor (HIF) Alpha Subunit with in Vitro Nanomolar Affinities 
Journal of Medicinal Chemistry  2014;57(20):8657-8663.
E3 ubiquitin ligases are attractive targets in the ubiquitin–proteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel–Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α interaction, however they exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities.
PMCID: PMC4207132  PMID: 25166285
11.  Structure-Based Design of Potent and Selective LeishmaniaN-Myristoyltransferase Inhibitors 
Journal of Medicinal Chemistry  2014;57(20):8664-8670.
Inhibitors of LeishmaniaN-myristoyltransferase (NMT), a potential target for the treatment of leishmaniasis, obtained from a high-throughput screen, were resynthesized to validate activity. Crystal structures bound to Leishmania major NMT were obtained, and the active diastereoisomer of one of the inhibitors was identified. On the basis of structural insights, enzyme inhibition was increased 40-fold through hybridization of two distinct binding modes, resulting in novel, highly potent Leishmania donovani NMT inhibitors with good selectivity over the human enzyme.
PMCID: PMC4211304  PMID: 25238611

Results 1-11 (11)