ChemMedChem

The cover picture shows the structure of MbtI, a salicylate synthase enzyme from Mycobacterium tuberculosis, which converts chorismate to salicylate in the first committed step of the biosynthesis of the siderophore mycobactin T. Also shown is a selection of the first reported inhibitors of this enzyme. These compounds were designed based on the substrate and intermediate of the enzymatic reaction. The background shows a colorized scanning electron micrograph of M. tuberculosis (image by J. Haney Carr and provided to the Public Health Image Library of the Centers for Disease Control and Prevention by R. Butler). The cover image was designed by A. Manos-Turvey. For more information, see the Full Paper by R. J. Payne et al. on p. 1067 ff.

The inside cover picture shows an N-aminoimidazole-based p38α MAP kinase inhibitor (11 f in the manuscript) docked in the target binding site (PDB ID: 3HL7). A novel synthetic route to tetrasubstituted N-aminoimidazoles was established. Acyl substitution of these N-aminoimidazoles yielded low nanomolar inhibitors (e.g., 11 f, IC₅₀ = 58 nM). For more details, see the Full Paper by S. A. Laufer et al. on p. 1134 ff.

Using estradiol derivatives, proteolysis targeting chimeras (PROTACs) that target the estrogen receptor were synthesized and tested for their activity. We describe how PROTACs can induce proteasome-mediated degradation of the estrogen receptor in living cells. This strategy represents a generic approach to target any cancer-promoting protein for degradation.

Binding of the anti-convulsive drug tiagabine (Gabitril) to the human γ-aminobutyric acid transporter GAT-1: tiagabine is shown in stick representation, and GAT-1 is shown as an atom-type coloured surface. Part of the surface has been removed for clarity.

The combination of NMR experimental data and docking tools can greatly increase the reliability of predicted docking poses. For the complex of the antibody SM3 with its epitope, the PLANTS docking program and the ChemPLP scoring function complemented with intra-ligand trNOE and STD distance constraints are able to correctly predict the complex structure as the best-ranked docking pose.

A new procedure for filtering millions of poses of small molecules based on QM calculations is described by application to the tyrosine kinase EphB4. This method does not require fixed partial charges and takes into account polarization and charge-transfer effects not captured by conventional force fields. Having carried out experimental tests on only 23 molecules, we thus identified a selective micromolar inhibitor of EphB4 from a library of 2.7×10⁶ compounds.

Small ligands of β₂-microglobulin (β₂-m) were characterised by a combined approach based on high-resolution mass spectrometry and in silico studies. This method offers rapid and precise information on affinity as well as insight on the structural requisites that a ligand should possess to inhibit β₂-m aggregation. The approach represents a valuable strategy for the rapid screening of β₂-m fibrillogenesis inhibitors.

A series of adamantyl ethanones were identified as potent inhibitors of human cellular 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The most active compounds identified have IC₅₀ values in the 50–70 nM range. Compound 72 is metabolically stable when incubated with human liver microsomes and shows very weak inhibition of cytochrome P450 enzymes. Docking studies with potent compounds revealed how these molecules may interact with the enzyme and cofactor.

Novel glycerophosphonocarbamates and dicarbamate analogues of 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH₃) possess potent activity against cultured tumor cells. The carbamates were more active against hormone-insensitive prostate cancer lines than toward cancer cells from other tissues. The cytotoxic effect was mediated by apoptosis. The lead compound is active against a prostate cancer xenograft in Rag2M mice when administered both orally and intravenously.

Magnesium chelation modes: For α,γ-diketo acid, when enolized hydroxy groups of the various tautomers are deprotonated in aqueous solution, those tautomers can form the most stable complexes with Mg²⁺, with the two magnesium ions separated by a distance of approximately 3.73 Å, and with each magnesium ion at the center of an octahedron. The aim of this study is to offer theoretical results to help design moieties capable of chelating two Mg²⁺ ions and aid in the future development of HIV-1 integrase inhibitors with novel scaffolds.

Salicylate synthase catalyzes the first committed step in the biosynthesis of mycobactin, an iron-chelating siderophore essential for the survival of Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB). The first inhibitors of M. tuberculosis salicylate synthase (MbtI), designed to mimic the substrate (chorismate) and intermediate (isochorismate) of the enzyme, were prepared with a view to the development of new TB therapies.

Oligopeptide anthraquinones derived from ametantrone were predicted to target the palindromic sequences (CCCGGG)₂ and (GGCGCC)₂, the latter of which is found in several oncogenes and is also part of the primer binding site (PBS) of the long terminal repeat of HIV-1. By referring to theoretical studies, we synthesized and investigated the DNA binding properties of the designed peptidyl-ametantrone derivatives and verified their ability to selectively recognize the desired DNA sequences.

A thiazolopyrimidine derivative resulting from high-throughput screening was found to be active toward 2-methylerythritol 2,4-cyclodiphosphate synthase (IspF) from Mycobacterium tuberculosis and Plasmodium falciparum, with respective IC₅₀ values of 6.1±0.8 and 9.6±1.5 μM. Some of the prepared derivatives exhibit weak in vitro activity against the protozoan parasite P. falciparum.

Blocking PC biosynthesis inP. falciparum: A new series of bis-thiazolium analogues with an aryl moiety and oxygen atoms in the linker were prepared, and their pharmacological activity was evaluated. SAR studies suggest that the optimal linker construct is an aromatic group with two n-butyl chains branched at the para position; two new leads (compounds 39 and 40) were selected for further development as potential antimalarial drugs.

The anti-H. pyloriactivity of a series of new metronidazole–deoxybenzoin derivatives has been demonstrated. The preliminary mechanism of the most potent compound's inhibitory effect was also determined. Compounds 17 and 34 are able to significantly decrease H. pylori water extract (HPE)-induced production of interleukin-8 in gastric mucosal cells, and do not show any effects on cell viability.

Deoxybenzoin derivatives: The immunosuppressive activity and cytotoxicity of a series of new deoxybenzoins were demonstrated. The preliminary inhibition mechanism of the most potent compound (31, SI>684.64) was also identified by flow cytometry, and this molecule does not exhibit significant cytotoxicity toward inactivated mouse lymph node cells.

A complex situation: The apoptosis-inducing agents [([9]aneS₃)RhCl(pp)]Cl₂ (pp=dppz , bpm) cause negligible necrotic damage and are highly selective towards malignant lymphoma cells in comparison to healthy leukocytes. While the dppz complex exhibits strong intercalative binding into DNA, no change in duplex B conformation is observed for the bpm complex.

We developed novel tetrasubstituted pyridinylimidazoles with acyl residues at the imidazole N1 position that interact with specific regions of p38 mitogen-activated protein (MAP) kinase α to improve both selectivity and activity. The substitution pattern was optimized by variation of the acyl group at the N1 position of the N-aminoimidazole core.

Altering Alzheimer's: Among a series of nonimidazole H₃ antagonists developed from manipulation or replacement of the heterocycle of 1,1′-octa-, -nona-, and -decamethylene-bis-piperidines, tacrine hybrids synergistically combine nanomolar and selective H₃ blockade with remarkable anticholinesterase activity. This strategy has the potential to facilitate treatment of cognitive disorders.

Wiley, Hoboken 2010. 586 pp., hardcover $ 149.95.—ISBN 978-0-470-26100-2

Wiley, Hoboken 2009. 459 pp., hardcover $ 125.00.—ISBN 978-0-470-22734-3

Humana Press, Totowa 2009. XVI+420 pp., softcover $ 59.95.—ISBN 978-1-60761-471-5