Advancement of GyrB Inhibitors for Treatment of Infections Caused by and Non-tuberculous Mycobacteria.

The prospect of ever increasing antibiotic resistance eroding currently available treatment options for bacterial infections underscores the need to continue to identify new antibiotics, preferably those that act on novel targets or with novel mechanisms of action. Bacterial gyrase B subunit (GyrB), an essential component of bacterial gyrase required for successful DNA replication, represents such a target. We describe recent examples of GyrB inhibitors and point out their potential utility for treatment of mycobacterial diseases caused by (TB) and non-tuberculous mycobacteria (NTM).

Regioselective Synthesis of a -4'' Carbamate,-6'' -Pr Substituted Cyclitol Analogue of SL0101.

An asymmetric synthesis of two analogues of SL0101 () has been achieved. The effort is aimed at the discovery of inhibitors of the p90 ribosomal S6 kinase (RSK) with improved bioavailability. The route relies upon the use of the Taylor catalyst to regioselectively install -3″ acetyl or carbamate functionality.

Synthesis of novel 5-substituted-2-aminotetralin analogs: 5-HT and 5-HT G protein-coupled receptor affinity, 3D-QSAR and molecular modeling.

The serotonin 5-HT G protein-coupled receptor (GPCR) is a proposed pharmacotherapeutic target for a variety of central and peripheral indications, albeit, there are no approved drugs selective for binding 5-HT. We previously reported that a lead analog based on the 5-substituted-N,N-disubstituted-1,2,3,4-tetrahydronaphthalen-2-amine (5-substituted-2-aminotetralin, 5-SAT) scaffold binds with high affinity at the 5-HT GPCR, and can treat symptoms of autism in mouse models; subsequently, the lead was found to have high affinity at the 5-HT GPCR. Herein, we report the synthesis of novel 5-SAT analogs to develop a 3-dimensional quantitative structure-affinity relationship (3D-QSAR) at the human 5-HT receptor for comparison with similar studies at the highly homologous 5-HT receptor.

A New, Short, and Stereocontrolled Synthesis of C-Symmetric 1,2-Diamines.

The previously unknown 5-spirocyclohexylisoimidazole has been made efficiently and simply by reaction of ammonia, glyoxal hydrate, and cyclohexanone. It is a very useful precursor for the diastereocontrolled synthesis of many C-symmetric 1,2-diamines, a class which is important for the generation of a variety of C-symmetric reagents and catalysts for enantioselective synthesis.

An Orally Active Phenylaminotetralin-Chemotype Serotonin 5-HT7 and 5-HT1A Receptor Partial Agonist that Corrects Motor Stereotypy in Mouse Models.

Stereotypy (e.g., repetitive hand waving) is a key phenotype of autism spectrum disorder, Fragile X and Rett syndromes, and other neuropsychiatric disorders, and its severity correlates with cognitive and attention deficits.

Reversal of the importance of steric and electronic effects in the base-promoted α-silylation of sulfides.

Lithiation of α-C-H groups in organic substrates by RLi or R2NLi followed by silylation with R'3SiCl generally provides analogous products regardless of the R' group of R'3SiCl. A striking exception using 3,4-benzothiophane as substrate depending on whether R' is methyl, phenyl, or isopropyl is demonstrated. With R' = Me or Ph, the geminal α,α-bis-silylated products result whereas with i-Pr3SiCl the trans-α,α'-bis-silylated sulfide is formed.

De novo synthesis and biological evaluation of C6″-substituted C4″-amide analogues of SL0101.

In an effort to improve upon the in vivo half-life of the known ribosomal s6 kinase (RSK) inhibitor SL0101, C4″-amide/C6″-alkyl substituted analogues of SL0101 were synthesized and evaluated in cell-based assays. The analogues were prepared using a de novo asymmetric synthetic approach, which featured Pd-π-allylic catalyzed glycosylation for the introduction of a C4″-azido group. Surprisingly replacement of the C4″-acetate with a C4″-amide resulted in analogues that were no longer specific for RSK in cell-based assays.

Improving the affinity of SL0101 for RSK using structure-based design.

Enhanced activity of the Ser/Thr protein kinase, RSK, is associated with transformation and metastasis, which suggests that RSK is an attractive drug target. The natural product, SL0101 (kaempferol 3-O-(3″,4″-di-O-acetyl-α-L-rhamnopyranoside), has been shown to be a RSK selective inhibitor. However, the Ki for SL0101 is 1 μM with a half-life of less than 30 min .