C2-Symmetric Bicyclo[3.3.1]nonadiene as a Chiral Ligand for Rhodium-Catalyzed Asymmetric Arylation of N-(4-Nitrobenzenesulfonyl)arylimines

A series of 2-(2-thienyl)cinchoninic acids 3, their derivatives 5 and 4-(3-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazolo-6-yl)-2-(2thienyl)quinolines 6 were synthesized. The structures of the newly synthesized compounds are confirmed by analytical, IR, NMR and mass spectral data. The newly synthesized compounds were evaluated for their anti-inflammatory, analgesic and anthelmintic activity. The results indicated that dinitrothiophene derivatives 5 are more active.

Synthesis and pharmacological properties of some quinoline derivatives.

There is a growing need for new antibiotics. Compounds that target the proton motive force (PMF), uncouplers, represent one possible class of compounds that might be developed because they are already used to treat parasitic infections, and there is interest in their use for the treatment of other diseases, such as diabetes. Here, we tested a series of compounds, most with known antiinfective activity, for uncoupler activity. Many cationic amphiphiles tested positive, and some targeted isoprenoid biosynthesis or affected lipid bilayer structure. As an example, we found that clomiphene, a recently discovered undecaprenyl diphosphate synthase inhibitor active against Staphylococcus aureus, is an uncoupler. Using in silico screening, we then found that the anti-glioblastoma multiforme drug lead vacquinol is an inhibitor of Mycobacterium tuberculosis tuberculosinyl adenosine synthase, as well as being an uncoupler. Because vacquinol is also an inhibitor of M. tuberculosis cell growth, we used similarity searches based on the vacquinol structure, finding analogs with potent (∼0.5-2 μg/mL) activity against M. tuberculosis and S. aureus. Our results give a logical explanation of the observation that most new tuberculosis drug leads discovered by phenotypic screens and genome sequencing are highly lipophilic (logP ∼5.7) bases with membrane targets because such species are expected to partition into hydrophobic membranes, inhibiting membrane proteins, in addition to collapsing the PMF. This multiple targeting is expected to be of importance in overcoming the development of drug resistance because targeting membrane physical properties is expected to be less susceptible to the development of resistance.

https://www.pnas.org/content/pnas/112/51/E7073.full.pdf

Antiinfectives targeting enzymes and the proton motive force

As a new type of C2-symmetric chiral diene ligands, which coordinate to a metal by their 1,5-cyclooctadiene framework, we prepared 2,6-disubstituted bicyclo[3.3.1]nona-2,6-diene (bnd*) and bicyclo[3.3.2]deca-2,6-diene (bdd*), and examined their catalytic activity and enantioselectivity for rhodium-catalyzed asymmetric 1,4-addition to α,β-unsaturated ketones and 1,2-addition to N-sulfonylimines. High enantioselectivity of the Ph-bnd* ligand was observed in the addition of phenylboroxine to N-tosylimine and N-4-nitrobenzenesulfonylimine of 4-chlorobenzaldehyde to give phenyl(4-chlorophenyl)methylamines in high enantiomeric excess (98–99% ee).

Linda M. Honig

Papers

Bicyclo[3.3.1]nonanes. IV. Dehydration of the bicyclo[3.3.1]nonane-2,6-diols

Bicyclo[3.3.1]nonanes. II. Synthesis and reactions of simple derivatives

Synthesis of potential antimalarials

Secondary isotope effects for solvolyses leading to classical norbornyl cations.

Synth. potentieller malariamittel