Piperazinobenzodiazepinones: New Encephalitic Alphavirus Inhibitors via Ring Expansion of 2-Dichloromethylquinazolinones.

Venezuelan and eastern equine encephalitis viruses are disease-causing, neuropathic pathogens with no approved treatment options in humans. While expanding the pharmacophoric model of antialphaviral amidines prepared via a quinazolinone rearrangement, we discovered that diamine-treated, 2-dihalomethylquinolinones unexpectedly afforded ring-expanded piperazine-fused benzodiazepinones. Notably, this new chemotype (19 examples) showed potent, submicromolar inhibition of virus-induced cell death, >7-log reduction of viral yield, and tractable structure-activity relationships across both viruses.

Ready Access to Benzannulated [5,5]-Oxaspirolactones Using Au(III)-Catalyzed Cascade Cyclizations.

This work showcases an unprecedented Au(III)-catalyzed cascade cyclization of 2-(4-hydroxyalkynyl)benzoates to access benzannulated [5,5]-oxaspirolactones related to biologically active natural products. This reaction proceeds through an initial 5--dig mode of hydroalkoxylation of the alkynol segment to give the oxocarbenium species (via cyclic enol-ether) followed by the addition of carboxylate onto the oxocarbenium that delivers the oxaspirolactone scaffold. While testing this method's scope, we found that the steric and electronic environment of the hydroxyl group could alter the reaction pathway that delivers isochromenone through a competitive 6--dig mode of attack of the carboxylate onto the tethered alkyne.

Design, Synthesis, and Structural Analysis of Cladosporin-Based Inhibitors of Malaria Parasites.

Here we have described a systematic structure activity relationship (SAR) of a set of compounds inspired from cladosporin, a tool compound that targets parasite () lysyl tRNA synthetase (KRS). Four sets of analogues, synthesized based on point changes in the chemical scaffold of cladosporin and other logical modifications and hybridizations, were assessed using high throughput enzymatic and parasitic assays along with pharmacokinetics. Co-crystallization of the most potent compound in our series () with KRS revealed its structural basis of enzymatic binding and potency.

Herbicidal bio-assay of isocladosporin enantiomers and determination of its plausible absolute configuration.

A fungal metabolite, isocladosporin was isolated from natural fungus, Cladosporium cladosporioides in the mid of 90s. Due to the lack of optical rotation of isolated natural product sample, the absolute configuration of the natural product remained undetermined for more than two decades. Herein, we demonstrated an SAR study of enantiomers of isocladosporin in herbicidal bio-assay against wheat coleoptile.

The biological process of lysine-tRNA charging is therapeutically targetable in liver cancer.

Background & Aims: Mature transfer RNAs (tRNA) charged with amino acids decode mRNA to synthesize proteins. Dysregulation of translational machineries has a fundamental impact on cancer biology. This study aims to map the tRNAome landscape in liver cancer patients and to explore potential therapeutic targets at the interface of charging amino acid with tRNA.

DFT/NMR Approach for the Configuration Assignment of Groups of Stereoisomers by the Combination and Comparison of Experimental and Predicted Sets of Data.

Quantum mechanical/nuclear magnetic resonance (NMR) approaches are widely used for the configuration assignment of organic compounds generally comparing one cluster of experimentally determined data (e.g., C NMR chemical shifts) with those predicted for all possible theoretical stereoisomers.

Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite.

The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral center antimalarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme-, and structure-based assays. We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS).