Allosteric differences dictate GroEL complementation of E. coli.

GroES/GroEL is the only bacterial chaperone essential under all conditions, making it a potential antibiotic target. Rationally targeting ESKAPE GroES/GroEL as an antibiotic strategy necessitates studying their structure and function. Herein, we outline the structural similarities between Escherichia coli and ESKAPE GroES/GroEL and identify significant differences in intra- and inter-ring cooperativity, required in the refolding cycle of client polypeptides.

Functional Differences between E. coli and ESKAPE Pathogen GroES/GroEL.

As the GroES/GroEL chaperonin system is the only bacterial chaperone that is essential under all conditions, we have been interested in the development of GroES/GroEL inhibitors as potential antibiotics. Using GroES/GroEL as a surrogate, we have discovered several classes of GroES/GroEL inhibitors that show potent antibacterial activity against both Gram-positive and Gram-negative bacteria. However, it remains unknown if GroES/GroEL is functionally identical to other GroES/GroEL chaperonins and hence if our inhibitors will function against other chaperonins.

A one-step, atom economical synthesis of thieno[2,3-]pyrimidin-4-amine derivatives via a four-component reaction.

A NaHPO-catalyzed four-component reaction between a ketone, malononitrile, S and formamide has been realized for the first time. This reaction provides a concise approach to thieno[2,3-]pyrimidin-4-amines, previously requiring 5 steps. The utility of this reaction was validated by preparing a multi-targeted kinase inhibitor and an inhibitor of the NRF2 pathway with excellent atom- and step-economy.

One-Step Synthesis of Thieno[2,3-]pyrimidin-4(3)-ones via a Catalytic Four-Component Reaction of Ketones, Ethyl Cyanoacetate, S and Formamide.

Thieno[2,3-]pyrimidin-4(3)-ones are important pharmacophores that previously required a three step synthesis with two chromatography steps. We herein report a green approach to the synthesis of this pharmacologically important class of compounds via a catalytic four-component reaction using a ketone, ethyl cyanoacetate, S and formamide. The reported reaction is characterized by step economy, reduced catalyst loading and easy purification.