Ring-fused nitrogen heterocycles by efficient synthetic strategies

Abstract

The first part of this work involved the synthesis of small molecules as potential inhibitors of the bacterioferritin B—bacterioferritin-associated ferredoxin (BfrB—Bfd) protein—protein interaction in Pseudomonas aeruginosa. BfrB is the main iron storage protein, which is central to bacterial iron homeostasis. The mobilization of iron from BfrB requires binding by a cognate ferredoxin (Bfd), thus BfrB—Bfd interaction is essential to the regulation of cytosolic iron levels in P. aeruginosa. The purpose of this project was to develop small molecules which could inhibit this protein—protein interaction and elicit perturbations in iron homeostasis that decrease bacterial fitness. Previous work from our research group involved the synthesis of 4-(alkylamino)isoindoline-1,3-diones which demonstrated promising inhibition of the BfrB—Bfd interaction. The current project focused on the synthesis of analogs that could be effective in a relatively low micromolar range. Consequently, 1- and 3-carbon linker analogs of the 4-(alkylamino)isoindoline-1,3-diones were synthesized and characterized. Based on molecular modeling, the following modifications below led to the synthesis of a series of twelve (12) new compounds.

Incorporation of new benzaldehyde components: Relatively inexpensive starting materials were used for the reaction. It was envisioned that the incorporation of these functionalities in the analogs of the 4-(alkylamino)isoindoline-1,3-diones would possibly increase the inhibitory effect.

Altering the carbon linker: Other modifications were made to the 4-(alkylamino)isoindo-line-1,3-diones by decreasing the 3-carbon linker to a 1-carbon linker with similar aromatic substitution patterns and comparing their activity data.

Substitution of the benzaldehyde component with other heterocyclic groups: The benzaldehyde component for both 1- and 3-carbon linkers was replaced with 2- and 3-furaldehyde and tetrahydrofuran analogs.

The second part of this work involved the design of new methods for the synthesis of bioactive heterocyclic scaffolds. A summary of these methods follows:

An efficient one-pot approach to 1-aryl-5-nitro-1H-indazoles and 1-aryl-1H-indazoles was developed and optimized.

A one-pot route to 4H-benzo[d][1,3]-oxazin-4-ones and dihydro analogs was designed from substituted anthranilic acid and ortho esters.

An efficient, inexpensive approach to bis-1,3,4-oxadiazoles was established using NH4Cl as a catalyst.

An efficient synthesis of naphthalene, dihydroquinoline and naphthyridine carboxylates and carbonitriles as well as quinolones was accomplished using Morita-Baylis-Hillman acetates.