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Synthesis methods for heterocyclic drug compounds

Ametsetor, Ebenezer
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 aim of this project was to develop small molecules which could inhibit this protein-protein interaction and elicit perturbations in iron homeostasis consequently leading to bacterial cell death. 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 and other heterocyclic derivatives were synthesized and characterized. Based on molecular modeling, the following modifications below led to the synthesis of new series of compounds. • Incorporation of new substituted benzaldehydes and altering the 3-carbon linker unit into a 1-carbon linker with similar substitution pattern: It was envisioned that, the incorporation of these functionalities in the analogs of the 4-aminoisoindoline-1,3-dione would possibly increase the inhibitory effect. We subsequently designed and synthesized a series of new compounds incorporating various substituents on the benzaldehyde component. • Replacing the benzaldehyde component with other heterocycles. • Replacing the 4-aminoisoindoline-1,3-dione component with different heterocycles.
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:• A domino Aza-Michael-SNAr-heteroaromatization route to C5-substituted1-alkyl-1H-indole-3-carboxylic esters was developed and optimized. • Naphthalenes and quinolines were prepared by domino reactions of Morita-Baylis-Hillman acetates. • Synthesis and elimination pathways of 1-methanesulfonyl-1,2-dihydroquinoline sulfonamides was developed. • A one-pot route to quinolin-2(1H)-ones and 1,8-naphthyridin -2(1H)-ones was accomplished using domino Knoevenagel-SNAr reactions.