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3. Recent Advances in Pyrimidine-Based Drugs.

Author

Nammalwar, Baskar and Bunce, Richard A.

Subjects
*DRUG discovery, *DRUG target, *PYRIMIDINES, *PHARMACEUTICAL chemistry, *DRUGS, *NEUROLOGICAL disorders
Abstract

Pyrimidines have become an increasingly important core structure in many drug molecules over the past 60 years. This article surveys recent areas in which pyrimidines have had a major impact in drug discovery therapeutics, including anti-infectives, anticancer, immunology, immuno-oncology, neurological disorders, chronic pain, and diabetes mellitus. The article presents the synthesis of the medicinal agents and highlights the role of the biological target with respect to the disease model. Additionally, the biological potency, ADME properties and pharmacokinetics/pharmacodynamics (if available) are discussed. This survey attempts to demonstrate the versatility of pyrimidine-based drugs, not only for their potency and affinity but also for the improved medicinal chemistry properties of pyrimidine as a bioisostere for phenyl and other aromatic π systems. It is hoped that this article will provide insight to researchers considering the pyrimidine scaffold as a chemotype in future drug candidates in order to counteract medical conditions previously deemed untreatable. [ABSTRACT FROM AUTHOR]

Published
2024
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10. Small Molecule Inhibitors of the BfrB–Bfd Interaction Decrease Pseudomonas aeruginosa Fitness and Potentiate Fluoroquinolone Activity

Author

Punchi Hewage, Achala N. D., primary, Yao, Huili, additional, Nammalwar, Baskar, additional, Gnanasekaran, Krishna Kumar, additional, Lovell, Scott, additional, Bunce, Richard A., additional, Eshelman, Kate, additional, Phaniraj, Sahishna M., additional, Lee, Molly M., additional, Peterson, Blake R., additional, Battaile, Kevin P., additional, Reitz, Allen B., additional, and Rivera, Mario, additional

Published
2019
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21. Small Molecule Inhibitors of the BfrB–Bfd Interaction Decrease Pseudomonas aeruginosaFitness and Potentiate Fluoroquinolone Activity

Author

Punchi Hewage, Achala N. D., Yao, Huili, Nammalwar, Baskar, Gnanasekaran, Krishna Kumar, Lovell, Scott, Bunce, Richard A., Eshelman, Kate, Phaniraj, Sahishna M., Lee, Molly M., Peterson, Blake R., Battaile, Kevin P., Reitz, Allen B., and Rivera, Mario

Abstract

The iron storage protein bacterioferritin (BfrB) is central to bacterial iron homeostasis. The mobilization of iron from BfrB, which requires binding by a cognate ferredoxin (Bfd), is essential to the regulation of cytosolic iron levels in P. aeruginosa. This paper describes the structure-guided development of small molecule inhibitors of the BfrB–Bfd protein–protein interaction. The process was initiated by screening a fragment library and followed by obtaining the structure of a fragment hit bound to BfrB. The structural insights were used to develop a series of 4-(benzylamino)- and 4-((3-phenylpropyl)amino)-isoindoline-1,3-dione analogs that selectively bind BfrB at the Bfd binding site. Challenging P. aeruginosacells with the 4-substituted isoindoline analogs revealed a dose-dependent growth phenotype. Further investigation determined that the analogs elicit a pyoverdin hyperproduction phenotype that is consistent with blockade of the BfrB–Bfd interaction and ensuing irreversible accumulation of iron in BfrB, with concomitant depletion of iron in the cytosol. The irreversible accumulation of iron in BfrB prompted by the 4-substituted isoindoline analogs was confirmed by visualization of BfrB-iron in P. aeruginosacell lysates separated on native PAGE gels and stained for iron with Ferene S. Challenging P. aeruginosacultures with a combination of commercial fluoroquinolone and our isoindoline analogs results in significantly lower cell survival relative to treatment with either antibiotic or analog alone. Collectively, these findings furnish proof of concept for the usefulness of small molecule probes designed to dysregulate bacterial iron homeostasis by targeting a protein–protein interaction pivotal for iron storage in the bacterial cell.

Published
2019
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45. Diastereoselective Synthesis of N-Alkylated Octahydroacridines via a Catalyst-Free SNAr Approach.

Author

Muddala, Nagendra Prasad, Nammalwar, Baskar, Selvaraju, Subhashini, and Bunce, Richard A.

Subjects
*ACRIDINES, *CHEMICAL synthesis, *CATALYST synthesis, *ALKYLATION, *CHEMICAL research
Abstract

A three-step diastereoselective synthesis of N-alkylated octahydroacridines has been developed from inexpensive starting materials. Alkylation of cyclohexanone with 2-fluorobenzyl bromide, followed by nitration para to the aromatic fluoro substituent provided the cyclization substrate in 61% yield. Finally, a tandem reductive amination- SNAr cyclization with NaCNBH3 furnished the target compounds in 74-92% yields. X-ray and 1H NMR studies permitted assignment of the stereochemistry of the B-C ring junction. The 3:1-10:1 preference for the cis-isomer was rationalized in terms of steric interactions in the imine reduction and a chair-like conformation for the cyclization. Hydride would be delivered to the molecular face opposite the fluoronitrobenzyl substituent at C-2 of the cyclohexanimine intermediate and the resulting amine would be positioned for addition to the SNAr acceptor ring via a chair-like conformation. [ABSTRACT FROM AUTHOR]

Published
2015
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