title: Design, synthesis and evaluation of Fe-S targeted adenosine 5'-phosphosulfate reductase inhibitors.
abstract: Adenosine 5'-phosphosulfate reductase (APR) is an iron-sulfur enzyme that is vital for survival of Mycobacterium tuberculosis during dormancy and is an attractive target for the treatment of latent tuberculosis (TB) infection. The 4Fe-4S cluster is coordinated to APR by sulfur atoms of four cysteine residues, is proximal to substrate, adenosine 5'-phopsphosulfate (APS), and is essential for catalytic activity. Herein, we present an approach for the development of a new class of APR inhibitors. As an initial step, we have employed an improved solid-phase chemistry method to prepare a series of N(6)-substituted adenosine analogues and their 5'-phosphates as well as adenosine 5'-phosphate diesters bearing different Fe and S binding groups, such as thiols or carboxylic and hydroxamic acid moieties. Evaluation of the resulting compounds indicates a clearly defined spacing requirement between the Fe-S targeting group and adenosine scaffold and that smaller Fe-S targeting groups are better tolerated. Molecular docking analysis suggests that the S atom of the most potent inhibitor may establish a favorable interaction with an S atom in the cluster. In summary, this study showcases an improved solid-phase method that expedites the preparation of adenosine and related 5'-phosphate derivatives and presents a unique Fe-S targeting strategy for the development of APR inhibitors.
authors.affiliation: a Department of Chemistry, The Scripps Research Institute , Jupiter , Florida , USA.
authors.forename: Hanumantharao
authors.initials: H
authors.lastname: Paritala
authors.forename: Yuta
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Kate S
authors.initials: KS
authors.lastname: Carroll
mesh_terms: D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry*; D007501:Iron / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000037:antagonists & inhibitors*; D060327:Solid-Phase Synthesis Techniques; D013455:Sulfur / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D013455:Sulfur; D007501:Iron; D050862:Oxidoreductases Acting on Sulfur Group Donors; C019618:adenylylsulfate reductase
keywords: Antibacterial nucleosides; enzyme inhibition; solid phase synthesis