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 N6-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.

Synthesis of Fucose Derivatives with Thiol Motifs towards Suicide Inhibition of Helicobacter pylori

“…Upon further investigation, we realised that compound 23 had degraded within 5 days. Interestingly, Paritala et al have also reported degradation upon isolation of a product containing the same 2-carbon thioacetyl motif [ 34 ]. They reported that stability of their product could be increased by replacing the thioacetyl group with that of a thiobenzoyl, perhaps suggesting that degradation was occurring due to migration of the acetyl group.…”

“…Alkyl bromide 24 was synthesised from 1,2-dibromoethane and sodium thiobenzoate in an 86% yield [ 35 ]. Paritala et al reported the use of microwave methodology to alkylate a primary amine in their synthetic pathway using 24 [ 34 ]. However, in our hands, we only observed S→N acyl-transfer using these conditions [ 32 ].…”

Addressing Latent Tuberculosis: New Advances in Mimicking the Disease, Discovering Key Targets, and Designing Hit Compounds

“…Besides its connections with oxidative stress and mycobacterial survival, this enzyme does not have a homologue in humans, turning it into a potentially attractive and selective therapeutic target [ 144 ]. Over the years, inhibitors of APSR have been reported, either discovered by HTS or designed as analogs of its substrate, APS [ 153 , 154 , 155 ]. However, only in 2016, a series of inhibitors derived from HTS were for the first time screened against nonreplicating M.tb , confirming the potential of this target for dormant bacilli.…”

Fe‐S Clusters Emerging as Targets of Therapeutic Drugs

“…The essential adenosine 5′-phosphosulfate reductase (APR) is a [4Fe-4S]-containing enzyme in M. tuberculosis . Several adenosine analogs were developed and selected for the presence of Fe and S binding groups such as thiols or carboxylic and hydroxamic acids, providing an improved solid-phase method as an approach for the development of a new class of APR inhibitors [ 95 ].…”