Tuberculosis, caused primarily by the bacillus Mycobacterium tuberculosis (Mtb), is the
leading cause of bacterial infectious disease mortality. Mtb scavenges the essential
micronutrient iron from its host via the synthesis, secretion, and reuptake of smallmolecule
iron chelators known as siderophores. Siderophores in Mtb, termed
mycobactins, have been linked to virulence through targeted genetic disruption of the
mycobactin biosynthetic pathway, validating inhibition of mycobactin biosynthesis for
the development of novel antitubercular agents. Mycobactins are synthesized by mixed
nonribosomal peptide synthetiase/polyketide synthase (NRPS/PKS) machinery in Mtb.
The NRPS assembly line is primed by an aryl acid adenylating enzyme (AAAE) from
Mtb known as MbtA. MbtA is an attractive therapeutic target due to lack of a human
homologue, availability of structural information from homologous AAAEs, and
extensive knowledge of the enzymatic mechanism of a functionally- and structurallysimilar
AAAE. The MbtA mechanism and a potent MbtA bisubstrate inhibitor, 5′-O-[N-
(salicyl)sulfamoyl]adenosine (Sal-AMS), are shown in the figure below. While
demonstrating some adequate pharmacokinetic parameters, Sal-AMS is ultimately
plagued by poor oral bioavailability. Previous studies in our lab indicate that an internal
hydrogen bond is formed between the phenol and charged sulfamate nitrogen atom
(estimated pKa around 2) of Sal-AMS, enforcing a coplanar arrangement of the salicyl
group when bound to the MbtA active site. We thus proposed the synthesis of
conformationally constrained analogues 1–3 to mimic the bound conformation of Sal-
AMS and potentially improve the oral bioavailability of the parent Sal-AMS compound
by removing two rotatable bonds and the charged sulfamate moiety. Oral bioavailability studies are dependent on the proposed analogues’ relative biochemical and antitubercular
potencies versus those of Sal-AMS. Herein is reported the synthesis, biochemical and
antitubercular evaluation of conformationally constrained analogues of Sal-AMS 1–3, as
well as its 2,3-dihydroxybenzoyl variant 4.
University of Minnesota M.S. thesis. December 2012. Major: Medicinal Chemistry. Advisor: Courtney Aldrich. 1 computer file (PDF); xii, 70 pages.
Engelhart, Curtis Alan.
Synthesis and evaluation of conformationally constrained analogues of SAL-AMS, a potent bisubstrate inhibitor of the mycobacterial aryl acid adenylating enzyme MbtA involved in mycobactin biosynthesis.
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