Conformationally Constrained Cinnolinone Nucleoside Analogues as Siderophore Biosynthesis Inhibitors for Tuberculosis

Surendra Dawadi, Helena I.M. Boshoff, Sae Woong Park, Dirk Schnappinger, Courtney C. Aldrich

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23 Scopus citations


5′-O-[N-(Salicyl)sulfamoyl]adenosine (Sal-AMS, 1) is a nucleoside antibiotic that inhibits incorporation of salicylate into siderophores required for bacterial iron acquisition and has potent activity against Mycobacterium tuberculosis (Mtb). Cinnolone analogues exemplified by 5 were designed to replace the acidic acyl-sulfamate functional group of 1 (pKa = 3) by a more stable sulfonamide linkage (pKa = 6.0) in an attempt to address potential metabolic liabilities and improve membrane permeability. We showed 5 potently inhibited the mycobacterial salicylate ligase MbtA (apparent Ki = 12 nM), blocked production of the salicylate-capped siderophores in whole-cell Mtb, and exhibited excellent antimycobacterial activity under iron-deficient conditions (minimum inhibitor concentration, MIC = 2.3 μM). To provide additional confirmation of the mechanism of action, we demonstrated the whole-cell activity of 5 could be fully antagonized by the addition of exogenous salicylate to the growth medium. Although the total polar surface area (tPSA) of 5 still exceeds the nominal threshold value (140 Å) typically required for oral bioavailability, we were pleasantly surprised to observe introduction of the less acidic and conformationally constrained cinnolone moiety conferred improved drug disposition properties as evidenced by the 7-fold increase in volume of distribution in Sprague-Dawley rats.

Original languageEnglish (US)
Pages (from-to)386-391
Number of pages6
JournalACS Medicinal Chemistry Letters
Issue number4
StatePublished - Apr 12 2018

Bibliographical note

Publisher Copyright:
© 2018 American Chemical Society.


  • Tuberculosis
  • conformationally constrained analogues
  • mycobactin
  • pharmacokinetics
  • siderophores


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