Synthesis and biological evaluation of orally active prodrugs and analogs of para-aminosalicylic acid (PAS)

Pooja V Hegde, Michael D Howe, Matthew D. Zimmerman, Helena I.M. Boshoff, Sachin Sharma, Brianna Remache, Ziyi Jia, Yan Pan, Anthony Baughn, Veronique Dartois, Courtney C. Aldrich

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Tuberculosis (TB) is one of the world's most deadly infectious diseases resulting in nearly 1.3 million deaths annually and infecting nearly one-quarter of the population. para-Aminosalicylic acid (PAS), an important second-line agent for treating drug-resistant Mycobacterium tuberculosis, has moderate bioavailability and rapid clearance that necessitate high daily doses of up to 12 g per day, which in turn causes severe gastrointestinal disturbances presumably by disruption of gut microbiota and host epithelial cells. We first synthesized a series of alkyl, acyloxy and alkyloxycarbonyloxyalkyl ester prodrugs to increase the oral bioavailability and thereby prevent intestinal accumulation as well as undesirable bioactivation by the gut microbiome to non-natural folate species that exhibit cytotoxicity. The pivoxyl prodrug of PAS was superior to all of the prodrugs examined and showed nearly quantitative absorption. While the conceptually simple prodrug approach improved the oral bioavailability of PAS, it did not address the intrinsic rapid clearance of PAS mediated by N-acetyltransferase-1 (NAT-1). Thus, we next modified the PAS scaffold to reduce NAT-1 catalyzed inactivation by introduction of groups to sterically block N-acetylation and fluorination of the aryl ring of PAS to attenuate N-acetylation by electronically deactivating the para-amino group. Among the mono-fluorinated analogs prepared, 5-fluoro-PAS, exhibited the best activity and an 11-fold decreased rate of inactivation by NAT-1 that translated to a 5-fold improved exposure as measured by area-under-the-curve (AUC) following oral dosing to CD-1 mice. The pivoxyl prodrug and fluorination at the 5-position of PAS address the primary limitations of PAS and have the potential to revitalize this second-line TB drug.

Original languageEnglish (US)
Article number114201
JournalEuropean Journal of Medicinal Chemistry
StatePublished - Mar 15 2022

Bibliographical note

Funding Information:
This work was supported by grants ( AI143784 and AI136445 ) from the National Institutes of Health and in part by the Intramural Research Program of NIAID ( AI000693 ). This research was supported [in part] by the Intramural Research Program of the NIAID, NIH . The NMR facility used for the characterization of compounds was supported in part by a NIH S10 instrumentation grant OD021536 (G. Veglia). We would like to thank Dr. Subhankar Panda and Dr. Gorakhnath Jachak for their help and guidance.

Publisher Copyright:
© 2022 Elsevier Masson SAS


  • Fluorination
  • Metabolism
  • N-acetyltransferase
  • Prodrug
  • Tuberculosis
  • para-Aminosalicylic acid (PAS)
  • Biological Availability
  • Aminosalicylic Acid/adverse effects
  • Prodrugs/pharmacology
  • Tuberculosis/drug therapy
  • Animals
  • Antitubercular Agents/pharmacology
  • Mice
  • Tuberculosis, Multidrug-Resistant/drug therapy

PubMed: MeSH publication types

  • Journal Article


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