Design, synthesis, and structure-activity relationship studies of tryptanthrins as antitubercular agents

Jae Min Hwang, Taegwon Oh, Takushi Kaneko, Anna M. Upton, Scott G. Franzblau, Zhenkun Ma, Sang Nae Cho, Pilho Kim

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

The natural product tryptanthrin (1a) represents a potential lead for new tuberculosis (TB) drugs since tryptanthrin and its synthetic analogues possess potent in vitro activity against Mycobacterium tuberculosis (Mtb). However, in spite of their in vitro activity, none of these agents have been shown to be efficacious in vivo against animal models of TB. Described herein are syntheses of new tryptanthrin analogues together with a systematic investigation of their in vitro antitubercular activity and ADME properties followed by pharmacokinetic characterization in rodents for the most promising compounds. Those with the best potency and oral bioavailability were progressed to evaluations of efficacy against acute murine TB. The work aimed to prove the concept that this compound class can limit growth of Mtb during infection as well as to establish the SAR for in vitro activity against Mtb and the range of in vitro ADME parameters for this class of natural products. Novel C-11-deoxy (5b) and A-ring-saturated (6) tryptanthrin analogues were discovered that maintained activity against Mtb and showed improved solubility compared to tryptanthrin as well as evidence of oral bioavailability in rodents. However, neither 5b nor 6 demonstrated efficacy against acute murine TB following administration at doses up to 400 mg/kg daily for 4 weeks. Although 5b and 6 failed to inhibit replication or kill Mtb in vivo, they illuminate a path to new structural variations of the tryptanthrin scaffold that may maximize the potential of this class of compounds against TB.

Original languageEnglish
Pages (from-to)354-367
Number of pages14
JournalJournal of Natural Products
Volume76
Issue number3
DOIs
Publication statusPublished - 2013 Mar 22

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Antitubercular Agents
Structure-Activity Relationship
Mycobacterium tuberculosis
Tuberculosis
Biological Products
Biological Availability
Rodentia
Pharmacokinetics
Scaffolds
Solubility
tryptanthrine
Animals
Animal Models
In Vitro Techniques
Growth
Infection
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

Cite this

Hwang, J. M., Oh, T., Kaneko, T., Upton, A. M., Franzblau, S. G., Ma, Z., ... Kim, P. (2013). Design, synthesis, and structure-activity relationship studies of tryptanthrins as antitubercular agents. Journal of Natural Products, 76(3), 354-367. https://doi.org/10.1021/np3007167
Hwang, Jae Min ; Oh, Taegwon ; Kaneko, Takushi ; Upton, Anna M. ; Franzblau, Scott G. ; Ma, Zhenkun ; Cho, Sang Nae ; Kim, Pilho. / Design, synthesis, and structure-activity relationship studies of tryptanthrins as antitubercular agents. In: Journal of Natural Products. 2013 ; Vol. 76, No. 3. pp. 354-367.
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Design, synthesis, and structure-activity relationship studies of tryptanthrins as antitubercular agents. / Hwang, Jae Min; Oh, Taegwon; Kaneko, Takushi; Upton, Anna M.; Franzblau, Scott G.; Ma, Zhenkun; Cho, Sang Nae; Kim, Pilho.

In: Journal of Natural Products, Vol. 76, No. 3, 22.03.2013, p. 354-367.

Research output: Contribution to journalArticle

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