Title:The Introduction of Hydrazone, Hydrazide, or Azepane Moieties to the Triterpenoid Core Enhances an Activity Against M. tuberculosis
Volume: 17
Issue: 2
Author(s): Oxana B. Kazakova*, Natalya I. Medvedeva, Irina E. Smirnova, Tatyana V. Lopatina and Alexander V. Veselovsky
Affiliation:
- Ufa Institute of Chemistry of the Ufa Federal Research Centre of the Russian Academy of Sciences, 71 Prospekt Oktyabrya, 450054, Ufa,Russian Federation
Keywords:
Triterpenoids, hydrazone, hydrazide, azepane, Mycobacterium tuberculosis, anti-tubercular agents.
Abstract: Background: Triterpenoids exhibit a wide spectrum of antimicrobial activity.
Objective: The objective of this study was to synthesize a series of nitrogen derivatives based on
lupane, oleanane, and ursane triterpenoids with high antitubercular activity.
Methods: Isonicotinoylhydrazones were prepared via the reaction of 3-oxotriterpenic acids or betulonic
aldehyde with isoniazid (INH) in yields of 54-72%. N-Acylation of betulonic or azepanobetulinic
acids led to lupane C28 hydrazides and dihydrazides. The derivatives were evaluated for
their in vitro antimycobacterial activities against Mycobacterium tuberculosis (MTB) H37RV and
single-drug resistance (SDR)-TB in the National Institute of Allergy and Infectious Diseases,
USA. Molecular docking was performed to evaluate the possible binding modes of investigated
compounds in the active site of Diterpene synthase (Rv3378c).
Results: The obtained compounds are represented by C3 or C28 conjugates with hydrazine hydrate
or INH. Some compounds demonstrated from high minimum inhibitory concentration (MIC ≤ 10
μg/mL) to excellent (MICs from 0.19 to 1.25 μg/mL) activity against MTB H37RV. Two lupane
conjugates with INH were the leading compounds against MTB H37RV and some SDR-strains with
MICs ranged from 0.19 to 1.70 μg/mL. Molecular docking of active compounds to diterpene synthase
showed that these moieties accommodate the active site of the enzyme.
Conclusion: It was revealed that the conjugation of lupanes with INH at C3 is more effective than
at C28 and the lupane skeleton is preferable among oleanane and ursane types. The replacement of
native hexacarbocyclic A ring to seven-member azepane ring is favorably for inhibition of both
MTB H37RV and SDR-strains. These data could possibly mean that the antitubercular activity
against INH-resistant strains (INH-R) came from both triterpenoid and isoniazid parts of the hybrid
molecules. Azepanobetulin showed the highest activity against both INH-R strains in comparison
with other triterpenoids and INH. Thus, the introduction of hydrazone, hydrazide (dihydrazide),
or azepane moieties into the triterpenoid core is a promising way for the development of
new anti-tubercular agents.
