Submit Manuscript  

Article Details


The Introduction of Hydrazone, Hydrazide, or Azepane Moieties to the Triterpenoid Core Enhances an Activity Against M. tuberculosis

Author(s):

Oxana B. Kazakova*, Natalya I. Medvedeva, Irina E. Smirnova, Tatyana V. Lopatina and Alexander V. Veselovsky   Pages 1 - 12 ( 12 )

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 antitubecular 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 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 are accommodate the active site of enzyme.

Conclusions: It was revealed that conjugation of lupanes with INH at C3 is more effective than at C28 and 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 triterpenoid core is a promising way for the development of new anti-tubercular agents.

Keywords:

triterpenoids, hydrazone, hydrazide, azepane, Mycobacterium tuberculosis

Affiliation:

Ufa Institute of Chemistry of the Ufa Federal Research Centre of the Russian Academy of Sciences, 71 Prospekt Oktyabrya, 450054, Ufa, Ufa Institute of Chemistry of the Ufa Federal Research Centre of the Russian Academy of Sciences, 71 Prospekt Oktyabrya, 450054, Ufa, Ufa Institute of Chemistry of the Ufa Federal Research Centre of the Russian Academy of Sciences, 71 Prospekt Oktyabrya, 450054, Ufa, Ufa Institute of Chemistry of the Ufa Federal Research Centre of the Russian Academy of Sciences, 71 Prospekt Oktyabrya, 450054, Ufa, Institute of Biomedical Chemistry, 10 Pogodinskaya str., 119121, Moscow



Read Full-Text article