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

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