Synthesis and antimycobacterial activity of triterpenic A-ring azepanes

• Published in: European journal of medicinal chemistry 2018-01, Vol.143, p.464-472
• Main Authors: Medvedeva, Natalya I., Kazakova, Oxana B., Lopatina, Tatyana V., Smirnova, Irina E., Giniyatullina, Gul'nara V., Baikova, Irina P., Kataev, Vladimir E.
• Format: Article
• Language: English
• Subjects: Antimycobacterial activity; Azepane; Beckmann rearrangement; Betulonic; Isoniazid; Oleanonic and ursonic acids; Single drug-resistant strain; Triterpenoids; Tuberculosis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.11.035

A series of A-ring azepanones and azepanes derived from betulonic, oleanonic and ursonic acids was synthesized and evaluated for their in vitro antimycobacterial activities against M. tuberculosis (MTB) H37Rv and SDR-TB in the National Institute of Allergy and Infectious Diseases. Triterpenic A-azepano-28-hydroxy-derivatives were synthesized by the reduction with LiAlH4 of triterpenic azepanones available from the Beckmann rearrangement of the corresponding C3-oximes. Modification of azepanes at NH-group and atoms С12, C20, C28 and C29 of triterpenic core led to the derivatives with oxo, epoxy, aminopropyl, oximino and acyl substituents. The primary assay of tested triterpenoids against MTB H37Rv demonstrated their MIC values ranged from 3.125 to >200 μM. Ursane type A-azepano-28-cinnamoates were the most active being 2 and 4 times more efficient than the initial 28-hydroxy-derivative. The follow-up testing revealed A-azepano-28-cinnamoyloxybetulin as a leader compound with MIC 2 and MBC 4 μM against MTB H37Rv and MICs 4, 1 and 1 μM against INH, RIF and OFX resistant strains, respectively. Five oleanane and ursane azepanes pronounced better activity than isoniazid against INH-R1 and rifampicin against INH-R2 strains. This work opens a new direction in the design and synthesis of new antitubercular agents basing on azepanotriterpenoids. [Display omitted] •A series of lupane, oleanane and ursane A-azepanotriterpenoids were synthesized.•The primary in vitro assay of tested triterpenoids against MTB H37Rv demonstrated MICs from 3.125 to ˃200 µM.•A-azepano-C28-cinnamoyloxybetulin is the most active compound with MICs 2 µM (MTB H37Rv) and from 1 to 4 µM (SDR strains).•Oleanane and ursane azepanes showed better activity than isoniazid against INH-R1 and rifampicin against INH-R2 strains.