Conjugates of several lupane, oleanane, and ursane triterpenoids with the antituberculosis drug isoniazid and pyridinecarboxaldehydes

Abstract

Conjugates of betulinic, oleanolic, ursolic, and glycyrrhetic acids and several of their derivatives with the antituberculosis drug isoniazid and 3-and 4-pyridinecarboxaldehydes were synthesized.Betulinic, oleanolic, ursolic, and glycyrrhetic acids have been successfully modified in the last decades to produce new biologically active compounds [1-6] of various structures including hydrazides and hydrazones [4] with antiviral and antitumor activity. It was shown recently that functionalization of the diterpenoid oxo-acid isosteviol by N-containing groups increased its antituberculosis activity, reducing the minimal inhibitory concentrations (MIC) from 50 to 1.5 Pg/mL [7]. Because antituberculosis activity is also typical of triterpenoids, namely betulin [8] and betulinic [8][9][10][11], oleanolic [10-13], and ursolic [10,14] acids, it seemed interesting to perform an analogous investigation of the isoprenoid series by studying the effect of their functionalization by the same N-containing groups that were used for isosteviol [7].Herein we report the synthesis of conjugates of betulinic, oleanolic, ursolic, and glycyrrhetic acids and 28-oxoallobetulone with the antituberculosis drug isoniazid (4-pyridinecarboxylic acid hydrazide) and 3-and 4-pyridinecarboxaldehydes.Mixed hydrazides 7-9 (Scheme 1) were synthesized via reaction of acid chlorides 4-6, which were prepared from triterpene acids 1-3, with isoniazid by refluxing in CHCl 3 in analogy with the previous work [15]. The target products were isolated by column chromatography in 71-77% yields. The PMR spectra turned out to be sufficiently characteristic to establish their structures. They showed resonances for amide protons at weak field (G 6.35 ppm, 8.15, 9.00-9.25, 10.15-10.90). Doubled resonances for the amide protons were noted in 7. This indicated that conformational equilibrium around the C(O)-N bond was occurring in solution. Protons of the pyridine rings of 7-9 appeared as doublets at G 7.56-7.68 (H-3c, H-5c) and 8.50-8.67 (H-2c, H-6c) ppm. 13 C NMR spectra exhibited resonances for C-28 (C-30) and C-7c at G 174.3-176.3 and 161.4-163.7 ppm.

Screening and Characterisation of Antimicrobial Properties of Semisynthetic Betulin Derivatives

“…To our knowledge, UA or OA having a C3 carbonyl and C28 carboxyl groups have not been assayed against any bacterial species, even though both have been used as a starting material in studies of related derivatives against Mycobacterium tuberculosis [39] , S. aureus and Klebsiella pneumoniae [40] . It would be highly interesting to investigate their antibacterial properties to further evaluate the hypothesis of favouring effect of both C3 carbonyl and C28 carboxyl groups in pentacyclic triterpenes.…”

Novel A-Ring Chalcone Derivatives of Oleanolic and Ursolic Amides with Anti-Proliferative Effect Mediated through ROS-Triggered Apoptosis

“…The solvents were purified and 3-oxo-, 3-oximino-triterpenoids were synthesized according to the standard methods. Compounds 5 , 6 , 25 , and 26 [ 65 ], 8 and 28 [ 66 ], 2,3-indole derivatives of compounds 3, 4 [ 67 ], and 15 [ 68 ] were obtained according to the methods described previously.…”

Evaluation of A-azepano-triterpenoids and related derivatives as antimicrobial and antiviral agents

“…Recently we have showed that triterpenoids with A-ring azepano- and hydrazido-, hydrazono-substituents are an important group of derivatives with antibacterial activities [ 22 – 25 ]. To compare the influence of substituents in different positions of the triterpene core on antibacterial, fungicidal, and antiviral activities, a series of previously synthesized compounds 1–22 (Fig.…”