Synthesis and antituberculosis activity of derivatives of Stevia rebaudiana glycoside steviolbioside and diterpenoid isosteviol containing hydrazone, hydrazide, and pyridinoyl moieties

Abstract

Conjugates of antitubercular drug Isoniazid (hydrazide of isonicotinic acid), nicotinic and alpha-picolinic acid hydrazides and glycoside steviolbioside from the plant Stevia rebaudiana as well as the product of its acid hydrolysis, diterpenoid isosteviol, were synthesized. Besides, isosteviol hydrazide and hydrazone derivatives as well as conjugates containing two isosteviol moieties connected by dihydrazide linker were also obtained. Both initial compounds and their synthetic derivatives inhibit the growth of Mycobacterium tuberculosis (H37Rv in vitro). The minimum concentration at which the growth of M. tuberculosis was inhibited by 100% (MIC) for stevioside and steviolbioside equals 7.5 and 3.8 microg/mL, respectively. MIC values for conjugates of the hydrazides of pyridine carbonic acids and steviolbioside as well as isosteviol are in the ranges 5-10 and 10-20 microg/mL, respectively. Maximum inhibitory effect against M. tuberculosis showed the conjugates of isosteviol and adipic acid dihydrazide (MIC values ranged from 1.7 to 3.1 microg/mL). Antitubercular activity of the compounds studied is higher than the activity of antitubercular drug Pyrizanamide (MIC = 12.5-20 microg/mL) but lower than the activity of antitubercular drug Isoniazid (MIC = 0.02-0.04 microg/mL).

Bioactivity Profile of the Diterpene Isosteviol and its Derivatives

“…Those parental compounds and their manufactured subsidiaries restrain the in vitro growth of M. tuberculosis (H37RV). The maximal inhibitory effect against M. tuberculosis was shown by the isosteviol conjugates with adipic acid dihydrazide (MIC 1.7 and 3.1 μg/mL) [ 133 ]. Isosteviol is a well-known growth regulator with a tendency to perform the oxidative phosphorylation shell of M. tuberculosis .…”

(–)‐Isosteviol as a Versatile Ex‐Chiral‐Pool Building Block for Organic Chemistry

“…Hydrazone derivatives 10 , like the pyridinecarbonyl‐substituted compounds with the nitrogen atom located at all possible positions in the pyridine ring (R′ = NHCOPyr), can be formed from the corresponding hydrazides. Thus, reaction of 2 or 4 with pyridinecarbonylhydrazides and p TsCl in methanol provides the corresponding hydrazones in good‐to‐excellent yields 23,24. Furthermore, the reaction of 2 with benzylamine under solvent‐free conditions gives access to imine derivative 11 in moderate yields 25…”

“…Table 1 displays a selection of those compounds that exhibit enhanced biological activity. The biological activities evaluated included the inhibition of α‐glucosidase,14 M. tuberculosis growth23,24 as well as seed germination and root elongation 29. Furthermore, the cytotoxic activity against B16‐F10 melanoma cells,11 staphylococcus aureus and bacillus subtilis ,10 were also studied.…”

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

“…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].…”

“…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.…”