Synthesis and antituberculosis activity of derivatives of the diterpenoid isosteviol with azine, hydrazide, and hydrazone moieties

Abstract

Derivatives of the diterpenoid isosteviol (16-oxo-ent-beyeran-19-oic acid) with azine, hydrazone, and hydrazide moieties were synthesized. They exhibited high tuberculostatic activity in vitro against the strain Mycobacterium tuberculosis H 37 R V (minimum inhibiting concentration in the range 6.3-1.7 Pg/mL).Only streptomycin, capreomycin, and kanamycin of all drugs used today for tuberculosis chemotherapy are isolated from natural sources [1]. All other tuberculosis drugs [1] and agents undergoing preclinical and clinical trials [2, 3] are products from organic syntheses. Nevertheless, over 50 metabolites of various structures that inhibit the growth of Mycobacterium tuberculosis in the range of minimum inhibiting concentrations (MIC) 60-3 Pg/mL have currently been isolated from natural plant sources [4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Diterpenoids [4,5,[8][9][10][11][12][13] and triterpenoids [4,5,11,[14][15][16][17] are most widely represented among them. The diterpenoid isosteviol (16-oxo-ent-beyeran-19-oic acid) (1) also exhibits moderate antituberculosis activity (MIC = 50 Pg/mL). Our group has investigated for several years chemical modification of 1 and its derivatives in which two isosteviol molecules are linked by a polymethylene spacer with C 16 atoms [18]. It was found that the length of the spacer affects considerably the activity. Increasing the number of methylenes in the spacer from one to eight decreases MIC from 25 to 12.5 Pg/mL [18]. These results were unusual because 1, its bis-derivatives [18], and the aforementioned di-and triterpenoids of different structures [4,5,[8][9][10][11][12][13][14][15][16][17] are not nitrogenous organic compounds yet they exhibit antituberculosis activity at the level of the N-containing antituberculosis drug pyrazinamide (MIC = 12.5 Pg/mL) [19,20]. This is probably evidence that they have a different mechanism of M. tuberculosis growth inhibition. It seemed interesting to determine how the introduction of pharmacophoric N-containing moieties (hydrazide and hydrazone) into 1 and its bis-derivatives [18] affects their antituberculosis activity.For this we reacted 1 and its acid chloride 4 with hydrazine hydrate and adipic acid hydrazide (Scheme 1) and studied the ability of the resulting products to inhibit the growth of M. tuberculosis.The reaction of 1 and an excess of hydrazine hydrate in MeOH gave not isosteviol hydrazone (3) but the azine 2, which was isolated as the salt (Scheme 1). The reason for this was probably that hydrazone 3 formed and reacted with both starting 1 and that formed via hydrolysis of 3. Compound 3 was obtained pure via reaction of 1 with a 10-fold excess of anhydrous hydrazine.The reaction of isosteviol acid chloride 4 with anhydrous hydrazine in CCl 4 produced 5. Its PMR spectrum showed characteristic resonances for protons of the ent-beyerane skeleton in addition to a broad singlet of the hydrazide amine at 3.83 ppm, a broad singlet of the hydrazone amine at 4.75, and a singlet of the hydrazide amide at 6.9. The reactio...

Bioactivity Profile of the Diterpene Isosteviol and its Derivatives

“…When two isosteviol molecules are linked by a polymethylene spacer with C16 atoms and increase the number of methylenes in the spacer from one to eight, it decreases the minimal inhibitory concentration. Hence, it is also found that functionalization of N-containing groups (hydrazide and hydrazone) into isosteviol and its bis-derivatives increase their antitubercular activity and reduce the minimal inhibitory concentrations (MIC) [ 129 , 131 , 132 ]. Furthermore, hydrazone subsidiaries and conjugates holding two isosteviol moieties with a dihydrazide linker were acquired.…”

Macrocyclic Derivatives of Diterpenoid Isosteviol with Hydrazide and Hydrazone Moieties

“…Thus the yields of macrocycles 15 and 16 were very similar at the acid chloride -pyridine ratio both 1:70 and 1:900. The 1 H NMR spectra of compounds 14-16 showed just a one set of signals characteristic for isosteviol 1 and its derivatives, [11][12][13]20,21,25,29] namely three singlets corresponding to С 18 Н 3 ,…”

“…198-200 °C [24] ). Diacid 8 was synthesized by the interaction of isosteviol with adipic acid dihydrazide, [21] m.p. > 300 °C (m.p.…”

“…[21] Taking into account results aforementioned [13,20] we suppose that a synthesis of macrocycles having several isosteviol moieties connected by dihydrazide and dihydrazone linkers could be an efficient approach to obtain novel isosteviol derivatives exhibiting higher antituberculosis activities.…”

Advances in Key Drug Target Identification and New Drug Development for Tuberculosis

“…Rv3377c cyclizes bicyclization and rearrangement of (E, E, E)-geranylgeranyl diphosphate to halimadienyl-diphosphate (HPP). Meanwhile, Rv3378c hydrolyzes HPP to the novel tricyclic diterpene edaxadiene, which directly inhibits phagosomal maturation in vitro [126][127][128]. Diterpenoid and triterpenoid acids, including isosteviol and betulinic, oleanolic, and ursolic acids, as well as binuclear isosteviol derivatives, showed moderate anti-TB activity by competitively binding to the active site of diterpene synthase.…”