Antiprotozoal activity of diterpenoids isolated from Zhumeria majdae- absolute configuration by circular dichroism

Reza Zadali; Samad Nejad Ebrahimi; Zahra Tofighi; Ali Es-haghi; Matthias Hamburger; Marcel Kaiser; Massimiliano D’ Ambola; Nunziatina De Tommasi; Abbas Hadjiakhoondi

doi:10.1007/s40199-020-00345-w

. 2020 May 11;28(2):455–462. doi: 10.1007/s40199-020-00345-w

Antiprotozoal activity of diterpenoids isolated from Zhumeria majdae- absolute configuration by circular dichroism

Reza Zadali ¹, Samad Nejad Ebrahimi ^2,^✉, Zahra Tofighi ¹, Ali Es-haghi ³, Matthias Hamburger ⁴, Marcel Kaiser ^5,⁶, Massimiliano D’ Ambola ⁷, Nunziatina De Tommasi ⁷, Abbas Hadjiakhoondi ^1,^8,^✉

PMCID: PMC7704868 PMID: 32394309

Abstract

Purpose

Zhumeria majdae, a unique species of the Zhumeria genus, is an endemic Iranian plant in the Lamiaceae family. Phytochemical investigation and biological activity of this plant are rarely reported. The current study aimed to find new antiprotozoal compounds from the roots of Z. majdae and to determine the absolute configuration of isolated compounds by circular dichroism.

Methods

The extraction process from roots and aerial parts of Z. majdae was carried out by hexane, ethyl acetate and methanol followed by testing their antiprotozoal effects against Leishmania donovani, Trypanosoma brucei rhodesiense, T. cruzi, and Plasmodium falciparum, respectively. Structure elucidation was done using 1D and 2D NMR spectroscopy and HREIMS spectrometry. In addition, experimental and theoretical circular dichroism spectroscopy was used to establish absolute configuration.

Results

In comparison with aerial parts, the hexane extract from roots showed superior activity against T. b. rhodesiense, L. donovani and P. falciparum with IC₅₀ values of 5.4, 1.6 and 2.1 μg/ml, respectively. From eight abietane-type diterpenoids identified in roots, six were reported for the first time in the genus Zhumeria. 11,14-dihydroxy-8,11,13-abietatrien-7-one (6) exhibited a promising biological activity against P. falciparum (IC₅₀ 8.65 μM), with a selectivity index (SI) of 4.6, and lanugon Q (8) showed an IC₅₀ value of 0.13 μM and SI of 15.4 against T. b. rhodesiense.

Conclusion

Altogether, according to the results, of 8 isolated compounds, dihydroxy-8,11,13-abietatrien-7-one (6) and lanugon Q (8) exhibited a promising activity against T. b. rhodesiense and P. falciparum. In conclusion, these compounds could be potential candidates for further analysis and may serve as lead compounds for the synthesis of antiprotozoal agents.

graphic file with name 40199_2020_345_Figa_HTML.jpg — Graphical abstract

Electronic supplementary material

The online version of this article (10.1007/s40199-020-00345-w) contains supplementary material, which is available to authorized users.

Keywords: Trypanosoma, Malaria, Lamiaceae, Abietane diterpenoids, Electronic circular dichroism

Introduction

Neglected diseases such as American trypanosomiasis (AT), human African trypanosomiasis (HAT), leishmaniasis, and malaria are among the leading causes of death in developing countries [1]. Because of limited efficacy, side effects, and resistance of parasites against existing medicines, there is an urgent need to discover new active compounds and develop innovative therapies to manage these diseases. In this regard, compounds obtained from natural sources play a significant role in the treatment of many of these diseases [2]. The vast molecular diversity of natural products and their successful track warrants a continued effort to discover pharmacologically active agents from natural sources [3–5]. Compounds such as quinine and artemisinin are regarded as highly successful leads for the development of new antiprotozoal medicines [2]. Plants belonging to the Lamiaceae family are considered a very good source for finding new natural products with promising bioactivities [6]. Zhumeria majdae Rech.f. & Wendelbo, which belongs to the Lamiaceae family, is an endemic plant species growing in Bandar Abbas, Hormozgan Province, Iran and is locally known as “Mohrekhosh” [7]. It is traditionally consumed by local people to treat gastrointestinal diseases and dysmenorrhea [8]. Previous studies of Z. majdae reported anticonvulsant, antinociceptive, and anti-inflammatory properties of the extracts [9, 10]. Three diterpenoids and some flavonoids derivatives have been purified and identified from the roots and aerial parts of Z. majdae [11, 12].

However, the phytochemical studies of this plant have been rarely investigated. Therefore, this study was conducted to investigate the effects of various extracts of Z. majdae on T. b. rhodesiense, T. cruzi, L. donovani and P. falciparum, to isolate and characterize compounds derived from active extracts, and to test purified compounds. To elucidate the structure of the isolated compounds, different spectroscopic techniques were applied such as 1D and 2D NMR together with HREIMS. Moreover, the absolute configuration of the isolates was investigated using a molecular modeling approach through simulation of electronic circular dichroism (ECD) spectroscopy.

Methods

General

The ECD spectra of compounds 1 and 8 were recorded in MeOH (16 μg/mL) using the Chirascan™ spectrometer. The NMR spectra of compounds 1, 2, 3, 6 and 8 were determined using the Bruker Avance III 500 MHz spectrometer operated at 500.13 MHz for ¹H and 125.77 MHz for ¹³C spectra recording. In this regard, a microprobe (1-mm TXI probe head) with a z-gradient was applied for ¹H-detected spectra. The ¹³C-NMR experiments were performed by applying 5-mm BBO probe head with a z-gradient. The NMR spectra of 4 and manool 7 were acquired using the Bruker NMR machine (DRX-600) at 300 K and 2D-NMR experiment was performed in CD₃OD in the phase-sensitive mode. Finally 5 was recorded on a Bruker advance 400 MHz spectrometer at 298 K. Separations was performed by using semi-preparative RP-HPLC on a C 18 μ-Bondapak column (Waters, 30 cm × 7.8 mm, 10 μm, flow rate 2.0 mL/min) with a Waters 590 series pump, a refractive index detector (Waters R 401), and U6K injector. Silica gel column chromatography (70–230 and 230–400 mesh, Merck) was used for large-scale separation and purification. TLC was analyzed using glass-coated silica gel 60 F₂₅₄ (0.20 mm thickness) plates (Merck). The development of TLC plates was monitored at 254 and 366 nm, and further visualized with cerium sulfate and 4-anisaldehyde -sulfuric acid spray reagents.

Plant material

The plant materials were collected from Tange-e-Zagh (altitude of 1300 m) in March 2016 (Bandar-e-Abbas, Hormozgan Province, Iran). The plant samples were identified by Mr. Mohammad A. Soltanipoor and a voucher specimen (7096) was deposited at the Herbarium of Hormozgan Agricultural and Natural Resources Research Center, Bandar-e-Abbas, Iran.

Extraction and isolation

Different parts of Z. majdae (roots and aerial parts) were dried at room temperature in shadow and ground using a mill. To obtain 25.5, 44.2, and 18.2 g of dry extracts, successive extractions on powdered roots (900 g) was carried out using hexane, EtOAc, and MeOH (3 × 2 L), respectively. Likewise, to obtain 0.67, 0.76 and 2.22 g of dry extracts, the aerial parts (30 g) were extracted using the same solvents by maceration (3 × 100 ml). The hexane extract of the roots (25 g) was subjected to fractionation by column chromatoghraphy with silica gel (70–230 mesh, 700 g) using elution with hexane−EtOAc (100/0 to 0/100) and MeOH was then increased (up to 20%) in EtOAc. A total of 15 fractions were collected based on TLC similarities. Fraction 1 (0.85 g) only consisted of abieta-8,11,13-triene (1). Fraction 4 (0.81 g) was separated using RP-HPLC and elution with isocratic MeOH:H₂O (75:25) to afford 12, 16-dideoxy aegyptinone B (2) (10 mg, t_R = 64 min) and ferruginol (3) (5.7 mg, t_R = 96 min). Fraction 5 (2.1 g) was separated on a silica gel column (230–400 mesh, 80 g) eluted with hexane−EtOAc (100/0 to 0/100) to obtain 14 fractions. Fraction 5b (0.329 g) was loaded on a silica gel column and then separated using elution with hexane:EtOAc (100/0 to 0/100) to yield seven fractions (5b₁-5b₇). Fraction 5b₅ (0.132 g) was purified by RP-HPLC using MeOH:H₂O (80:20) to afford sugiol (4) (0.8 mg, t_R = 20 min) and Δ⁹-ferruginol (5) (0.5 mg, t_R = 64 min). 11,14-dihydroxy-8,11,13-abietatrien-7-one (6) (20 mg) was obtained from fraction 5d (0.975 g) by recrystallization using hexane. Fraction 5d (0.975 g) was separated on a silica gel column (230–400 mesh, 40 g) eluted hexane−EtOAc (100/0 to 0/100) to yeild nine fractions (5d₁-5d₉). To obtain manool (7) (3 mg, t_R = 100 min), fraction 5d₄ (0.767 g) was injected into RP-HPLC followed by separation with MeOH:H₂O (78:22). Finally, precipitation of fraction 6 in hexane yielded lanugon Q (8) (10 mg).

Spectroscopic data and characterization of constituents

Abieta-8,11,13-triene (1) ¹H-NMR (500 MHz, Methanol-d₄) δ 1.62 (1H, m, H-1a), 1.19 (1H, m, H-1b), 1.74 (1H, m, H-2a), 1.61 (1H, m, H-2b), 1.50 (1H, m, H-3a), 1.24 (1H, m, H-3b), 1.38 (1H, m, H-5), 1.90 (1H, m, H-6a), 1.62 (1H, m, H-6b), 2.91 (1H, m, H-7a), 1.28 (1H, m, H-7b), 7.20 (1H, d, J = 8.2 Hz, H-11), 7.02 (1H, d, J = 8.2 Hz, H-12), 6.9 (1H, s, H-14), 2.85 (1H, sept, J = 6.9 Hz, H-15), 1.25 (3H, d, J = 6.9 Hz, Me-16), 1.25 (3H, d, J = 6.9 Hz, Me-17), 0.96 (3H, s, Me-18), 1.21 (3H, s, Me-19), 0.95 (3H, s, Me-20). ¹³C NMR (125 MHz, Methanol-d₄) δ 38.0 (C-1), 18.0 (C-2), 41.7 (C-3), 33.3 (C-4), 50.0 (C-5), 19.3 (C-6), 30.0 (C-7), 141.0 (C-8), 147.5 (C-9), 37.0 (C-10), 124.4 (C-11), 123.7 (C-12), 126.0 (C-13), 123.8 (C-14), 34.0 (C-15), 24.0 (C-16), 24.0 (C-17), 33.3 (C-18), 24.0(C-19), 22.0 (C-20). (Figure S1-S4).

12, 16-dideoxy aegyptinone B (2) ¹H-NMR (500 MHz, CDCl₃) δ 1.62 (2H, m, H-1), 1.73 (2H, m, H-2), 1.56 (1H, m, H-3), 7.05 (1H, s, H-6), 7.01 (1H, s, H-12), 2.92 (1H, sept, J = 6.9 Hz, H-15), 1.09 (3H, d, J = 6.9 Hz, Me-16), 1.09 (3H, d, J = 6.9 Hz, Me-17), 1.23 (3H, s, Me-18), 1.23 (3H, s, Me-19), 2.47 (3H, s, Me-20). ¹³C NMR (125 MHz, CDCl₃) δ 28.0 (C-1), 19.0 (C-2), 37.0 (C-3), 34.7 (C-4), 155.3 (C-5), 129.8 (C-6), 138.6 (C-7), 126.5 (C-8), 138.0 (C-9), 144.9 (C-10), 182.0 (C-11), 140.7 (C-12), 144.5 (C-13), 182.5 (C-14), 27.2 (C-15), 21.6 (C-16), 21.6 (C-17), 31.0 (C-18), 31.4 (C-19), 16.5 (C-20). (Figure S5- S9).

Ferruginol (3) ¹H-NMR (400 MHz, Methanol-d₄) δ 2.25 (1H, m, H-1a), 1.35 (1H, m, H-1b), 1.87 (1H, m, H-2a), 1.61 (1H, m, H-2b), 1.51 (1H, m, H-3a), 1.27 (1H, m, H-3b), 1.30 (1H, m, H-5), 1.78 (1H, m, H-6a), 1.69 (1H, m, H-6b), 2.82 (1H, dd, J = 10, 6.3 Hz, H-7a), 2.73 (1H, m, H-7b), 6.65 (1H, s, H-11), 6.76 (1H, s, H-14), 3.18 (1H, sept, J = 6.8 Hz, H-15), 1.19 (3H, d, J = 6.8 Hz, Me-16), 1.19 (3H, d, J = 6.8 Hz, Me-17), 0.97 (3H, s, Me-18), 0.96 (3H, s, Me-19), 1.19 (3H, s, Me-20). ¹³C NMR (125 MHz, Methanol-d₄) δ 39.9 (C-1), 20.4 (C-2), 42.6 (C-3), 33.0 (C-4), 51.9 (C-5), 20.3 (C-6), 30.0 (C-7), 134.7 (C-8), 147.7 (C-9), 36.0 (C-10), 111.0 (C-11), 151.0 (C-12), 125.2 (C-13), 127.0 (C-14), 27.2 (C-15), 23.0 (C-16), 23.0 (C-17), 33.5 (C-18), 21.9 (C-19), 23.0 (C-20). (Figure S10, S11, S12 and S13).

Sugiol (4) ¹H-NMR (600 MHz, Methanol-d₄) δ 6.77 (1H, s, H-11), 7.80 (1H, s, H-14), 3.12 (1H, sept, J = 6.8 Hz, H-15), 1.13 (3H, d, J = 6.8 Hz, Me-16), 1.13 (3H, d, J = 6.8 Hz, Me-17), 0.93 (3H, s, Me-18), 0.85 (3H, s, Me-19), 1.12 (3H, s, Me-20). (Figure S14).

Δ⁹-Ferruginol (5) ¹H-NMR (400 MHz, Methanol-d₄) δ 2.14 (1H, m, H-1a), 1.59 (1H, m, H-1b), 1.82 (1H, m, H-2a), 1.70 (1H, m, H-2b), 1.57 (1H, m, H-3a), 1.30 (1H, m, H-3b), 2.04 (1H, t, J = 2.9 Hz, H-5), 5.83 (2H, dd, J = 9.6, 2.8 Hz, H-6), 6.46 (1H, dd, J = 9.6, 2.8 Hz, H-7), 6.82 (1H, s, H-11), 6.61 (1H, s, H-14), 3.22 (1H, sept, J = 6.8 Hz, H-15), 1.21 (3H, d, J = 6.8 Hz, Me-16), 1.21 (3H, d, J = 6.8 Hz, Me-17), 0.99 (3H, s, Me-18), 0.96 (3H, s, Me-19), 1.01 (3H, s, Me-20). ¹³C NMR (125 MHz, Methanol-d₄) δ 37.7 (C-1), 21.0 (C-2), 42.7 (C-3), 32.3 (C-4), 53.0 (C-5), 127.4 (C-6), 128.9 (C-7), 125.1 (C-8), 147.1 (C-9), 37.4 (C-10), 110.0 (C-11), 153.8 (C-12), 131.5 (C-13), 124.8 (C-14), 27.0 (C-15), 23.2 (C-16), 23.2 (C-17), 35.0 (C-18), 21.7 (C-19), 34.0 (C-20). (Figure S15- S18).

11,14-dihydroxy-8,11,13-abietatrien-7-one (6) ¹H-NMR (500 MHz, CDCl₃) δ 3.25 (1H, m, H-1a), 1.44 (1H, m, H-1b), 1.76 (1H, m, H-2a), 1.62 (1H, m, H-2b), 1.51 (1H, m, H-3a), 1.31 (1H, m, H-3b), 1.85 (1H, dd, J = 10.6, 6.8 Hz, H-5), 2.68 (2H, dd, J = 10.6, 3.8 Hz, H-6), 6.81 (1H, s, H-12), 3.33 (1H, sept, J = 7 Hz, H-15), 1.21 (3H, d, J = 7 Hz, Me-16), 1.21 (3H, d, J = 7 Hz, Me-17), 0.97 (3H, s, Me-18), 1.00 (3H, s, Me-19), 1.42 (3H, s, Me-20). ¹³C NMR (125 MHz, CDCl₃) δ 36.0 (C-1), 19.2 (C-2), 41.1 (C-3), 33.0 (C-4), 49.0 (C-5), 36.0 (C-6), 206.0 (C-7), 115.0 (C-8), 136.0 (C-9), 41.0 (C-10), 145.0 (C-11), 124.0 (C-12), 135.0 (C-13), 155.8 (C-14), 26.0 (C-15), 22.4 (C-16), 22.4 (C-17), 33.1 (C-18), 21.6 (C-19), 18.0 (C-20) (Fig. S19-S23). HREIMS m/z 339.1888[M + Na]⁺, calcd. For C₂₀H₂₈O₃, 316.2038.

Manool (7) ¹H-NMR (600 MHz, Methanol-d₄) δ 1.77 (1H, m, H-1a), 1.06 (1H, m, H-1b), 1.61 (1H, m, H-2a), 1.61 (1H, m, H-2b), 1.41 (1H, m, H-3a), 1.23 (1H, m, H-3b), 1.56 (1H, m, H-5), 1.75 (1H, m, H-6a), 1.35 (1H, m, H-6b), 2.40 (1H, m, H-7a), 2.00 (1H, td, J = 13, 5.3 Hz, H-7b), 1.14 (1H, m, H-9), 1.57 (1H, m, H-11a), 1.38 (1H, m, H-11b), 1.72 (2H, m, H-12), 5.92 (1H, dd, J = 17.5, 11 Hz, H-14), 5.20 (1H, dd, J = 17.5, 1.5 Hz, H-15a), 5.03 (1H, dd, J = 11,1.5 Hz, H-15b), 1.25 (3H, s, Me-16), 4.83 (1H, brs, H-17a), 4.56 (1H, brs, H-17b), 0.90 (3H, s, Me-18), 0.84 (3H, s, Me-19), 0.72 (3H, s, Me-20).¹³C NMR (125 MHz, CDCl₃) δ 41.0 (C-1), 20.4 (C-2), 43.4 (C-3), 34.1 (C-4), 58.9 (C-5), 36.0 (C-6), 40.3 (C-7), 149.9 (C-8), 57.0 (C-9), 39.5 (C-10), 18.9 (C-11), 42.8 (C-12), 74.2 (C-13), 146.7 (C-14), 111.9 (C-15), 27.4 (C-16), 107.2 (C-17), 34.5 (C-18), 22.2 (C-19), 15.0 (C-20) (Fig. S24-S27).

Lanugon Q (8) ¹H-NMR (500 MHz, CDCl₃) δ 2.84 (1H, m, H-1a), 1.65 (1H, m, H-1b), 1.63 (1H, m, H-2a), 1.50 (1H, m, H-2b), 1.32 (1H, m, H-3a), 1.13 (1H, m, H-3b), 2.48 (1H, s, H-5), 6.42 (1H, s, H-7), 3.46 (1H, m, H-15), 4.72 (1H, t, J = 9.5 Hz, H-16a), 4.16 (1H, dd, J = 9.2, 6.7 Hz, H-16b), 1.27 (3H, d, J = 6.8 Hz, Me-17), 1.02 (3H, s, Me-18), 1.19 (3H, s, Me-19), 1.18 (3H, s, Me-20). ¹³C NMR (125 MHz, CDCl₃) δ 37.3 (C-1), 18.6 (C-2), 42.6 (C-3), 32.0 (C-4), 63.0 (C-5), 200.3 (C-6), 128.0 (C-7), 127.0 (C-8), 180.0 (C-9), 42.0 (C-10), 143.0 (C-11), 178.0 (C-12), 117.0 (C-13), 166.0 (C-14), 35.0 (C-15), 80.6 (C-16), 18.7 (C-17), 33.3 (C-18), 21.0 (C-19), 18.7 (C-20) (Fig. S28-S32). HREIMS m/z 351.1510 [M + Na]⁺, calcd. For C₂₀H₂₈O₃, 328.1675.

Antiprotozoal assay

The antiprotozoal activity and cytotoxic assay of the extracts and isolated compounds were determined according to a previously reported protocol [13]. All tests were performed in two independent repetitions. Antiprotozoal assays were carried out in 96-well plates for Plasmodium falciparum (NF54 strain), T. brucei rhodesiense (STIB 900 strain), T. cruzi (Tulahuen strain C2C4 w/LacZ), and L. donovani (strain MHOM-ET-67/L82). Cytotoxicity assays were performed with rat skeletal L-6 cells (primary cell line obtained from rat skeletal myoblasts, Basel, Swiss Tropical Institute). Sigmoidal growth inhibition curves were used to calculate the IC₅₀ values using the Excel software.

Computational details

To determine the absolute configuration of 11,14-dihydroxy-8,11,13-abietatrien-7-one (6) and lanugon Q (8), 2D and 3D structures were constructed using the Maestro 10.2 platform and conformation analysis was done using the MacroModel 9.1 by applying OPLS-2005 force field in H₂O (Schrödinger, LLC, New York). Conforms within 3 kcal/mol energy were selected for geometrical optimization using the density functional theory (DFT) at the B3LYP level of theory and a basis set of 6-31G** using the Gaussian 09 program package [14, 15]. The ECD spectra were simulated using TD-DFT/B3LYP/6-31G** level of theory in the MeOH. The calculated spectra were visualized using SpecDis version1.6 with a half-bandwidth of 0.3 eV [16].

Results

Isolation and molecular elucidation

RP-HPLC and column chromatography were used to isolate substances from potent extract. Moreover, characterization of isolates was done through 1-D and 2-D NMR experiments as well as HREIMS. ECD was applied to determine the absolute configuration of optically active components. Thus, large-scale extraction of roots with hexane and subsequent purification and elucidation yielded eight abietane-type diterpenoids including abieta-8,11,13-triene (1) [17], 12, 16-dideoxy aegyptinone B (2) [12], ferruginol (3) [18], sugiol (4) [19], Δ⁹-ferruginol (5) [20], 11,14-dihydroxy-8, 11,13-abietatrien-7-one (6) [21, 22], manool (7) [12], and lanugon Q (8) [20, 23] (Fig. 1). These compounds were identified through analysis of their spectroscopic data and comparison with previously published data. It should also be noted that 12, 16-dideoxy aegyptinone B(2), ferruginol (3) and manool (7) were observed in several subfractions through tracing by ¹H-NMR.

Fig. 1 — Structures of diterpenes 1–8 isolated from roots of *Zhumeria majdae*

A literature search showed that the absolute configuration of 11,14-dihydroxy-8,11,13-abietatrien-7-one (6) and lanugon Q (8) were not studied. The experimental ECD spectrum of 11,14-dihydroxy-8,11,13-abietatrien-7-one (6) showed two positive Cotton effects (CE) around 400 and 210 nm and two negative CEs at 310 and 275 nm. These effects are correlated with the π → π* transition of extended α,β-carbonyl and quinone groups. The theoretical simulated ECD spectrum for 5S and 10S showed a good agreement with experimental data, while the enantiomer showed the opposite sign (Fig. 2a). On the other hand, lanugon Q (8) indicated three negative CEs in the ECD spectrum at 350, 290, and 205 nm and two positive CEs at 360 and 250 nm. These CEs were initiated from π → π* transition ascribed to the presence of extended quinone chromophore. The comparison of simulated spectra for two stereoisomers (5S, 10S, 15S and 5S, 10S, 15R), and experimental data for lanugon Q (8) showed that 5S, 10S, 15S matched better with three negative and two positive CEs (Fig. 2b).

Fig. 2 — Comparison of experimental and TDDFT simulated ECD spectra of compounds 6 (a) and 8 (b). Calculations were performed with TDDFT at the B3LYP/6–31 G** level with MeOH as the solvent

Antiprotozoal activity

The antiprotozoal activity of different extracts of Z. majdaie was tested in vitro. The cytotoxicity effect of the extracts was also evaluated against L6-cells. Extracts of the roots showed greater activity than extracts obtained from aerial parts (Table 1). The hexane extract of the roots was the most potent extract against T. b. rhodesiense (IC₅₀ of 5.4 μg/ml), L. donovani (IC₅₀ of 1.6 μg/ml), and P. falciparum (IC₅₀ of 2.1 μg/ml). Meanwhile, the compounds responsible for antiprotozoal activity in the hexane extract were identified by separation, purification and structure elucidation using chromatographic and spectroscopic techniques, respectively. Hence, based on the structure and quantity of isolated compounds, current study investigated the effects of 12, 16-dideoxy aegyptinone B (2), 11,14-dihydroxy-8,11,13-abietatrien-7-one (6) and lanugon Q (8) against the abovementioned parasites. The antiprotozoal activity of ferruginol (3) and Δ⁹-ferruginol (5) were previously investigated [24]. Furthermore, in order to assess the selectivity of active substances toward the protozoan parasites, their cytotoxic activity against rat skeletal myoblast L6-cells was determined. According to Table 2, 11,14-dihydroxy-8,11,13-abietatrien-7-one (6) and lanugon Q (8) had the highest activity against T. b. rhodesiense with IC₅₀ values of 1.82 and 0.13 μM, respectively. Regarding antiplasmodial effects, 11,14-dihydroxy-8,11,13-abietatrien-7-one (6) showed the highest activity compared to other compounds (IC₅₀ 8.65 μM). It was found that the higher selectivity of 11,14-dihydroxy-8, 11,13-abietatrien-7-one (6) and lanugon Q (8) was limited to T. b. rhodesiense. On the other hand, while 12, 16-dideoxy aegyptinone B (2) showed a potent activity against T. b. rhodesiense (IC₅₀ of 3.63 μM), no potency was observed against P. falciparum.

Table 1.

IC₅₀ (μg/mL) values of Z. majdae extracts against P. falciparum, T. cruzi, T. b. rhodesiense, and L. donovani, along with cytotoxic activity against L-6 cells^a

Plant part	Extract/Medicine	T. b. rhodesiense	T. cruzi	L. donovani	P. falciparum	Cytotoxicity
	hexane	5.4 ± 0.5	10.6 ± 2.3	1.6 ± 0.2	2.1 ± 0.4	6.1 ± 0.1
	EtOAc	8.0 ± 1.2	23.5 ± 2.5	2.2 ± 0.1	2.9 ± 0.7	17.4 ± 0.3
	MeOH	20.1 ± 2.2	67.6 ± 1.3	11.7 ± 0.3	11.6 ± 1.7	64.9 ± 3.7
Aerial part	hexane	13.6 ± 1.4	41.2 ± 3.6	6.9 ± 0.1	3.2 ± 0.4	11.8 ± 2.5
	EtOAc	14.9 ± 1.8	58.2 ± 3.2	7.8 ± 2.1	9.3 ± 2.0	50.9 ± 1.9
	MeOH	37.3 ± 1.2	63.5 ± 4.1	65.5 ± 4.1	55.1 ± 3.8	>100.0
Melarsoprol		0.009 ± 0.0030	-	-	-	-
Benznidazole		-	1.010 ± 0.1800	-	-	-
Miltefosine		-	-	0.128 ± 0.0440	-	-
Chloroquine		-	-	-	0.001 ± 0.0008	-
Podophyllotoxin		-	-	-	-	0.003 ± 0.0008

Open in a new tab

^aEach value corresponds to the mean ± standard deviation from two independent repetitions

Table 2.

IC₅₀ values (μM) of compounds (2, 6 and 8) against P. falciparum and T. b. rhodesiense along with cytotoxic activity against L-6 cells. ^a

Compounds	T. b. rhodesiense	SI	P. falciparum	SI	Cytotoxicity
2	3.63 ± 0.47	1.72	not active	-	6.25 ± 0.12
6	1.82 ± 0.14	21.90	8.65 ± 0.26	4.60	39.75 ± 0.24
8	0.13 ± 0.01	15.40	15.6 ± 0.42	0.13	2.00 ± 0.11
Melarsoprol	0.003 ± 0.001		-		-
Chloroquine	-		0.004 ± 0.002		-
Podophyllotoxin	-		-		0.005 ± 0.002

Open in a new tab

^aEach value corresponds to the mean ± standard deviation from two independent repetitions. SI = Selectivity index (IC₅₀ against L-6 cells divided by IC₅₀ against parasites)

Discussion

Twenty five years ago, the phytochemical investigation of the roots of Z.majdae resulted in the identification of three diterpenoids, including 12,16-dideoxy aegyptinone B, 12-deoxy (2) salvipisone, and manool (7) [12]. It was then shown that 12,16-dideoxy aegyptinone B (2) had antimalarial and antileishmanial activity against P. falciparum and L. donovani with IC₅₀ values of 1.3 and 1.4 μg/ml, respectively [25].

In the present study, although all 8 isolated compounds were known, only 12, 16-dideoxy aegyptinone B (2) and manool (7) were previously reported to be present in this plant. The rest of the compounds, including abieta-8,11,13-triene (1), ferruginol (3), Sugiol (4), Δ⁹-ferruginol (5), 11,14-dihydroxy-8,11,13-abietatrien-7-one (6), and lanugon Q (8), were described in Zhumeria for the first time. The results showed that the investigated isolates were potent against protozoan parasites including T. b. rhodesiense, and P. falciparum; however, none of them exhibited antiprotozoal activity against T. cruzi and L. donovani. Among all compounds, 11,14-dihydroxy-8,11,13-abietatrien-7-one (6) and Lanugon Q (8) were the most active components. 11,14-dihydroxy-8,11,13-abietatrien-7-one (6) was previously isolated from the heartwood of Chamaecyparis obtusa var. formosana, roots of Euonymus lutchuensis, and whole plant of Caryopteris incana (Thumb.) Miq [21, 22, 26]. 11,14-dihydroxy-8,11,13-abietatrien-7-one (6), which contains a keto group at C-7 and functionalizes by OH groups at C-11 and C-14, is a 8,11,13-abietatrien derivative. Several studies have shown the biological activities of abietane diterpenoids with 8,11,13-abietatrien scaffold [27]. In this regard, ferruginol (3) and Δ⁹-ferruginol (5), which share a similar scaffold, have been recently described to have a promising antiplasmodial activity (IC₅₀ 0.9 μM) [24, 28]. Thus, our findings regarding the antiprotozoal activity of 11,14-dihydroxy-8,11,13-abietatrien-7-one (6) as a 8,11,13-abietatrien derivative are in agreement with previous studies.

Lanugon Q (8) has been reported in leaf glands of Plectranthus lanuginosus and roots of Salvia apiana. Similar to 11,14-dihydroxy-8,11,13-abietatrien-7-one (6), no study has yet exploreed the antiprotozoal potential of Lanugon Q (8) [20, 23]. This compound has a tanshinone scaffold. Abietane derivatives containing ortho-quinone or a para-quinone C-ring and dihydrofuran or a furan D-ring are considered as two main characteristic rings of tanshinones. Tanshinones are one of the well-known groups of abietane-type diterpenes isolated from a number of Salvia species, which have a broad spectrum of biological activities. Many diterpenoid quinones are included in this group. In this regard, tanshinone IIA, as one of the major components of tanshinones, is responsible for an array of activities; for example, it has antitumor and antioxidant effects, dilates coronary arteries, enhances coronary flow through activating potassium channels, and has antiparasitic activity against T. b. rhodesiense and P. falciparum [6, 27, 29].

This study is the first pharmacological investigation of 11,14-dihydroxy-8,11,13-abietatrien-7-one (6) and lanugon Q (8) to provide preliminary evidence for the antiprotozoal properties of these active substances. A SI value of more than 15 for 11,14-dihydroxy-8,11,13-abietatrien-7-one (6) and lanugon Q (8) suggested that these compounds could be used as potential antiprotozoal agents for the development of new therapies to counteract human African trypanosomiasis. The present findings are consistent with the results of recent studies describing the antiprotozoal activity of abietane diterpenoids. For instance, one study reported the antiprotozoal activity of Salvia sahendica, an indigenous Iranian plant, and investigated the potency of a number of diterpenoids against different protozoan parasites [24]. In another study, diterpenoids isolated from the aerial parts of Perovskia abrotanoides, another endemic plant in Iran, were tested against T. b. rhodesiense, T. cruzi, L. donovani, and P. falciparum and the results showed that compounds belonging to abietane derivatives exhibited a promising antiprotozoal activity [24, 28]. Altogether, the results of this study suggest that the greater antiprotozoal activity of roots versus aerial parts of Z.majdae could be attributed to lanugon Q (8) as a tanshinone-type diterpenoid and 11, 14-dihydroxy-8, 11, 13-abietatrien-7-one (6) as a abieta-8,11,13-triene derivative.

Conclusion

The aim of the present study was to discover active compounds in the roots of Z. majdae to develop new therapies for treatment of some tropical diseases. The antiprotozoal activity of purified compounds was assessed and the absolute configuration of 11,14-dihydroxy-8,11,13-abietatrien-7-one (6) and lanugon Q (8) was established by theoretical and calculated ECD spectra. This study showed that among eight isolated compounds, 11,14-dihydroxy-8,11,13-abietatrien-7-one (6) and lanugon Q (8) had the highest activity against P. falciparum and T. b. rhodesiense, respectively. In conclusion, these compounds could be considered for future drug development studies. Therefore, further experimental investigations such as drug design studies combined with cell-free assay between ligand and receptor are needed to understand the possible mechanism of action of these compounds against parasites.

Electronic supplementary material

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Acknowledgments

The authors wish to thank Tehran University of Medical Sciences for supporting this work. This research was supported by Tehran University of Medical Sciences and Health Services Grants (No. 45974). This work was part of the Ph.D. thesis of Mr. Reza Zadali.

Author contributions

Reza Zadali carried out the phytochemical techniques along with the interpretation of spectra and antiprotozoal activity results, Abbas Hadjiakhoondi and Samad Nejad Ebrahimi supervised this project and suggested the idea to start the current project, Ali Es-Haghi and Zahra Tofighi have participated in analyzing the data and writing the manuscript. Nunziatina De Tommasi, Matthias Hamburger, and Massimiliano D'Ambola have contributed to phytochemical purification techniques, measuring, and interpretation of related spectra. Marcel Kaiser conducted the antiprotozoal assay. The current manuscript was critically read and approved by all authors.

Compliance with ethical standards

Conflict of interest

The authors state no conflict of interest.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Samad Nejad Ebrahimi, Email: s_ebrahimi@sbu.ac.ir.

Abbas Hadjiakhoondi, Email: abbhadji@tums.ac.ir.

References

1.Stuart K, Brun R, Croft S, Fairlamb A, Gürtler RE, McKerrow J, Reed S, Tarleton R. Kinetoplastids: related protozoan pathogens, different diseases. J Clin Invest. 2008;118(4):1301–1310. doi: 10.1172/JCI33945. [DOI] [PMC free article] [PubMed] [Google Scholar]
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4.Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod. 2016;79(3):629–661. doi: 10.1021/acs.jnatprod.5b01055. [DOI] [PubMed] [Google Scholar]
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7.Jalili A, Jamzad Z. Red data book of Iran; a preliminary survey of endemic, rare & endangered plant species in Iran. Research Institute of Forest & Rangelands: Tehran; 1999. p. 341. [Google Scholar]
8.Zargari A. Medicinal plants. Tehran University Press: Tehran; 1995. p. 136. [Google Scholar]
9.Mandegary A, Sharififar F, Abdar M, Arab-Nozari M. Anticonvulsant activity and toxicity of essential oil and methanolic extract of Zhumeria majdae Rech, a unique Iranian plant in mice. Neurochem Res. 2012;37(12):2725–2730. doi: 10.1007/s11064-012-0863-5. [DOI] [PubMed] [Google Scholar]
10.Hosseinzadeh H, Ramezani M, Fadishei M, Mahmoudi M. Antinociceptive, anti-inflammatory and acute toxicity effects of Zhumeria majdae extracts in mice and rats. Phytomedicine. 2002;9(2):135–141. doi: 10.1078/0944-7113-00097. [DOI] [PubMed] [Google Scholar]
11.Mirshafie B, Mokhber-Dezfouli N, Manayi A, Saeidnia S, Ajani Y, Gohari AR. Alpha-amylase inhibitory activity and phytochemical study of Zhumeria majdae Rech. f. and Wendelbo. Pharmacogn Res. 2015;7, 309(4). [DOI] [PMC free article] [PubMed]
12.Rustaiyan A, Samadizadeh M, Habibi Z, Jakupovic J. Two diterpenes with rearranged abietane skeletons from Zhumeria majdae. Phytochemistry. 1995;39(1):163–165. doi: 10.1016/0031-9422(94)00692-M. [DOI] [Google Scholar]
13.Adams M, Zimmermann S, Kaiser M, Brun R, Hamburger M. A protocol for HPLC-based activity profiling for natural products with activities against tropical parasites. Nat Prod Commun. 2009;4(10):1934578X0900401013. [PubMed]
14.Frisch MJ, Hratchian HP, Nielsen AB. Gaussian 09: Programmer's Reference. gaussian; 2009.
15.Frisch MJ, Trucks G, Schlegel H, Scuseria G, Robb M, Cheeseman J et al. Gaussian 09, Revision D. 01, Gaussian. Inc.: Wallingford, CT. 2009.
16.Bruhn T, Schaumlöffel A, Hemberger Y, Bringmann G. SpecDis: quantifying the comparison of calculated and experimental electronic circular dichroism spectra. Chirality. 2013;25(4):243–249. doi: 10.1002/chir.22138. [DOI] [PubMed] [Google Scholar]
17.Corral JMD, Gordaliza M, Salinero M, Feliciano AS. 13C NMR Data for abieta-8, 11, 13-triene diterpenoids. Magn Reson Chem. 1994;32(12):774–781. doi: 10.1002/mrc.1260321211. [DOI] [Google Scholar]
18.Kelecom A. An abietane diterpene from the labiate Coleus barbatus. Phytochemistry. 1984;23(8):1677–1679. doi: 10.1016/S0031-9422(00)83467-6. [DOI] [Google Scholar]
19.Wang YR, Yu Y, Li SM, Liu W, Li W, Morris-Natschke SL, Goto M, Lee KH, Huang XF. Salvisertin a, a new Hexacyclic Triterpenoid, and other bioactive Terpenes from Salvia deserta root. Chem Biodivers. 2018;15(4):e1800019. doi: 10.1002/cbdv.201800019. [DOI] [PMC free article] [PubMed] [Google Scholar]
20.González AG, Aguiar ZE, Grillo TA, Luis JG. Diterpenes and diterpene quinones from the roots of Salvia apiana. Phytochemistry. 1992;31(5):1691–1695. doi: 10.1016/0031-9422(92)83130-Q. [DOI] [Google Scholar]
21.Zhao S-M, Chou G-X, Yang Q-S, Wang W, Zhou J-L. Abietane diterpenoids from Caryopteris incana (Thunb.) Miq. Org Biomol Chem. 2016;14(14):3510–3520. doi: 10.1039/C6OB00139D. [DOI] [PubMed] [Google Scholar]
22.Inaba Y, Hasuda T, Hitotsuyanagi Y, Aoyagi Y, Fujikawa N, Onozaki A, Watanabe A, Kinoshita T, Takeya K. Abietane diterpenoids and a sesquiterpene pyridine alkaloid from Euonymus lutchuensis. J Nat Prod. 2013;76(6):1085–1090. doi: 10.1021/np400110g. [DOI] [PubMed] [Google Scholar]
23.Schmid JM, Rüedi P, Eugster CH. Diterpenoide Drüsenfarbstoffe aus Labiaten: 22 neue Coleone und Royleanone aus Plectranthus lanuginosus. Helv Chim Acta. 1982;65(7):2136–2163. doi: 10.1002/hlca.19820650721. [DOI] [Google Scholar]
24.Ebrahimi SN, Zimmermann S, Zaugg J, Smiesko M, Brun R, Hamburger M. Abietane diterpenoids from Salvia sahendica–antiprotozoal activity and determination of their absolute configurations. Planta Med. 2013;29(02):150–156. doi: 10.1055/s-0032-1328063. [DOI] [PubMed] [Google Scholar]
25.Moein MR, Pawar RS, Khan SI, Tekwani BL, Khan IA. Antileishmanial, antiplasmodial and cytotoxic activities of 12, 16-dideoxy aegyptinone B from Zhumeria majdae Rech. f. & Wendelbo. Phytother Res. 2008;22(3):283–285. doi: 10.1002/ptr.2305. [DOI] [PubMed] [Google Scholar]
26.Kuo Y-H, Chen C-H, Huang S-L. New Diterpenes from the heartwood of Chamaecyparis obtusa var. formosana. J Nat Prod. 1998;61(6):829–831. doi: 10.1021/np970531+. [DOI] [PubMed] [Google Scholar]
27.Wu Y-B, Ni Z-Y, Shi Q-W, Dong M, Kiyota H, Gu Y-C, Cong B. Constituents from Salvia species and their biological activities. Chem Rev. 2012;112(11):5967–6026. doi: 10.1021/cr200058f. [DOI] [PubMed] [Google Scholar]
28.Tabefam M, Farimani MM, Danton O, Ramseyer J, Kaiser M, Ebrahimi SN, Salehi P, Batooli H, Potterat O, Hamburger M. Antiprotozoal diterpenes from Perovskia abrotanoides. Planta Med. 2018;84(12/13):913–919. doi: 10.1055/a-0608-4946. [DOI] [PubMed] [Google Scholar]
29.Ślusarczyk S, Zimmermann S, Kaiser M, Matkowski A, Hamburger M, Adams M. Antiplasmodial and antitrypanosomal activity of tanshinone-type diterpenoids from Salvia miltiorrhiza. Planta Med. 2011;77(14):1594–1596. doi: 10.1055/s-0030-1270933. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ESM 1^{(4.6MB, docx)}

(DOCX 4707 kb)

[CR1] 1.Stuart K, Brun R, Croft S, Fairlamb A, Gürtler RE, McKerrow J, Reed S, Tarleton R. Kinetoplastids: related protozoan pathogens, different diseases. J Clin Invest. 2008;118(4):1301–1310. doi: 10.1172/JCI33945. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR2] 2.Shen B. A new golden age of natural products drug discovery. Cell. 2015;163(6):1297–1300. doi: 10.1016/j.cell.2015.11.031. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR3] 3.Davison EK, Brimble MA. Natural product derived privileged scaffolds in drug discovery. Curr Opin Chem Biol. 2019;52:1–8. doi: 10.1016/j.cbpa.2018.12.007. [DOI] [PubMed] [Google Scholar]

[CR4] 4.Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod. 2016;79(3):629–661. doi: 10.1021/acs.jnatprod.5b01055. [DOI] [PubMed] [Google Scholar]

[CR5] 5.Goodarzi S, Hadjiakhoondi A, Yassa N, Khanavi M, Tofighi Z. Essential oils chemical composition, antioxidant activities and total phenols of Astrodaucus persicus. Iran J Basic Med Sci. 2016;19(2):159. [PMC free article] [PubMed] [Google Scholar]

[CR6] 6.Bisio A, Pedrelli F, D'Ambola M, Labanca F, Schito AM, Govaerts R, de Tommasi N, Milella L. Quinone diterpenes from Salvia species: chemistry, botany, and biological activity. Phytochem Rev. 2019;18(3):665–842. doi: 10.1007/s11101-019-09633-z. [DOI] [Google Scholar]

[CR7] 7.Jalili A, Jamzad Z. Red data book of Iran; a preliminary survey of endemic, rare & endangered plant species in Iran. Research Institute of Forest & Rangelands: Tehran; 1999. p. 341. [Google Scholar]

[CR8] 8.Zargari A. Medicinal plants. Tehran University Press: Tehran; 1995. p. 136. [Google Scholar]

[CR9] 9.Mandegary A, Sharififar F, Abdar M, Arab-Nozari M. Anticonvulsant activity and toxicity of essential oil and methanolic extract of Zhumeria majdae Rech, a unique Iranian plant in mice. Neurochem Res. 2012;37(12):2725–2730. doi: 10.1007/s11064-012-0863-5. [DOI] [PubMed] [Google Scholar]

[CR10] 10.Hosseinzadeh H, Ramezani M, Fadishei M, Mahmoudi M. Antinociceptive, anti-inflammatory and acute toxicity effects of Zhumeria majdae extracts in mice and rats. Phytomedicine. 2002;9(2):135–141. doi: 10.1078/0944-7113-00097. [DOI] [PubMed] [Google Scholar]

[CR11] 11.Mirshafie B, Mokhber-Dezfouli N, Manayi A, Saeidnia S, Ajani Y, Gohari AR. Alpha-amylase inhibitory activity and phytochemical study of Zhumeria majdae Rech. f. and Wendelbo. Pharmacogn Res. 2015;7, 309(4). [DOI] [PMC free article] [PubMed]

[CR12] 12.Rustaiyan A, Samadizadeh M, Habibi Z, Jakupovic J. Two diterpenes with rearranged abietane skeletons from Zhumeria majdae. Phytochemistry. 1995;39(1):163–165. doi: 10.1016/0031-9422(94)00692-M. [DOI] [Google Scholar]

[CR13] 13.Adams M, Zimmermann S, Kaiser M, Brun R, Hamburger M. A protocol for HPLC-based activity profiling for natural products with activities against tropical parasites. Nat Prod Commun. 2009;4(10):1934578X0900401013. [PubMed]

[CR14] 14.Frisch MJ, Hratchian HP, Nielsen AB. Gaussian 09: Programmer's Reference. gaussian; 2009.

[CR15] 15.Frisch MJ, Trucks G, Schlegel H, Scuseria G, Robb M, Cheeseman J et al. Gaussian 09, Revision D. 01, Gaussian. Inc.: Wallingford, CT. 2009.

[CR16] 16.Bruhn T, Schaumlöffel A, Hemberger Y, Bringmann G. SpecDis: quantifying the comparison of calculated and experimental electronic circular dichroism spectra. Chirality. 2013;25(4):243–249. doi: 10.1002/chir.22138. [DOI] [PubMed] [Google Scholar]

[CR17] 17.Corral JMD, Gordaliza M, Salinero M, Feliciano AS. 13C NMR Data for abieta-8, 11, 13-triene diterpenoids. Magn Reson Chem. 1994;32(12):774–781. doi: 10.1002/mrc.1260321211. [DOI] [Google Scholar]

[CR18] 18.Kelecom A. An abietane diterpene from the labiate Coleus barbatus. Phytochemistry. 1984;23(8):1677–1679. doi: 10.1016/S0031-9422(00)83467-6. [DOI] [Google Scholar]

[CR19] 19.Wang YR, Yu Y, Li SM, Liu W, Li W, Morris-Natschke SL, Goto M, Lee KH, Huang XF. Salvisertin a, a new Hexacyclic Triterpenoid, and other bioactive Terpenes from Salvia deserta root. Chem Biodivers. 2018;15(4):e1800019. doi: 10.1002/cbdv.201800019. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR20] 20.González AG, Aguiar ZE, Grillo TA, Luis JG. Diterpenes and diterpene quinones from the roots of Salvia apiana. Phytochemistry. 1992;31(5):1691–1695. doi: 10.1016/0031-9422(92)83130-Q. [DOI] [Google Scholar]

[CR21] 21.Zhao S-M, Chou G-X, Yang Q-S, Wang W, Zhou J-L. Abietane diterpenoids from Caryopteris incana (Thunb.) Miq. Org Biomol Chem. 2016;14(14):3510–3520. doi: 10.1039/C6OB00139D. [DOI] [PubMed] [Google Scholar]

[CR22] 22.Inaba Y, Hasuda T, Hitotsuyanagi Y, Aoyagi Y, Fujikawa N, Onozaki A, Watanabe A, Kinoshita T, Takeya K. Abietane diterpenoids and a sesquiterpene pyridine alkaloid from Euonymus lutchuensis. J Nat Prod. 2013;76(6):1085–1090. doi: 10.1021/np400110g. [DOI] [PubMed] [Google Scholar]

[CR23] 23.Schmid JM, Rüedi P, Eugster CH. Diterpenoide Drüsenfarbstoffe aus Labiaten: 22 neue Coleone und Royleanone aus Plectranthus lanuginosus. Helv Chim Acta. 1982;65(7):2136–2163. doi: 10.1002/hlca.19820650721. [DOI] [Google Scholar]

[CR24] 24.Ebrahimi SN, Zimmermann S, Zaugg J, Smiesko M, Brun R, Hamburger M. Abietane diterpenoids from Salvia sahendica–antiprotozoal activity and determination of their absolute configurations. Planta Med. 2013;29(02):150–156. doi: 10.1055/s-0032-1328063. [DOI] [PubMed] [Google Scholar]

[CR25] 25.Moein MR, Pawar RS, Khan SI, Tekwani BL, Khan IA. Antileishmanial, antiplasmodial and cytotoxic activities of 12, 16-dideoxy aegyptinone B from Zhumeria majdae Rech. f. & Wendelbo. Phytother Res. 2008;22(3):283–285. doi: 10.1002/ptr.2305. [DOI] [PubMed] [Google Scholar]

[CR26] 26.Kuo Y-H, Chen C-H, Huang S-L. New Diterpenes from the heartwood of Chamaecyparis obtusa var. formosana. J Nat Prod. 1998;61(6):829–831. doi: 10.1021/np970531+. [DOI] [PubMed] [Google Scholar]

[CR27] 27.Wu Y-B, Ni Z-Y, Shi Q-W, Dong M, Kiyota H, Gu Y-C, Cong B. Constituents from Salvia species and their biological activities. Chem Rev. 2012;112(11):5967–6026. doi: 10.1021/cr200058f. [DOI] [PubMed] [Google Scholar]

[CR28] 28.Tabefam M, Farimani MM, Danton O, Ramseyer J, Kaiser M, Ebrahimi SN, Salehi P, Batooli H, Potterat O, Hamburger M. Antiprotozoal diterpenes from Perovskia abrotanoides. Planta Med. 2018;84(12/13):913–919. doi: 10.1055/a-0608-4946. [DOI] [PubMed] [Google Scholar]

[CR29] 29.Ślusarczyk S, Zimmermann S, Kaiser M, Matkowski A, Hamburger M, Adams M. Antiplasmodial and antitrypanosomal activity of tanshinone-type diterpenoids from Salvia miltiorrhiza. Planta Med. 2011;77(14):1594–1596. doi: 10.1055/s-0030-1270933. [DOI] [PubMed] [Google Scholar]

PERMALINK

Antiprotozoal activity of diterpenoids isolated from Zhumeria majdae- absolute configuration by circular dichroism

Reza Zadali

Samad Nejad Ebrahimi

Zahra Tofighi

Ali Es-haghi

Matthias Hamburger

Marcel Kaiser

Massimiliano D’ Ambola

Nunziatina De Tommasi

Abbas Hadjiakhoondi

Abstract

Purpose

Methods

Results

Conclusion

Electronic supplementary material

Introduction

Methods

General

Plant material

Extraction and isolation

Spectroscopic data and characterization of constituents

Antiprotozoal assay

Computational details

Results

Isolation and molecular elucidation

Fig. 1.

Fig. 2.

Antiprotozoal activity

Table 1.

Table 2.

Discussion

Conclusion

Electronic supplementary material

Acknowledgments

Author contributions

Compliance with ethical standards

Conflict of interest

Footnotes

Contributor Information

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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