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other·phytochemistry, pharmacology, anti-inflammatory, natural products·PMC10725009

Phytochemical investigation and anti-inflammatory potential of Atriplex leucoclada Boiss

BMC Complementary Medicine and Therapies · 7 authors, 4 centres

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This study isolated nine compounds from Atriplex leucoclada, eight reported for the first time from this species, and demonstrated that both the n-hexane and defatted methanol extracts exhibit selective COX-2 inhibition in vitro (IC50 5.96 and 14.4 μg/mL, respectively) with selectivity indices comparable to ibuprofen. Molecular docking confirmed high binding affinities of the identified compounds to COX-2, suggesting A. leucoclada as a promising source of safe anti-inflammatory agents.

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**Background:** Inflammation is a self-defense mechanism mediated by prostaglandins synthesized via cyclooxygenase (COX) enzymes. COX-1 is constitutively expressed in many tissues, while COX-2 is induced at sites of inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause side effects such as gastrointestinal bleeding, renal failure, and thrombosis. Herbal medicines offer potential alternatives with fewer adverse effects. The genus *Atriplex* (Amaranthaceae) includes halophytic plants with reported anti-inflammatory, antioxidant, and antidiabetic activities. *Atriplex leucoclada* Boiss. (cut-leaf saltbush) is a perennial shrub native to the Saudi Arabian desert, but its phytochemical content and biological potential have been underexplored. This study aimed to investigate the metabolic content and anti-inflammatory potential of *A. leucoclada*.

**Methods:** Dried aerial parts (700 g) were defatted with n-hexane to yield 1.7 g of ATH extract, then extracted with 80% methanol to yield 45 g of ATD extract. The ATD extract (30 g) was fractionated on polyamide-6 using a H2O-MeOH gradient, followed by silica gel and Sephadex LH-20 column chromatography to isolate pure compounds. Structures were elucidated using 1D and 2D NMR spectroscopy. The ATH extract was analyzed by GC-MS. Anti-inflammatory activity was assessed in vitro using COX-1 and COX-2 inhibitor screening kits (BioVision), with ibuprofen as a positive control. Samples were tested at concentrations 0.01–100 μg/mL, and IC50 values were calculated. Molecular docking was performed using AutoDock Vina in Pyrx, with COX-1 (PDB: 6Y3C) and COX-2 (PDB: 5IKV) proteins.

**Key Results:** Nine compounds were isolated from ATD: 20-hydroxyecdysone (1), phytol (2), β-sitosterol (3), stigmasterol (4), palmitic acid (5), luteolin (6), β-sitosterol-3-O-β-D-glucopyranoside (7), pallidol (8), and isorhamnetin 3-O-β-galactopyranoside (9). All except compound 1 are reported for the first time from *A. leucoclada*; luteolin (6) and pallidol (8) are first reports from the genus *Atriplex*. GC-MS analysis of ATH identified 27 metabolites (85.97% of total), with major classes: terpenoids (31.27%), fatty acids and derivatives (21.18%), and steroids (20.25%). Phytol (21.24%) and cholest-5-en-3-ol (12.50%) were the main components. In vitro COX inhibition assays showed concentration-dependent activity. IC50 values for ATD were 41.22 μg/mL (COX-1) and 14.4 μg/mL (COX-2); for ATH, 16.74 μg/mL (COX-1) and 5.96 μg/mL (COX-2); for ibuprofen, 6.88 μg/mL (COX-1) and 2.68 μg/mL (COX-2). Selectivity indices (SI = IC50 COX-1/IC50 COX-2) were 2.86 for ATD, 2.81 for ATH, and 2.56 for ibuprofen, indicating promising COX-2 selectivity. Molecular docking revealed binding affinities for isolated compounds ranging from -9.0 to -6.4 kcal/mol (COX-1) and -8.5 to -6.6 kcal/mol (COX-2). For GC-MS-detected compounds, scores ranged from -8.9 to -5.5 kcal/mol (COX-1) and -8.3 to -5.1 kcal/mol (COX-2). Luteolin showed the highest binding affinity to COX-2 (-8.5 kcal/mol), followed by β-sitosterol-3-O-β-D-glucoside and stigmasterol (both -8.4 kcal/mol).

**Clinical Implications:** This study provides the first detailed phytochemical profile of *A. leucoclada*, identifying nine compounds and 27 GC-MS-detected metabolites. Both extracts demonstrated selective COX-2 inhibition with SI values higher than ibuprofen, suggesting potential as safer anti-inflammatory agents with reduced gastrointestinal side effects. Molecular docking supported these findings, showing high binding affinities of key compounds to COX-2. The results highlight *A. leucoclada* as a valuable source of natural anti-inflammatory compounds. Future studies should evaluate the in vivo efficacy and safety of these extracts or isolated compounds, alone or in combination with conventional NSAIDs.

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phytochemistry

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ORIGINAL PAPER

PMC10725009

Phytochemical investigation and anti-inflammatory potential of Atriplex leucoclada Boiss

BMC Complementary Medicine and Therapies

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ABSTRACT

Background The plant kingdom has long been considered a valuable source for therapeutic agents, however, some plant species still untapped and need to be phytochemically and biologically explored. Although several Atriplex species have been investigated in depth, A. leucoclada, a halophytic plant native to Saudi Arabian desert, remains to be explored for its phytochemical content and biological potentials. Herein, the current study investigated the metabolic content and the anti-inflammatory potential of A . leucoclada. Methods Powdered aerial parts of the plant were defatted with n-hexane then the defatted powder was extracted with 80% methanol. n-Hexane extract (ATH) was analyzed using GC–MS, while the defatted extract (ATD) was subjected to different chromatographic methods to isolate the major phytoconstituents. The structures of the purified compounds were elucidated using different spectroscopic methods including advanced NMR techniques. Anti-inflammatory activity of both extracts against COX-1 and COX-2 enzymes were examined in vitro. Molecular docking of the identified compounds into the active sites of COX-1 and COX-2 enzymes was conducted using pdb entries 6Y3C and 5IKV, respectively. Results Phytochemical investigation of ATD extract led to purification and identification of nine compounds. Interestingly, all the compounds, except for 20-hydroxy ecdysone (1), are reported for the first time from A. leucoclada , also luteolin (6) and pallidol (8) are isolated for the first time from genus Atriplex . Inhibitory activity of ATD and ATH extracts against COX-1 and COX-2 enzymes revealed concentration dependent activity of both fractions with IC 50 41.22, 14.40 μg/ml for ATD and 16.74 and 5.96 μg/ml for ATH against COX-1 and COX-2, respectively. Both extracts displayed selectivity indices of 2.86 and 2.80, respectively as compared to 2.56 for Ibuprofen indicating a promising selectivity towards COX-2. Molecular docking study supported in vitro testing results, where purified metabolites showed binding affinity scores ranged from -9 to -6.4 and -8.5 to -6.6 kcal/mol for COX-1 and 2, respectively, in addition the binding energies of GC–MS detected compounds ranged from -8.9 to -5.5 and -8.3 to -5.1 kcal/mol for COX-1 and 2, respectively as compared to Ibuprofen (-6.9 and -7.5 kcal/mol, respectively), indicating high binding affinities of most of the compounds. Analysis of the binding orientations revealed variable binding patterns depending on the nature of the compounds. Our study suggested A . leucoclada as a generous source for anti-inflammatory agents. Supplementary Information The online version contains supplementary material available at 10.1186/s12906-023-04281-5.

CITATION EXPORT

Hayam S. Ahmed, Enas I. A. Mohamed, Elham Amin et al.. Phytochemical investigation and anti-inflammatory potential of Atriplex leucoclada Boiss. BMC Complementary Medicine and Therapies. (2023). https://doi.org/10.1186/s12906-023-04281-5

AUTHORS

7 · 4 CENTRES

Hayam S. Ahmed, Enas I. A. Mohamed, Elham Amin, Abeer S. Moawad, Mohamed Sadek Abdel-Bakky, Suliman A. Almahmoud, Naglaa Afifi

1https://ror.org/05pn4yv70grid.411662.60000 0004 0412 4932Department of Pharmacognosy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514 Egypt
2https://ror.org/01wsfe280grid.412602.30000 0000 9421 8094Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraydah, 51452 Saudi Arabia
3https://ror.org/01wsfe280grid.412602.30000 0000 9421 8094Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah, 51452 Saudi Arabia
4https://ror.org/05fnp1145grid.411303.40000 0001 2155 6022Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, 11751 Egypt