A Comprehensive Overview on the Role of Phytocompounds as Gastroprotective Agents

Abstract

Peptic ulcer is a major health disease which could be defined as destruction in different parts of the gastrointestinal track mainly the lining mucosa of the stomach as well as the proximal duodenum. Additionally, the treatment of this illness emphases different challenges as the currently available medications have major side effects as well as limited effectiveness. On the other hand, natural products exhibited a chief role in prevention and curing various health issues. Different natural metabolites such as alkaloids (as isocorydine), flavonoids (as Sofalcone), terpenoids (as aescine), coumarins (as esculin), and tannins (as castalagin) exhibited a great part in the prevention in addition to healing of peptic ulcer with different mechanisms of action such as H₂ antagonists or Inhibition of the gastric H⁺, K ⁺ -ATPase. One hundred and eighty-five secondary metabolites were reported from higher plants and marine ecosystem. Therefore, this review provides an overview of the natural products obtained from different plants and marine sources as potential candidates with well reported gastro protective potential along with their mechanism of action and structural aspects whenever applicable. Herbal formulations and natural products in clinical trials have been mentioned in this review. Finally, drug likeness property, ADME/Toxicity profile of the compounds were evaluated.

Introduction

Peptic ulcer is considered as a destruction of the lining mucosa of the gastrointestinal system. ¹ Different parts in the gastrointestinal system as; the stomach, the esophagus, the proximal duodenum, jejunum are mainly affected in peptic ulcer disease.^2,3 Moreover, an imbalance among some endogenous aggressive factors is implicated in the development of this illness as leukotrienes, refluxed bile, hydrochloric acid, and reactive oxygen species.^1,4 The pathogenesis of peptic ulcers continues to be prevalent. Moreover, different factors contribute to the progress of gastric damage as long term consumption of non-steroidal anti-inflammatory medications, alcohol consumption, smoking, stressful lifestyle, alcohol intake, Helicobacter pylori infections, in addition to previous family history.^5,6 Consequentially, searching for suitable medications for the prevention and treatment of peptic ulcers is an important challenge facing the scientists nowadays as it is definitely a chief human disease influencing mainly 8% to 10% of the population. ⁷

The incidence of this disease is greater in men than in women. ⁸ While current approaches in our understanding have highlighted the multifactorial pathogenesis of gastric ulcers, secretion of gastric acid is still distinguished as a noteworthy part of this illness, consequently the key therapeutic object to control acid secretion utilizing antacids, H₂ receptor blockers as ranitidine, famotidine, anticholinergics as; pirenzepin, telezipine or proton pump blockers as omeprazole, lansoprazole. ⁹ On the other hand, gastric ulcer medication encounters recently a chief drawback as majority of the remedy currently depicted in the market reveal partial efficacy against gastric illness and are often associated with numerous drawbacks, ⁸ as antacid common side effects include (alkalosis, belching, nausea, and abdominal cramps), H₂ receptor blockers can cause on the long term use (lethargy, headache, dizziness, impotence, skin rashes, ranitidine and cimetidine can cause reversible mental confusion in elderly patients, anticholinergic as; pirenzepin, telezipine cause blurred vision, dry mouth, and constipation, proton pump blockers as omeprazole, lansoprazole cause osteoporosis, vitamin B12 deficiency, and hypomagnesemia. Therefore, it is necessary to investigate new therapeutic alternatives with lower adverse effects, which enhance the ulcer healing process and prevent new relapses. ¹⁰ In this context, utilizing natural molecules is in continuous extension all over the world for the prevention as well as treatment of different pathologies. Moreover, natural metabolites are ranked at the top in the pharmaceutical industry as inspiring sources of novel potentially bioactive metabolites.^3,11‐13 Furthermore, clinical investigation has documented the efficacy of different natural metabolites for the cure of gastroduodenal illness. ¹⁴ The medicinal properties of numerous plants are attributed mainly to the existence of varied group of metabolites such as; flavonoids, alkaloids, steroids, phenolic compounds, terpenoids, tannins, phenolic acids as well as anti-oxidant micronutrients, eg, Cu, Mn, Zn. ¹⁵ These secondary molecules exhibited their activity through various mechanism of actions as; inhibition of the gastric H+, K + -ATPase, reduce gastric acid secretion, protection of gastric mucosa, H₂-antagonists, as well as increase the synthesis of prostaglandin ( Figure 1 ).

Figure 1.

Different Mechanism of Actions Exerted by Natural Metabolites as Gastro Protective Agents.

Considering the medicinal properties of natural metabolites in preventing and reducing of the gastric lesions caused by various ulcerogenic elements, the overview of the current review is to focus on the chemical structures and the mechanism of action of different metabolites isolated from plants and marine organisms. Data collection was carried out on Pubmed in addition to Google Scholar covering all the published articles till 2023. In this review, the literature search was carried out using databases with keywords Natural Products and antiulcer and gastroprotective. The ADME (Absorption, Distribution, Metabolism, and Excretion) properties of the natural compounds analyzed in this study were evaluated using well-established theoretical and computational methods. Specifically, absorption rates and overall drug-likeness were assessed based on Lipinski's Rule of Five (Ro5) and Veber's rule, which are widely accepted criteria for predicting oral bioavailability and pharmacokinetic behavior.

Lipinski's Rule of Five evaluates compounds against the following parameters. First, molecular weight (MW) should be below 500 Daltons. Second, the Log P (partition coefficient between octanol and water) value should be less than 5. Third, compounds should have no more than 5 hydrogen bond donors (HBD). Finally, there should be no more than 10 hydrogen bond acceptors (HBA). Compounds that satisfy these conditions are more likely to exhibit favorable absorption and permeability characteristics. ¹⁶ Veber's rule complements these criteria by incorporating additional parameters related to molecular flexibility and polarity. Specifically, it requires compounds to have a total of 10 or fewer rotatable bonds (RTB) and a polar surface area (TPSA) not exceeding 140 Ų. These metrics are critical for evaluating molecular properties that influence oral bioavailability. ¹⁷ These drug likeness profiling were predicted using Swiss ADME server. ¹⁸

Inhibition of the Gastric H+, K + -ATPase

The membrane-bound enzyme, gastric H⁺, K ⁺ -ATPase, is located in the apical membrane of parietal cells. It mainly pumps protons into the gastric region utilizing energy obtained from ATP hydrolysis. ¹⁹ Therefore, this enzyme considered as a promising pharmacological target for the innovation of drugs for the treatment of acid-associated disturbance ( Figure 2 ). In this context, different flavonoidal metabolites as minimiflorin (1), mundulin (2), as well as the chalcone lonchocarpin (3) were obtained from Lonchocarpus oaxacensis in addition to L. guatemalensis roots. ²⁰ Minimiflorin exhibited the highest activity with IC₅₀ value of 9.6 ± 0.9 µg/ml, followed by mundulin and lonchocarpin with their IC₅₀ values of 70 ± 10 and 171 ± 35 µg/ml, respectively. They inhibit gastric H+, K + -ATPase by different mechanisms as binding to the active site, which prevents the pump from hydrolyzing ATP (which is a necessary step for active proton exchange between gastric lumen and cytosol). Additionally, they can exert their effect through their antioxidant properties; reduce oxidative stress in gastric mucosal cell, which indirectly decreasing the activity of H+, K + -ATPase. Moreover, the hydroxyl group in flavonoids play an important role in their inhibitory effect through binding to the lysine residue of the H⁺ /K⁺ ATPase.^21,22 Additionally, jacareubin (4), 6-desoxyjacareubin (5), 1,3,5,6-tetra-hydroxy-2-(3-hydroxy-3-methylbutyl)-xanthone (6), along with 1-hydroxy-35,6-tri-O-acetyl-2(3,3-dimethylallyl)-xanthone (7) are xanthones derivatives previously obtained from Calophyllum brasilienses heartwood. Jacareubin (4) exhibited powerful inhibition of gastric H⁺, K ⁺ -ATPase enzyme with IC₅₀ value of 46.7 ± 7.6, followed by 6-desoxyjacareubin, 1,3,5,6-tetra-hydroxy-2-(3-hydroxy-3-methylbutyl)-xanthone, as well as 1-hydroxy-35,6-tri-O-acetyl-2(3,3-dimethylallyl)-xanthone with IC ₅₀ values of 1581 ± 37, 173 ± 8.6, and 16 05 ± 216, respectively. ²³

Figure 2.

Chemical Structures of Compounds 1-19.

Additionally, palmonine F (8), cholest-5-ene-3b,7a-diol (9), (22E)- cholesta-5,22-diene-3b,7a-diol (10), ergosta-5,24(28) diene 3b,7a-diol (11) in addition to cholesta-5,22-diene-3b-ol (12) are diterpenoid sterols were isolated from Mediterranean gorgonian Eunicella singularis. They achieved their gastroprotective potential through increasing the levels of gastric hexosamine and improving the gastric barrier strength both physically and by the blockage of H⁺, K⁺ /ATPase pump. ¹⁹ Moreover, boldine (13) is an alkaloid previously obtained from Peumus boldus. During in vivo evaluation of its gastroprotective potential, it was capable of protecting the gastric mucosa against the damage caused by ethanol/HCl as well as indomethacin, which was verified by reducing the lesion region and histological investigation. Additionally, the alkaloid decreased the oxidative stress as well as inflammatory mediators in ethanol-ulcerated tissue. It also has elevated mucin-like glycoprotein quantity. Consequently, its effect is mainly depend on non-protein sulfhydryl groups in addition to prostanoids. ²⁴ Taxifolin (14), a flavonoid was isolated from Mimusops balata showed potent ability to inhibit the proton pump activity. ²⁵ Furthermore, xyloccensin-E (15) as well as xyloccensin-I (16) limonoids derivatives were obtained from Xylocarpus molluccens fruits. They exhibited inhibition of the proton pump potential with IC₅₀ values of 157.93 and 218.95 μg/ml, respectively. ²⁶ (+)-O-Methylarmepavine (17), N-Methylcorydaldine (18), isocorydine (19) alkaloids were isolated from Annona squamosa twigs. N-methylcorydaldine (18) showed the highest anti secretory activity followed by isocorydine, and (+)-O-methylarmepavine with IC₅₀ values of 60.9, 88.42, and 111.83 μg/ml, respectively. ²⁷

Reduce Gastric Acid Secretion

Reducing gastric acid production and regeneration of gastric mucosal has been the chief approaches for available medication of peptic ulcer illness. Various natural secondary metabolites achieved their gastroprotective potential through reducing gastric acid secretion. They are known for their anti-inflammatory, antioxidant, and cytoprotective effects, which could indirectly reduce gastric acid section by modulating inflammatory pathway or improving mucosal defense mechanism.^28,29 In this context, aescine (20) a triterpene glucoside, was obtained from the horse chestnut Aesculus hippocastanum dried seeds. It exerted its gastro protective potential through in vivo antisecretory action ( Figure 3 ) with non-prostaglandin dependent mechanisms. ³⁰ On the other hand, castalagin (21), pedunculagin (22), and phyllyraeoidin (23) are groups of tannins, which were previously isolated from Quercus suber as well as Q. coccifera. They showed protective potential against ethanol-induced gastric ulcer. Their protection percentage ranged from 66% to 83% with castalagin (21) being the most potent one. ³¹ Trifolirhizin (24) is a tetra-acetate glucoside was previously isolated from Sophora flacescens root belongs to family Leguminosae. It exhibited in vivo gastroprotective and antibacterial action against H. pylori as well as HCl ethanol-induced gastric lesion in rats. Its activity originated from reduction of total acid output, scavenging of the free radicals and the antibacterial potential against H. pylori. ³¹ Additionally, marrubiin (25) a diterpene, was obtained from Marrubium vulgare leaves. It showed gastroprotective potential in ethanol-, and indomethacin-induced ulcer rat models through stimulating the mucus synthesis as an important gastroprotective factor and reducing acid gastric secretion. ³² Alpha-pinene (26), a monoterpene molecule mostly found in volatile oils with gastroprotective potential isolated from different medicinal plants, including Hyptis species. Pretreatment with alpha pinene inhibited significantly the gastric mucosal lesions induced by ethanol, reduced the volume as well as the acidity of the gastric juice and elevated the mucus gastric wall. ³³

Figure 3.

Chemical Structure of Compounds 20-26.

H₂-Antagonists

Nowadays, H2- antagonists, as omeprazole as well as antimuscarinics, mainly base the available medical treatment of gastric ulcer on inhibiting the gastric acid secretion. In this context, hesperidin (27), neohesperidin (28) are dihydrochalcones were isolated from Citrus aurantium fruit and Agathsoma serratifolia leaves, respectively ( Figure 4 ). They exhibited a significant capacity in reducing the ulcer index in cold-restraint mediated ulcer in a dose-dependent manner. Additionally, they showed their action through inhibiting the histaminergic activity and reducing the acid and pepsin output. ²⁵ Trans-crotonin (29) and trans dehydrocrotonin (30) are nor-clerodane diterpene obtained from Croton cajucara bark.

Figure 4.

Chemical Structure of Compounds 27-31.

They performed their gastroprotective activity through increase PGE2 production and a noncompetitive antagonist of H₂ receptor as well as by reducing the maximum response of the receptor regardless of the concentration of histamine. ³⁴ Papain a nitrogenous molecule (31) was isolated from the unripe fruit of Papaya proteinase. It effectively protected the exogenous ulcer and decreased the histamine-mediated acid secretion in rats. ³⁵

Increase the Synthesis of Prostaglandins

The chief mechanism of NSAID-related damage of the gastroduodenal mucosa is cyclooxygenase-1 (COX-1) inhibition, which is responsible for prostaglandin synthesis. Additionally, it is associated with reducing mucosal blood flow, low mucus and bicarbonate secretion, and cell proliferation inhibition. NSAIDs reversibly inhibit the enzyme in a concentration-dependent manner. Those compounds increase the synthesis of prostaglandin by enhancing the activity of cyclooxygenase (COX) pathway, this enzyme catalyzes the conversion of arachidonic acid into prostaglandin particularly prostaglandin E2 (PGE2) which promotes mucus and bicarbonate secretion while improving mucosal blood flow, thereby strengthening the gastric barrier and accelerating tissue repair. ³⁶ Ferruginol (32) is a diterpene metabolite was isolated from Podocarpus ferrugneus ( Figure 5 ). It showed a gastroprotective potential through stimulating the synthesis of gastric PGE2, reducing gastric acid output as well as improving the anti-oxidant potential of the gastric mucosa by conserving GSH levels. ³⁷ Additionally, rutin (33) a natural flavonoid compound, was previously isolated from several plants such as Carpobrotus edulis and Ruta graveolens. It exerted its gastroprotective activity through increasing PGE2 levels in ethanol-related injury in rats model. ³⁸ Sofalcone (34), a flavonoid metabolite which was isolated from Sophora subprostrata. It has been utilized for gastritis and gastric ulcers treatment in Japan and South Korea. Moreover, different studies have suggested that sofalcone (34) exerted its activity through inhibiting 15-hydroxy-prostaglandin (PG)-dehydrogenase, increasing blood flow in mucosa as well as maintaining the mucosal macromolecular glycoprotein. ³⁹ Furthermore, dehydroleucodine (35) a guaianolide type sesquiterpene lactone was obtained from Artemisia douglasiana. It exerted its effect through increasing prostaglandin (PG) production. Additionally inhibiting sulfhydryl-containing compounds of the mucosa. ³⁴ Niga-ichigoside F1 (36) as well as 2β,3β-19-α-trihydroxyursolic acid (37), are pentacyclic triterpenes which were reported from Rubus imperialis. Their gastroprotective potential was estimated in the HCl/ethanol-induced ulcer in mice model. Consequently, these triterpenes metabolites significantly reduced the lesion index, total lesion area, in addition to percentage of lesion in comparison to the control group. Moreover, they also strengthened the defensive factors as; stimulating mucus synthesis in addition to preserving the high levels of prostaglandin contents of the gastric mucosa. ⁴⁰ Lapachol (38) was obtained from Tabebuia heptaphylla rhizome. In a dose-dependent manner, they elevated PGE2 synthesis by 2.5 and 2.3 fold, respectively. ⁴¹ 1,3-Dicyclohexyl-2-cyperenyl-isourea (39), and dihydroprenyl lapachol cyperenate (40) are sesquiterpene compounds which were obtained from Jatropha isabelii rhizomes. At a dose of 231 μM, the former one increased PGE2 synthesis by 4.4-fold, while the later one increased PGE2 synthesis by 8.2 and 2.5-fold at a dose of 331 and 167 μM, respectively. ²³ Myricetin (41) is a flavonoidal metabolite obtained from various vegetables and fruits. It exhibited its potential through oxidative damage prevention, promoting PGE2 production, as well as inhibiting NF-κB activation. ²⁵ Moreover, tannic acid (42) is a phenolic compound obtained from various plants as, teas, grains, and fruits. It showed gastroprotective potential through inhibiting the K⁺ ATP channels, NO, –SH, as well as elevating PGE2 synthesis. ⁴² Oleanolic acid (43) is a triterpene compound widely distributed in various plants as Fabiana imbricata and Lantana camara. It played a great gastroprotective activity against peptic ulcers stimulated by pylorus ligature and ethanol in rats. Diligustilide (44), a dimeric phthalide was obtained from Ligusticum porteri roots and rose (Apiaceae). The anti-ulcer potential of diligustilide depended upon the participation of the endogenous non-protein –SH groups as well as prostaglandins on the ethanol gastric ulcer lesions. ⁴³ Violacein (45) an indole alkaloid previously obtained from Chromobacterium violaceum. It provided a noteworthy gastroprotective potential in an indomethacin-induced ulcer model through maintaining some vital protein molecules, which was mediated by endogenous prostaglandins, NOS, K ⁺ ATP channel opening, inhibition of apoptosis as well as gastric microvascular permeability. ⁴⁴ 2S, 3R, 4E, 8E-2-(Heptadecanoylamino)- heptadeca-4, 8-diene-1, 3-diol (46) is a ceramide was obtained from the soft coral Cespitularia stolonifera. It exhibited a significant increase in mucus production by increasing in mucosal PGE2. 24-Methyl- cholesta-5, 24(28)-diene-3β-ol (47), 24- methylcholesta-5,24(28)-diene-3β-acetate (48), 4-methyl-24- methylcholesta-22-ene-3-ol (49), are steroids obtained previously from Cespitularia stolonifera soft coral. They exerted their gastroprotective potential through increasing in mucus production with an increase in mucosal PGE2. ⁴⁵

Figure 5.

Chemical Structure of Compounds 32-49.

Protect Gastric mucosa:

Arbutin (50), a hydroquinone glycoside was isolated from Turnera diffusa as a native plant growing in America and Africa ( Figure 6 ). Additionally, it is traditionally utilized for the treatment of different diseases as diabetes mellitus, diarrhea, peptic ulcer, and alcoholism. It protected the mucosal membrane, enhanced mucus production, elevated level of NO, IL-10 as well as inhibited acid secretion to stabilize the inflammation and mucosal erosion induced by ethanol and aspirin. ⁴⁶ Additionally, naringenin (51) a flavone, was isolated from Grapefruit Greek oregano, Tart cherries and Citrus aurantium. It increased both the amount of mucus and its glycoprotein content, enhanced total proteins. hexosamines, neutral glycoproteins and sulphated macromolecules. ⁴⁷ Solidagenone (52) is a labdane diterpene which was obtained from the rhizomes of Solidago chilensis. It exerted its gastroprotective potential by increasing mucosal defensive factors independent of endogenous prostaglandin. ³⁹ Moreover, kolaflavanone (53), garcinia biflavonoid GB1 (54), garcinia biflavonoid GB2 (55), are biflavonoids were obtained from Garcinia kola seeds. They decreased gastric lesions produced by indomethacin as well as acidified ethanol. The impacts of kolaflavanone on both indomethacin in addition to ethanol-induced hemorrhagic erosion could be accompanied with an elevation in gastric mucosal blood flow as well as gastric mucus secretion. Anisaldehyde (56), benzaldehyde (57), eugenol (58) and anethol (59), are mono methoxybenzene metabolites which were previously isolated from Pimpinella anisum. They inhibited the ulcerative lesions in all animals treated with necrotizing agents by maintaining the structural integrity of the gastric epithelium. ³⁷ Sofalcone (60) is a chalcone obtained from Sophora subprostrata. It enhanced gastric blood flow, promoted the synthesis of muco-substances of the gastric mucosa as well as elevated the impacts on gastric tissue PGs contents. ²⁵ Cashew gum (CG) (61) is a hetero polysaccharide metabolite which was isolated from Anacardium occidentale. Its gastroprotective mechanism is depending on elevating adherent gastric mucus, decreasing in free radical production as well as lipid peroxidation. ³² Isoliquiritigenin (62) a chalcone, was obtained from Glycyrrhiza glabra. It inhibited gastric ulcer induced by indomethacin through increase gastric mucus secretion, which counteract the reduction in COX2 level caused by indomethacin. ⁴⁸ Rhamnogalacturonan (63) a polysaccharide, was isolated from Acmella oleracea. It exhibited its gastroprotective potential through acting as a protective coating to the mucosa surface by increasing mucus synthesis scavenging radicals, as well as diminishing acid and pepsin secretion. ⁴⁹ Limonene (64) is a monoterpene molecule was obtained from Citrus aurantium. It revealed its gastroprotective potential through increasing the gastric mucus, which neutralizes H⁺ concentration in the gastric juice. ⁵⁰ Ginsenoside Rb1 (65), a steroid glycoside, which was obtained from Panex ginseng. It decreased gastric acidity by promoting mucus and bicarbonate secretion. ³⁷ 2’,3,4,4’,6'-pentahydroxychalcone (66), 2’,3,4-trihydroxychalcone (67). 2’,4’,6'trihydroxychalcone (68). 2’,4'-dihydroxy-3’,5'-diprenyl-4-O-prenyl-chalcone (69). 2’,4'-dihydroxy-3'-methoxychalcone (70). 2’,4'-dihydroxy-5'-prenyl-4-O-prenylchalcone (71). 2’,4,4’,6'-tetrahydroxychalcone (72). 2’,4,4'-trihydroxy-3,3’,5'-tris-(3-methylbut-2-enyl) chalcone (73), 2’,4,4'-trihydroxy-3,3’,5,5'-tetrakis-(3-methyl-but-2-enyl)-4,4'-bis-(O-3-methylbut-2-enyl)chalcone (74), 2’,4,4'-trihydroxy-3,3’,5,5'-tetrakis-3-methyl-but-2-enyl) chalcone (75), 2’,4,4'-trihydroxy-3,3’,5-tris-(3-methylbut-2-enyl)-4-4'-di-O-allylchalcone (76). 2’,4,4'trihydroxy-3,3'-bis-(3-methylbut2-enyl) chalcone (77). 2’,4,4'-trihydroxy-3,3'-diprenylchalcone (78). 2’,4,4'-trihydroxy-3,5,5'-tris-(3-methylbut-2-enyl)-4'-O-(3-methylbut-2-enyl) chalcone (79). 2’,4,4'-trihydroxychalcone (80). 2’,4-dihydroxy-3-prenyl-4'-O-prenylchalcone (81). 2’,4-dihydroxy-4'-methoxy-3-5-bis-(3-methyl-but-2-enyl) chalcone (82). 2'-hydroxy-4,4'-di oprenylchalcone (83). 2,4'-di-O-prenylchalcone (84). 2,4,4'-trihydroxy-3,3’,5'-tris-(3-methylbut-2-enyl)-4-O-allyl-4-O-propargylchalcone (85). 3’,5'-dihydroxy-4'-prenyl-5-O-prenylchalcone (86). 3,3’,4-trihydroxychalcone (87). 3,4,4'4'-trihydroxychalcone (88). 4'-hydroxy-3'-prenyl-4-O-prenylchalcone (89). 4,4'-di-O-geranyl chalcone (90). 4,4'-di-O-prenylchalcone (91). 4,4'-dihydroxy-3,3'-diprenylchalcone (92). 4,4'-dimethoxy-3,3'-diprenylchalcone (93). 4-hydroxy-3-prenyl-4'-O-prenylchalcone (94). 2’,4-bis-(carbomethoxy)-4'-(3-carboxy-2-butenyl-oxy)dihydrochalcone (95). 2’,4-bis(carboxymethoxy)-4'-(3-methyl-2-butenyl-oxy)dihydrochalcone (96). 2'-carboxymethoxy-4-4'-bis-(3-methyl-2-butenyl-oxy) dihydrochalcone (97) are chalcone derivatives isolated from the Chinese crude drug Sophora subprostrata root. They significantly raised gastric blood flow, promoted the production of mucosubstances of the gastric mucosa with enhanced effects on PGs contents. ⁵¹ Sophoradin (98) is another chalcone was isolated from Sophora tonkinensis. It exhibited noteworthy elevation in gastric blood flow, with stimulating the production of mucosubstances of the gastric mucosa as well as increasing the impacts on gastric tissue PGs contents. ⁵²

Figure 6.

Chemical Structure of Compounds 50-102.

On the other hand, leucocyanidin (99) is a flavonoid, which is the major metabolite in unripe plantain banana (Musa sapientum L. var. paradisiaca. It exerted a significant protection in aspirin-induced lesions. ⁵³ Epitaondiol (100), sargaol (101) a meroditerpene and chromene derivatives, respectively, obtained from Stypopodium flabelliforme brown algae They showed a significant gastroprotective potential to the gastric mucosa in the HCl/EtOH model in mice with ED₅₀ values of 40, 35 mg/kg, respectively (Areche, San-Martín, Rovinosa, & Sepúlveda, 2011). Arabinogalactan (102) is a polysaccharide constitutes the cell wall of different plants as mango Mangifera indica L. and Lyciumm ruthenicum Murr. They exhibited a protective potential to the gastric tissue by decreasing acid and pepsin secretion, improving the mucous synthesis coating the entire mucosal membranes.^54,55 All these compounds protect the gastric mucosa through their antioxidant activity; by neutralizing reactive oxygen species (ROS) and reducing oxidative stress, which is a major factor in gastric mucosal injury. This helps protect gastric epithelial cells from damage caused by free radicals, commonly associated with conditions like gastritis and peptic ulcers.

Additionally, they possess powerful anti-inflammatory effects through inhibiting the production of pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-1β, which are involved in gastric mucosal inflammation. Reducing inflammation minimizes tissue damage and promotes healing of the gastric lining. Moreover, they exert cytoprotective potential by enhancing the production of protective gastric mucosal factors, such as prostaglandins which increase mucus and bicarbonate secretion, strengthening the mucosal barrier against gastric acid and other irritants^36,56

Gastroprotective Through Anti-Oxidant Properties:

Arabinoxylan (103), a polysaccharide, was isolated from sugarcane bagasse Figure 7 . It exhibited a significant gastroprotection by inhibiting the reduction of the gastric wall mucus, with powerful anti-oxidant properties. ⁵⁷ Astragaloside IV (104), a glycosylated cycloartane-type triterpene obtained from Astragalus zahlbruckneri. This molecule significantly inhibited leucocyte adhesion to endothelial cells, scavenged free radical of both superoxide and hydroxyl radicals, as well as inhibited the synthesis and release of different inflammatory mediators as interleukin-1 and tumor necrosis factor. It has been estimated that NO serves as an anti-oxidant in mucosal dysfunction related to ischemia–inflammatory conditions of the gastrointestinal tract. ⁵⁸ Additionally, kolaviron (105) a biflavonoid, was isolated from Garcinia kola seed. This metabolite showed protection against the oxidation of serum lipoprotein both in vitro and in vivo, by exerting metal chelation, anti-oxidant in addition to scavenging of radical species implicated in the oxidative process. ³⁷ Quercetin (106) is a flavonoid found in different food sources such as fruits, vegetables, nuts, and seeds. It exhibited significant gastroprotective potential in ethanol-induced gastric ulcer through its antiperoxidative, anti-oxidant and anti-histaminic effects. ⁵⁹ It displayed stronger antioxidant and anti-inflammatory properties at lower concentrations than kaempferol (108) with IC₅₀ values as 1.84,5.318, receptively making it effective in oxidative stress-related gastric disorders. Desmosdumotin C (107) is a chalcone, previously isolated from Mitrella kentia. It exhibited gastroprotective potential by decreasing gastric ulcer lesions, reduction of edema as well as leucocytes infiltration in comparison to the control group. Moreover, it was observed that desmosdumotin C preserved glutathione (GSH) level, reduced malondialdehyde (MDA) level, elevated NP-SH content as well as NO level. ⁶⁰ Kaempferol (108) is a flavonoid was obtained from various green vegetables as spinach and herbs such as dill and chives. Additionally, it showed gastroprotective potential through preserving glycoproteins levels, inhibiting neutrophil accumulation in addition to MPO potential, therefore adjusting the pro-inflammatory cytokines levels, and enhancing NO production. ⁶¹ Additionally, nobiletin (109), a flavonoid isolated from various citrus fruits showed gastroprotective potential through enhancing anti-oxidant potential, promoting the levels of PGE2, and reducing pro-inflammatory cytokines through the MAPK pathway. ⁶² Garcinol (110) a polyisoprenylated benzophenone, was isolated from Garcinia indica rind. It showed its anti-ulcer activity through its free radical scavenging properties. ⁶³ 3,5-diprenyl-4-hydroxyacetophenone (111), is acetophenone obtained from Ageratina pichinchens. It hindered gastric mucous loss and enhanced the removal of free radicals formed because of the ethanol-induced mucosal ulcer. 4a, 24-dimethyl-5a-cholest-8b,18-dihydroxy,22Een-3b-ol (ST-1) (112) is a steroid obtained from the soft coral Nephthea sp. It showed its gastroprotective potential through the reduction in oxidative damage and leukotriene activity. ⁶⁴ Lupeol (113) is a pentacyclic terpenoid found in olives, mangos, and Japanese pear. This metabolite reduced oxidative stress as well as inflammation impacted by H. pylori. ⁶⁵ 3-Hydroxy-β-lapachone (114), cyperenoic acid (115) are a naphthoquinone and sesquiterpene metabolites previously isolated from Tabebuia heptaphylla bark, and the rhizomes of Jatropha isabeli, respectively. They showed their potential through reinforcement of the defensive factors such as GSH, which exerted protective effect against damage induced by free radicals and incorporated in reducing the formation of gastric lesions. ⁶⁶ Isoorientin (116) is a flavonoid glycoside, found in various plants such as Eremurus persicus. It showed protective potential through decreasing MDA level and increasing SOD activity as well as GSH levels in the stomach tissue of rats. ⁶⁷ These metabolites mainly exerted their gastroprotective potential through chelation of transition metal ions, inhibition of oxidant enzymes, and regeneration of α- tocopherol from α- tocopheroxyl radicals. Additionally, they promote gastric mucosa formation, decrease acid mucosal secretion, suppress the production of pepsinogen and diminish the ulcerogenic lesions. ⁶⁸

Figure 7.

Chemical Structure of Compounds 103-115.

Mixed Mechanism of Action:

Calein D (117) is a germacrene sesquiterpene lactone isolated from Calea urticifolia Figure 8 . It significantly diminished the ulcer index with maximum effect at a dose of 30 mg/kg in ethanol-induced gastric ulcer.^69,70 Escin (118) is a triterpenoid saponin obtained from Aesculus hippocastanum. Escin exerted its gastroprotective potential on relieving inflammation through regulating the glucocorticoid receptors (GR), which is unlike the mechanisms of action of both GCS and NSAIDs. ⁷¹ Biochin A (119) and formononetin (120) two flavonoids were isolated from Andrographis paniculata with powerful anti-ulcer potential by preserving the mucin content and antioxidants in stomach. ³⁷ Rutaecarpine (121) a quinazolino carboline alkaloidal component isolated from Evodia rutaecarpa and Bentham Rutaceae. It stimulated the endogenous CGRP, which is a sensory neuropeptide present exclusively in primary afferent nerve in the stomach release through activation of vanilloid receptors. ⁷² Hypolaetin-8-glucoside (122), a flavonoid which was isolated from Sideritis mugrunensis. It exerted its potential through selective inhibitor of 5- lipoxygenase. ⁷³ Additionally, silymarin (123) a flavonoid which was isolated from Silybum marian. It exerted its potential through protecting gastric mucosal NO, NP-SH as well as the alteration of capsaicin-sensitive gastric sensory afferents. ⁷⁴ Moreover, atractylenolide III (124) a sesquiterpenoid which was previously obtained from Atractylodes ovata. It inhibited MMP-2 and MMP-9 expression, decreased the ECM damage and prevented gastric ulcer formation. ⁷⁵ Citral (125) is a monoterpenoid found in lemon, limes orange with anti-nociceptive potential, and counteracting gastric injury induction. ⁶⁵ O, C- (3)-seco-9-ene-6β-taondiol (126) is a meroterpenoid obtained from Stypopodium flabelliforme Chilean Seaweed. It exhibited its activity through the enhancement of prostaglandins, sulfhydryl groups, and NO production. ⁷⁶

Figure 8.

Chemical Structure of Compounds 117-126.

Unknown Mechanism Activity:

Diverse natural metabolites showed potent anti-ulcer activities. Unfortunately, some of them still their mechanism of action remains unexplored ( Figure 9 ). In this context, cordatin (127) a furan diterpene, was isolated from Aparisthmium cordatum. Although its mechanism of action is unknown, it looked to be associated with antisecretory property. ⁷⁷ Additionally, ternatin (128) a tetramethoxyflavone, was isolated from Egletes viscosa. Pretreatment of animals with this flavonoid (25 and 50 mg/kg, i.p.) significantly inhibited gastric lesions caused by ethanol but no effect on those induced by restraint stress or indomethacin which is probable to its involvement of a prostaglandins-independent mechanism of gastro protection. ⁷⁸ Aparisthman (129), a diterpene was isolated from Aparisthmium cordatum. While the mechanism responsible for its anti-ulcerogenic potential remains unknown, it appeared to be associated with a significant increase of the stomach defensive mechanisms such as prostaglandin production and mucus synthesis. ³⁴ Centipedic acid (130) a diterpene obtained from Egletes viscosa flower buds. It afforded gastroprotective effect by various and complementary ways, as affecting the levels of NP-SH, endogenous prostaglandins, nitric oxide, and TRPV1-receptor as well as K ATP channel activation. ⁷⁹ Theasaponin A2 (131) is a triterpene saponin was isolated from Tea Seed Camellia sinensis. It showed an inhibitory potential on ethanol-related gastric mucosal lesions in rats at a dose of 5.0 mg/kg, p.o.. ⁸⁰ Mangiferin (132) is a glugcosylxanthone was isolated from Mangifera indica L. It exhibited gastroprotective potential against gastric injury related to ethanol and indomethacin via the antisecretory as well as anti-oxidant properties. ⁸¹ Acetyl aleuritolic acid (133), Jatrophone (134), Jatropholone A (135), and Jatropholone B (136) are groups of terpenoid metabolites which were isolated from Jatropha isabelli. They showed potent gastroprotective as reducing gastric lesions by 88%–91%.. ⁸² 11-hydroxy-4-amorphen-15-oic acid (137) is a sesquiterpene isolated from Fabiana imbricate. It reduced the gastric lesions in HCl/EtOH-induced gastric injury in mice by 68% at 100 mg/kg in a dose dependent manner. ³⁷ Camelliosides A (138) and B (139) are nor-oleanane- triterpene saponins were previously obtained from Camellia japonica. They revealed gastroprotective potential on ethanol- and indomethacin-related gastric lesions. ³⁹ Ginsenoside Rd (140) is an oligoglycoside previously obtained from Panax ginseng. It showed inhibitory potentials on ethanol- and indomethacin-related gastric mucosal lesions in rats. ³⁷ Linalool (141) and Linalyl acetate (142) are acyclic monoterpenes which were previously obtained from Lavandula hybrid. They showed a significant reduction in ethanol-caused gastric injury to rats. ³⁷ Baicalin (143) is a flavonoid previously obtained from Coptis chinesis, and Rheum officinale. It significantly alleviated chronic gastritis through suppressing the inflammatory regulators and hindering Akt/NF-κB activation. ⁸³ Pterogynidine (144) is a flavonoid which was obtained from Alchornea glandulosa with potent anti-ulcerogenic effects. ³⁷ Methyl gallate (145) and gallic acid (146) are hydroxybenzoates derivatives and previously obtained from Alchornea glandulosa. They exerted potent anti-ulcerogenic effects.. ³⁷ Ascorbic acid (147) is a phenolic metabolite which was obtained from Cissus quadrangularis. It showed powerful gastroprotective potential. 15-acetoxyimbricatolic acid (148) as well as 15-acetoxylabd-8(9)-en-19-oic acid (149) are diterpenes obtained from Araucaria araucana. They showed potent gastroprotective potential at doses of 50 and 100 mg/kg in mice, respectively. ³⁷ Moreover, esculin (150) a coumarin derivative which was obtained from Aesculus hippocastanum L. (Horse-chestnut). It exerted its gastroprotective potential through promoting endogenous prostaglandins, nitric oxide production, activation of K ATP channels, reduction of free radicals and alteration of anti-oxidant enzyme systems. ⁸⁴ 3-β-hydroxy-3-deoxibarbatusin (BBOH) (151) and Barbatusin (BB) (152) are diterpenes, which were previously obtained from Plectranthus grandis. They effectively decreased the gastric lesions by 59% and 96%, and 32% and 76%, at doses of 5 and 10 mg/kg, respectively. ⁸⁵ Butein (153) is a chalcone which was obtaind from Glyzrrhiza glabra. It prevented the formation of gastric mucosal lesion caused by oral administration of severe necrosing elements as 60% ethanol. ²⁵ Xanthoangelol E (154) is a chalcone obtained from Angelica keiskei. It showed antisecretory effect due to inhibiting the gastric H⁺, K ⁺ -ATPase. ⁸⁶ 2’,4’,7-trihydroxy-5-methoxy-8-(5-hydroxy-5-methyl-2-iso-propenylhexyl) (155) a flavanone was previously obtained from Sophera angustifolia. It showed a powerful gastroprotective activity. ²⁵ Naringin (156) a flavanone was obtained from Citrus paradisi and Citrus aurantium peel. It revealed gastroprotective activity by decreasing the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), inducible nitric oxide synthase (iNOS), as well as caspase-3 levels in indomethacin-induced ulcer. ⁸⁷

Figure 9.

Chemical Structure of Compounds 127-185.

Additionally, sigmoidin A (157) a flavanone was isolated from Erythrina sigmoidea. It showed its potent effect in stress-induced ulcers at 50.0 mg/kg. ²⁵ Sophoranone (158) a flavanone which was isolated from Sophora subprostrata. It exhibited potent potential against Pylorus ligation as well as stress-induced ulcers. ²⁵ (dl) Catechin (159) a flavan was isolated from Camellia sinensis. It showed anti-oxidant potential and mucus protection against ischaemia–reperfusion-induced gastric ulcers. ⁸⁸ 3-O-Methyl: (+) catechin (160) a flavan was isolated from Camellia sinensis (L.). It showed activity against stress-related ulcers/s.c. with ED₅₀ value of 13.2 mg/kg/s.c, phenylbutazone-caused ulcers/s.c., in addition to reserpine-related ulcers/s.c.. ²⁵ Cyanidan-3- glucoside (161) a flavan was obtained from Camellia sinensis. It exhibited gastroprotective potential through removal of the ethanol-related lipid peroxides as well as free radicals which may offer a potential therapy for the treatment of gastric lesions. ⁸⁹ 35,7-trihydroxy-2-(3,4-dihydroxyphenyl)-1-benzopyrylium chloride (162) is an anthocyanidin obtained from Vaccinium Myrtillus. It exhibited a promising anti-ulcer potential by potentiating the defensive barriers of the gastrointestinal mucosa. ⁹⁰ Eupatilin (163) a flavone was isolated from Artemisia asiatica. It showed powerful anti-ulcer properties. ⁹¹ Gnaphaloside A (164) a flavone was isolated from Gnaphalium L. It showed potent activity against reserpine-related ulcers/gastric intubation at 0.05 mL/g. ²⁵ Gossypin (165) a flavone was obtained from Aphis gossypii. It showed potent anti-gastric ulcer activities. ⁹² Hypolaetin-8-O-β-d-glucoside (166) a flavone was obtained from Sideritis leucantha. It showed potent activity against cold stress-related ulcers/i.p. and ethanol-related gastric lesions/s.c. with ED₅₀ values of 57.3, 68.0 mg/kg, respectively. ⁷³ Luteolin (167) a flavone was obtained from Aflatunia ulmifolia. It exhibited activity against reserpine-induced gastric ulcers. ²⁵ Vexibinol (168) a flavone was isolated from Sophra flavescence. It showed potent activity as gastric mucosal protective and antisecretory agent. ⁹³ Additionally, genistin (169) an isoflavone was obtained from Genista rumelica. It exerted a protective potential against IND-related gastropathy through hindering inflammatory mediators, neutrophil infiltration, suppression of oxidative stress generation as well as replenishing of NO levels regardless of gastric acidity. ⁹⁴ Procyanidin B-2 (170) and Procyanidin B-4 (171) are biflavonoids which were obtained from Cinchona pubescens. They showed potent activity against Stress-induced ulcers (water immersion)/ gastric intubation.. ²⁵ Carnosol (172) is a diterpene obtained from Sphacele chamaedryoides. It exhibited gastroprotective potential by 69.9, 63.0, at doses of 20, 10 mg/kg, respectively. ⁹⁵ 6,7-Dehydroroyleanone (173) a diterpene previously isolated from Sphacele chamaedryoides with gastroprotective effect by 54.4%. ⁹⁵ Royleanone (174) a diterpene obtained from Sphacele chamaedryoides (Balbis) Briq. It showed gastroprotective effect by 70.8%. ⁹⁵ 7,20-Epoxyroyleanone (175) another diterpene obtained from Sphacele chamaedryoides with gastroprotective effect by 65.0%. ⁹⁵ Taxoquinone (176), Horminone (177), and 7-Oxo-11,12,14-trihydroxy-8,11, 13-abietatrien-20-al (178) are quinone derivatives obtained from Sphacele chamaedryoides. ⁹⁵ They exerted their gastroprotective potential by 35.8, 52.7, 53.0%, respectively. Rosmarinic acid (179), a polyphenol which was isolated from Salvia plebeian. It significantly decreased ulcerative index related to HCl/EtOH as well as indomethacin /bethanechol in mice. ⁵⁸ Tenuifloroside (180), and Verbascoside (181) are flavonoids obtained from Castilleja tenuiflora. They showed significant effect through decreasing the ulcerated area. ⁹⁶ Zingerone (182) is a phenolic compound obtained from Zingiber officinale. It showed a protective potential on the ethanol-related gastric ulcer attributed to its free radical scavenging potential. ⁹⁷ Capsaicin (183) is a phenylpropanoid compound isolated from different sources as Bell paper. It decreases lesion formation by influencing afferent neuron and inhibiting the development of hemorrhagic lesions in a concentration-dependent manner but did not change the ethanol-related fall in the gastric potential difference. ⁹⁸ Chlorogenic acid (184) ⁹⁹ is a phenylcoumarin, isolated from Hintonia latiflora and Hintonia standleyana. Its mechanism involved diminishing the neutrophil in- flux into the affected area and anti-oxidant potentials. ¹⁰⁰ Ellagic acid (185) is a phenolic metabolite obtained from Careya arborea. Treatment with ellagic acid enhanced ulcer healing by affecting IL-4, EGF/HGF levels and enhancing COX-2 expression. ¹⁰¹

Additionally, different plant extracts showed gastroprotective potential against different ulcerogenic agents. They exerted their potential through different mechanisms of action as, hindering the acidity, increasing of mucus content, inhibiting histamine production, anti H. pylori potential, as well as antioxidant activities. In this context, Aloe vera showed inhibitory activity to gastric ulcer acid secretion in mice and rats as well as protected gastric mucosal damage in rats. ¹⁰² The methanolic extract and different fractions of Elaeocarpus grandis were evaluated against indomethacin-induced ulcer method. Additionally, the ethyl acetate fraction was the most potent one. ¹³ Moreover, the total ethanolic extract of Ocimum forskolei and its deprived fractions were screened for their anti-ulcer activity with the dichloromethane was the most potent one. ³ Moreover, the crude extract of Olea europea showed significant anti-ulcer potential against indomethacin related ulcer in rats at a dose of 300 mg kg ⁻¹. ¹⁰³

Additionally, Psidium guava seeds extract showed potent gastro protective potential with significant reduction in the inflammation induced by indomethacin. ¹² Moreover, Melissa officinalis exhibited promising anti-ulcer potential in ethanol-related gastric ulcer at doses of 500 mg kg ⁻¹. ¹⁰⁴ Additionally, the roots and leaves of Reichardia picroides showed significant gastroprotective potential in HCl/EtOH-induced ulcer models with the root extract was the most potent one at a dose of 500 mg kg ^{−1. 105} Additionally, the total extract of Caesalpinia coriaria pods exhibited significant anti-ulcer potential in ethanol and indomethacin related ulcer in rats at doses of 100, 300 mg kg ⁻¹. ¹⁰⁶ Moreover, there are different herbal formulations have been investigated for their gastro-protective effect as Phy-Blica-D (Traditional Thai Polyherbal Formula) against ethanol-induced gastric ulcers in rats. Rats treated with only 80% ethanol (vehicle group) exhibited significant increases in their ulcer area and ulcer index (UI). Moreover, the levels of ROS and MDA markedly increased in the vehicle group compared with the normal control group. Daily oral administration of Phy-BlicaD (500 and 1000 mg/kg) for 7 days not only significantly decreased the ulcer area and UI, but also remarkably decreased the ROS and MDA levels in gastric tissue. The findings suggested that Phy-Blica-D reduced oxidative stress and enhanced antioxidant enzyme activities, indicating their potential gastroprotective effect by suppressing oxidative stress and stimulating antioxidant enzymes. ¹⁰⁷ Other herbal formulations as; Yelathy Chooranam (Taxus buccata, Piper nigrum, Eletaria cardamomum, Syzygium aromaticum, Cinnamomum zeylanicum, Zingiber officinale, and Curcuma angustifolia), NR-ANX-C (Camellia sinensis (green tea), Withania somnifera (Ashwagandha), Ocimum sanctum (holy basil), Shilajit, and Triphala) showed remearkable anti-ulcer potential through their antioxidant properties, inhibition of acid secretion, and enhancement of mucosal defense. ¹⁰⁸ On the other hand, several clinical trials revealed that consumption of plants containing polyphenols showed a noticeable decrease in different inflammatory markers and H. pylori with remarkable antioxidant properties, which help in exerting their gastroprotective properties. ¹⁰⁹

Screening of Natural Compounds for Drug-Likeness:

The commonly employed method for identifying drug-like molecules involves applying Lipinski's “Rule of Five” (Ro5). This rule encompasses criteria such as a molecular weight (MW) below 500 Daltons, a partition coefficient between octanol and water (Log P (o/w)) lower than 5, a maximum of five hydrogen bond donors (HBD), and no more than ten hydrogen bond acceptors (HBA). These conditions serve as indicators of a promising candidate for drug development. ¹⁶ Additionally, the Veber rule proposes that a compound exhibiting 10 or fewer rotatable bonds (RTB) and a polar surface area (TPSA) not exceeding 140 Å2 is likely to possess favorable oral bioavailability. ¹⁷

As illustrated in Table S1 , a total of 185 natural compounds underwent assessment for drug-like characteristics using the Lipinski and Veber criteria. The outcomes revealed that 127 compounds (approximately 73.91%) adhered to both the Lipinski and Veber criteria, implying a high likelihood of possessing favorable oral bioavailability. Conversely, 57 compounds (approximately 26.09%) did not comply with these criteria, suggesting a potential for poor oral bioavailability. ( Figure 10 ). For example, aescine (20) disobey lipinski and verbers rules because of its high MW that exceeding 500 Daltons and possesses a higher number of hydrogen bond donors and acceptors than the rule permits, and for verbers rules,RTB exceed 10,and TPSA more than 140 Å2.

Figure 10.

Drug Likeness Pie Chart.

The non-compliance of compounds like aescine underscores the need for structural optimization to enhance their drug-like properties. Several strategies can be employed to address these limitations. First, the number of rotatable bonds can be reduced to decrease molecular flexibility, potentially improving absorption and metabolic stability. Second, masking polar groups or modifying functional groups can lower TPSA and minimize excessive hydrogen bonding, thus enhancing permeability. Third, prodrug development strategies may be explored, where polar hydroxyl groups are temporarily masked with lipophilic groups or bio-reversible linkages to facilitate absorption. Additionally, fragment-based drug design approaches can be applied, wherein larger molecules are broken into smaller, bioactive fragments with improved compliance. Lastly, introducing lipophilic substituents, such as alkyl or aromatic groups, can improve the partition coefficient (logP), enabling better membrane permeability while maintaining solubility.These optimization strategies highlight the importance of balancing physicochemical properties to achieve favorable drug-likeness.

Conclusion and Future Prospectives

Peptic ulcer is a common human illness which affects mainly the stomach in addition to the proximal duodenum in the gastrointestinal tract. Natural secondary metabolites have a key part in the treatment and prevention of gastric ulcer. This article aims to review natural gastroprotective metabolites which have been recognized. Natural gastroprotective molecules are distinguished by their structural variety, safety, as well as nontoxic quality. Numerous examples of bioactive secondary molecules as phenolic compounds, terpenoids, flavonoids, alkaloids, and coumarins ( Figure 11 ) where flavonoids represented the major fraction, as recent in vivo clinical studies have demonstrated the gastroprotective effects of flavonoids in various experimental models. These naturally occurring polyphenols, showed potential in protecting and repairing gastric mucosa. Accordingly, bioactive metabolites with varied chemical designs in addition to their modes of action are beneficial therapeutic platforms for the introduction of novel bioactive molecules.

Figure 11.

Chemical Classes of Secondary Metabolites Responsible for the Gastro Protective Potential.

On the other hand, analysis of the available reviewed data has showed some considerable gaps in investigating natural molecules with gastroprotective potential. Firstly, more structure–activity relationships studies should be carried out for the bioactive molecules obtained from the different plant and marine organisms Exploring the cellular and molecular properties of these molecules will be of a promising value in establishing new bioactive metabolites. Additionally, synthetic analogs of bioactive molecules of gastroprotective potential should be developed concerning with enhancing the efficacy and safety, in addition to broadening the room of their biological investigations. Fortunately, most of natural compounds were estimated to enhance drug-likeness profiles. Finally, the area of preclinical as well as clinical studies carried out on secondary metabolites with anti-ulcer potential still at its beginning. Accordingly, more studies should be carried out towards those natural treasures to translate them into prevailing market products as they afford an endless resource of novel gastro protective metabolites. Future studies should focus on synthesizing and evaluating modified analogs of non-compliant compounds to validate their pharmacokinetic profiles and therapeutic potential. Such modifications not only expand the drug discovery pipeline but also contribute to the rational design of compounds with improved ADME properties.

Supplemental Material

sj-docx-1-npx-10.1177_1934578X251329870 - Supplemental material for A Comprehensive Overview on the Role of Phytocompounds as Gastroprotective Agents

Supplemental material, sj-docx-1-npx-10.1177_1934578X251329870 for A Comprehensive Overview on the Role of Phytocompounds as Gastroprotective Agents by Omnia Hesham Abdelhafez, Nourhan Hisham Shady, Mohamed Hisham, Khadija Essa awad, Rania Atef Hashem, Rania Ahmed Fouad, Habiba Ahmed, Randa Khaled Hassan, Rofaida Sayed Gomaa and Usama Ramadan Abdelmohsen in Natural Product Communications