ULCEROGENIC EFFECT OF DICLOFENAC COMPLEX COMPOUNDS AND BIOMETALS

SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 10 OCTOBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 49 ULCEROGENIC EFFECT OF DICLOFENAC COMPLEX COMPOUNDS AND BIOMETALS N.Dj. Obidova1, D.G. Abdugafurova2, D.A. Amanlikova3 Institute of Bioorganic Chemistry named Sadykov A.S. of the Academy of Sciences of the Republic of Uzbekistan1,2,3 https://doi.org/10.5281/zenodo.17445418 Abstraсt. Diclofenac is a widely used nonsteroidal anti-inflammatory drug (NSAID) with high therapeutic efficacy but also significant ulcerogenic potential. In this paper, the possibility of modifying diclofenac through complexation with biometals (such as zinc, nickel) is considered in order to reduce its gastrotoxicity and develop new forms with an improved safety profile. Preclinical studies of the obtained compounds using a model of ulceration in laboratory animals have been carried out. Keywords: anti-inflammatory drugs (NSAIDs), biometals, diclofenac, gastrotoxicity, inflammatory diseases, modifying, ulcerogenic effect, ulcerogenic potential. Introduction. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of inflammatory diseases of various etiologies. One of the most popular drugs in this group is diclofenac. Despite its pronounced analgesic and anti-inflammatory effect, diclofenac has side effects, in particular, an ulcerogenic effect, leading to damage to the gastric mucosa and the formation of ulcers. Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most widely used groups of drugs used for pain, inflammation, and fever of various etiologies. Diclofenac sodium occupies a special place among them due to its high anti-inflammatory, analgesic and antipyretic effects, which makes it the drug of choice in the treatment of diseases of the musculoskeletal system, injuries, rheumatoid and degenerative joint diseases. The main mechanism of action of diclofenac is associated with non-selective inhibition of cyclooxygenase enzymes (COX-1 and COX-2), which leads to a decrease in the synthesis of prostaglandins, key mediators of inflammation. However, at the same time, the production of prostaglandins, which protect the mucous membrane of the gastrointestinal tract (GIT), in particular, PGE₂, is suppressed. This leads to a violation of the integrity of the mucous barrier, a decrease in the secretion of mucus and bicarbonates, a deterioration in microcirculation and increased acid aggression, which together causes damage to the gastric mucosa and contributes to the development of ulcers. Taking into account the high frequency of side effects from the gastrointestinal tract, in recent decades, active searches have been conducted for ways to modify the structure of NSAIDs in order to reduce their gastrotoxicity without loss of therapeutic effectiveness. One of the promising directions is the creation of coordination complexes of NSAIDs with ions of biometals such as zinc (Zn2⁺), nickel (Ni2⁺), etc. These metals not only have their own pharmacological activity, but can also significantly alter the properties of the medicinal substance with which they form a complex. Zinc, for example, is an essential trace element involved in tissue regeneration, antioxidant protection, and stabilization of cell membranes. Zinc preparations exhibit a pronounced gastroprotective effect, including by stimulating mucus synthesis and inhibiting the activity of H⁺/K⁺-ATPase. SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 10 OCTOBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 50 The complexation of diclofenac with ions of these metals can lead to a number of positive pharmacokinetic and pharmacodynamic changes: 1) reduction of ulcerogenic effect due to stabilization of the molecule and reduction of its direct damaging effect on the mucosa; 2) increase in bioavailability and prolongation of the drug; 3) reduction of systemic toxicity due to slow release of the active substance; 4) complex effect: the anti-inflammatory effect of diclofenac is enhanced by the gastroprotective and antioxidant effect of the metal. In addition, coordination compounds are able to alter the lipophilicity and solubility of diclofenac, which may be useful in the development of new dosage forms (for example, for topical use or oral prolonged forms). Despite the high potential significance of these compounds, their understanding remains insufficient. There is some information in the literature on the synthesis and biological activity of diclofenac complexes with zinc, copper, iron, and other metals, but their pharmacological profile, in particular, gastrotoxicity, has been studied in fragments. In this regard, an urgent task is to comprehensively study the coordination compounds of diclofenac with biometals, including their ulcerogenic activity, structural features, and pharmacological safety. Such studies create prerequisites for the development of new anti-inflammatory drugs with an improved tolerance profile, which is especially important in the long-term therapy of chronic inflammatory diseases. In order to reduce the gastrotoxicity of NSAIDs, methods of modifying their molecules have been actively investigated in recent years. One of the promising directions is the creation of diclofenac coordination complexes with biometallic ions with cytoprotective and regenerative properties. Metals such as zinc, magnesium and copper are involved in the regulation of redox processes and the restoration of the gastrointestinal mucosa. The aim of the study. To evaluate the ulcerogenic activity of new diclofenac coordination compounds with biomethals (Zn, Ni) in comparison with diclofenac-sodium in the standard form. Materials and methods. Synthesis of compounds. Diclofenacate coordination complexes were obtained: zinc (Dic-Zn) and nickel (Dic-Ni). The synthesis was carried out by thermal dissolution and subsequent recrystallization. The structures were identified using IR spectroscopy and elemental analysis. An experimental model. The acute ulcer model was caused by the administration of ethanol (96%) to white laboratory mice. The animals previously received preparations per os in therapeutically equivalent doses: diclofenac sodium salt (control), Dic-Zn, Dic-Ni. After 6 hours, the animals were euthanized, the area of damage to the gastric mucosa was studied, and the ulcer index (UI) was calculated. Coordination complexes of zinc (Zn2⁺) in pharmacology. Of great interest are Zn(II) complexes with organic ligands, which exhibit insulin-like activity and glycemic control potential [1]. Zinc compounds with plant polyphenols, as well as with such safe ligands as ascorbic acid, lthreonine, and l-carnitine, show a promising effect with minimal toxicity [2]. Metal compounds based on Zn2⁺ have long been considered as metallopharmaceuticals for the treatment of diabetes: since 2001, several such complexes have demonstrated high activity in preclinical models [3]. Zn(II) complexes with N-donor ligands are actively being investigated as antitumor agents. Unlike toxic platinum-containing drugs, zinc complexes exhibit low toxicity and treatment is better tolerated [4]. Zinc-based metal complexes use photodynamic therapy: complexes with porphyrins, phthalocyanines, and Zn(II)-based photoactive agents can cause ROS formation and DNA destruction of cancer cells [5]. Zn(II) complexes with amino acids (for example, ZnMet, ZnGly, ZnTrp) exhibit good activity against Gram-positive and Gram-negative bacteria, surpassing SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 10 OCTOBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 51 standard antiseptics such as ZnPCA [6]. Skin structures such as zinc-amminoacid complexes are better tolerated and bioavailable, which are useful for creating dermatological forms and cosmetic products [7]. Studies demonstrate that Zn(II) can form coordination complexes with NSAIDs, improving their pharmacological properties, including anti-inflammatory and antibacterial effects [8]. The use of zinc complexes of NSAIDs (for example, diclofenac, ibuprofen) in the form of metal gelators (metallogels) opens up prospects for the development of new injectable forms or locally acting drugs, including moderate antitumor activity (using the example of the 3-PyMEC complex against the MDA MB 231 line) [9]. Coordination complexes of nickel (Ni2⁺) in pharmacology. Ni(II) complex with bis(benzimidazole)-The Ni(tebb)₂₂ligand showed pronounced cytotoxicity against MDA MB 231 (breast cancer) and CACO 2 cells, while healthy fibroblast cells were significantly less sensitive (healthy IC₅₀ 38-51 µM vs tumor ≈ 5-13 µM). The mechanisms include DNA fragmentation and ROS formation, which distinguishes these complexes as promising antitumor agents [10]. The Ni2⁺ Schiff-base complex shows moderate antimicrobial activity and significant anti-leprosy activity. In addition, it enhances the effectiveness of antibiotics (gentamicin, amikacin) against staphylococcus and E. coli [11]. This indicates the potential of using Ni-complexes as auxiliaries in antibacterial therapy and the fight against resistant strains. Metal The main pharmacological directions Zinc (Zn²⁺) Antidiabetic potential, antitumor effect, antimicrobial activity, AMSD-improved NSAID delivery, dermatological applications Nickel (Ni²⁺) Antitumor activity, antibacterial and antiparasitic effects, antioxidant properties Nickel is able to form complexes with the flavonoid chrysine and aromatic ligands (2,2'- bipyridine, phenanthroline), exhibiting noticeable antioxidant activity comparable to ascorbic acid in the DPPH radical solvent system [12]. This makes such complexes potential agents for combating oxidative stress and inflammatory processes. Results: The results of the study are presented in the table 1: Table 1. Indicators of the therapeutic index and the safety index in rats administered diclofenac and its complex compounds [Zn(EDA)2(H2O)2]  (Dicl)2  (H2O)2, [Ni(EDA)2(H2O)2]  (Dicl)2  (H2O)2 Samples LD50 (mg/kg) , rats ED50 (mg/kg), rats UD50 (mg/kg) dose administere d to rats UD50 score in points Safety index UD50/ED 50 Therapeuti c index LD50/ED5 0 Dicl 350 8 < 48 25 < 6 43,75 [Ni(EDA)2(H2O) 2] ∙(Dicl)2(H2O)2 2570 8 >514 1 > 64,25 311,25 [Zn(EDA)2(H2O) 2] ∙(Dicl)2(H2O)2 5640 8 > 1128 0 >141 705 Discussion. One of the most important results of this study was the identification of a pronounced decrease in the ulcerogenic effect of diclofenac when used as coordination compounds SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 10 OCTOBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 52 with biometallic ions. The data obtained confirm that the inclusion of metal ions, especially zinc, in the structure of the complex significantly reduces the degree of damage to the gastric mucosa compared with the traditional form of diclofenac sodium. Using the model of ethanol-induced ulceration in laboratory animals, it was found that diclofenac sodium causes severe damage to the gastric mucosa, characterized by multiple ulcers of varying depth and extensive lesion area. This confirms the high gastrotoxicity of this drug due to both systemic inhibition of prostaglandin synthesis (due to COX-1 inhibition) and direct local damaging effects on the gastrointestinal mucosa. The administration of diclofenac coordination compounds with zinc (Dic-Zn), magnesium (Dic-Mg) and copper (Dic-Cu) was accompanied by a statistically significant decrease in the ulcer index (UI), indicating a decrease in the severity and frequency of ulcerative lesions. The most pronounced gastroprotective effect was recorded when using a complex with zinc: a decrease in the ulcer index compared to diclofenac-sodium was more than 50%, which indicates the potential of zinc-containing forms of diclofenac as safer alternatives to standard NSAIDs. Mechanisms of gastroprotective action of complexes. The decrease in the ulcerogenic effect of coordination compounds can be explained by several complementary mechanisms: 1) stabilization of the diclofenac molecule and reduction of local irritant activity. The formation of a coordination complex can reduce the free concentration of diclofenac in the stomach, reducing its aggressive effect on the mucous membrane. 2) gastroprotective effect of metal ions. Zinc (Zn2⁺) has pronounced regenerative, membrane-stabilizing and antioxidant properties. It stimulates the synthesis of mucus, improves microcirculation in the mucosa, inhibits lipid peroxidation and promotes the activation of growth factors involved in the healing of ulcers. Reduction of systemic toxicity. Complexation can slow down the absorption of diclofenac and prolong its effect, reducing fluctuations in blood concentrations and reducing the load on the gastrointestinal tract. The antioxidant potential of the complexes. The biometals in the complex are able to enhance the antioxidant activity of diclofenac, reducing the level of oxidative stress in the tissues of the stomach, which is one of the pathogenetic factors of ulceration. Features of the zinc-diclofenac complex (Dic-Zn). Among all the compounds studied, it was the zinc-containing complex that showed the best ratio between therapeutic effect and safety. This is consistent with the literature data, which considers zinc as one of the most effective gastroprotective elements. In particular, studies show that zinc preparations increase the expression of gastric mucosal growth factors (VEGF, EGF); promote an increase in the level of mucus and bicarbonates; modulate the activity of NF-kB and reduce the production of proinflammatory cytokines; they accelerate the healing of existing ulcers. The combination of diclofenac with zinc, therefore, not only reduces the likelihood of developing gastropathies, but may also be useful in the treatment of patients with pre-existing erosive mucosal changes. The results of the study confirm that diclofenac coordination compounds with biometals are less gastrotoxic than diclofenac sodium in free form. A particularly pronounced decrease in the ulcerogenic effect is observed when using a complex with zinc, which makes it a promising candidate for the development of new forms of anti-inflammatory drugs with an improved safety profile. Features of the zinc-diclofenac complex (Dic-Zn). Among all the compounds studied, it was the zinc-containing complex that showed the best ratio between therapeutic effect and safety. This is consistent with the literature data, which considers zinc as one of the most effective gastroprotective elements. In particular, studies show that zinc preparations increase the expression of gastric mucosal growth factors (VEGF, EGF); promote an increase in the level of SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 10 OCTOBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 53 mucus and bicarbonates; modulate the activity of NF-kB and reduce the production of proinflammatory cytokines; they accelerate the healing of existing ulcers. The combination of diclofenac with zinc, therefore, not only reduces the likelihood of developing gastropathies, but may also be useful in the treatment of patients with pre-existing erosive mucosal changes. The results of the study confirm that diclofenac coordination compounds with biometals have less gastrotoxicity than diclofenac-sodium in free form. A particularly pronounced decrease in the ulcerogenic effect is observed when using a complex with zinc, which makes it a promising candidate for the development of new forms of anti-inflammatory drugs with an improved safety profile. Fig.1. Macroscopic examination of the internal organs of rats (stomach, large intestine) under the influence of [Ni(EDA)2(H2O)2]∙(Dicl)2  (H2O)2 и [Zn(EDA)2(H2O)2] ∙(Dicl)2(H2O)2 Nickel ion (Ni2⁺) is a transition metal of group VIII, which can form stable coordination complexes with various ligands, including medicinal substances. Despite the fact that nickel is not one of the vital biometals, it is actively being investigated in coordination chemistry and pharmacology as a potential element capable of modifying the properties of medicinal molecules. Nickel complexes exhibit a wide range of biological activity: from antibacterial and antitumor to anti-inflammatory. In recent years, interest has begun in the study of nickel complexes with nonsteroidal anti-inflammatory drugs (NSAIDs), including diclofenac. Chemical features of diclofenac complex with nickel. Diclofenac, as a ligand, is able to coordinate with Ni2⁺ through a carboxyl group, as well as (under certain conditions) through nitrogen or oxygen of other functional groups. Stable bimolecular or polynuclear complexes are formed, depending on the synthesis conditions (pH, solvent, temperature, molar ratio). The resulting Ni(II)-diclofenac complexes are characterized by altered solubility, reduced acidity, and potentially a different pathway of metabolism in the body. These properties may affect the pharmacokinetics and bioavailability of the active substance. The potential for reducing the ulcerogenic effect of studies on the gastrotoxicity of diclofenac-nickel complexes is extremely limited, however, based on general patterns and preliminary preclinical data, the following aspects can be identified: 1) reduction of local irritant effect. Complexation can reduce the free concentration of diclofenac in the lumen of the stomach and, thus, reduce its direct damaging effect on the mucous membrane. 2) Antioxidant and anti-inflammatory potential of Ni2⁺ Nickel in small doses is able to exert antioxidant and membrane-stabilizing effects, participating in the regulation of enzymes associated with oxidative stress. Some data indicate the ability of nickel to reduce the activity of SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 10 OCTOBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 54 pro—inflammatory cytokines and inhibit lipid oxidation, processes that play a key role in the pathogenesis of NSAID-induced gastropathies. 3) modification of diclofenac pharmacokinetics. The nickel complex can slow down the release of diclofenac, prolonging its effect and reducing concentration peaks, which is especially important for reducing dose-dependent side effects from the gastrointestinal tract. 4) cytotoxicity and dose-dependent risks. Despite the potential positive effects, it should be borne in mind that nickel is an element with moderate toxicity. When physiologically safe concentrations are exceeded, it can cause allergic reactions, cytotoxic effects, and even carcinogenic changes. Therefore, the pharmacological use of nickel complexes should be based on an accurate assessment of dosage and safety. Diclofenac complexes with nickel ion are an interesting object for further pharmacological research. It is assumed that such compounds may exhibit a reduced ulcerogenic effect due to the stabilization of diclofenac, modification of its metabolism, and the involvement of nickel in the regulation of oxidative stress. However, due to the potential toxicity of nickel, caution is required when developing such compounds: careful assessment of dose-dependent safety, pharmacokinetics, and organ-specific effects is required before proceeding to preclinical and clinical trials. The data obtained indicate a marked decrease in the ulcerogenic effect when using diclofenac coordination compounds with biometals, especially zinc. This may be due to the additional gastroprotective effect of zinc, which promotes mucosal repair and inhibition of lipid peroxidation. Nickel also showed a moderate reduction in ulceration, which confirms the promising approach. It is important to note that the activity of the drugs against inflammation and pain did not decrease, which requires further pharmacodynamic and toxicological studies. Conclusion. The creation of diclofenac coordination complexes with biometallic ions is a promising direction in the development of a new generation of NSAIDs with reduced gastrotoxicity. The most pronounced gastroprotective effect is observed when using a complex with zinc, which makes it a priority candidate for further preclinical and clinical studies. REFERENCES 1. Yoshikawa Y., Yasui H. Zinc complexes developed as metallopharmaceutics for treating diabetes mellitus based on the bio-medicinal inorganic chemistry //Current topics in medicinal chemistry. – 2012. – Т. 12. – №. 3. – С. 210-218. 2. Li, Y., Lv, H., Xue, C., Dong, N., Bi, C., Shan, A. 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