The COX-2-targeted anti-inflammatory activity of novel 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives and their structure–activity relationship were established

At the Department of Pharmacology and toxicology of the Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, in collaboration with the Laboratory of Alkaloids and the Department of Organic Synthesis, extensive studies are being conducted to investigate the biological activities of natural and synthetic chemical compounds. Within the framework of these studies, the anti-inflammatory properties of novel 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 1,4-disubstituted 1H-1,2,3-triazole derivatives have been systematically evaluated.

The anti-inflammatory activity of 33 derivatives of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline was investigated using formalin- and carrageenan-induced inflammation models. The results revealed a structure–activity relationship, demonstrating that the biological activity of these compounds is strongly determined by the nature of the substituents as well as their positional and spatial arrangement within the C-ring (1-Ar- moiety).

The effects of 1,2,3,4-tetrahydroisoquinoline (THIQ) derivatives on the levels of pro-inflammatory and anti-inflammatory cytokines in blood serum were studied in rats with experimentally induced formalin inflammation. The findings demonstrated that many compounds exhibiting pronounced anti-inflammatory activity (≥60%) significantly modulated the levels of IL-4, IL-6, and TNF-α, promoting their restoration toward their normal physiological values. These results indicate a substantial regulatory effect of the investigated compounds on the proliferative phase of the inflammation.

A comparative assessment of the compounds was also performed in the carrageenan-induced inflammation model based on their ability to modulate prostaglandin E₂ (PGE₂) and thromboxane B₂ (TXB₂) levels. The combined in vivo data suggest that the anti-inflammatory effects of active 1-aryl-1,2,3,4-tetrahydroisoquinolines are associated with modulation of cyclooxygenase activity and cytokine-mediated inflammatory pathways. Most of the investigated compounds were identified as non-selective cyclooxygenase inhibitors capable of suppressing both COX-1 and COX-2 isoforms, whereas only one compound demonstrated pronounced selectivity toward COX-2.

Molecular docking studies and molecular dynamics simulations of the interaction between 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives and the active site of COX-2 (PDB ID: 1PXX) revealed that nitro-substituted derivatives exhibited the highest binding stability compared with brominated analogues. This enhanced stability was attributed to their ability to establish favorable electrostatic interactions and hydrogen bonds within the enzyme active site. Furthermore, the observed influence of –NH₂, –OH, and –OCH₃ substituents in the C-ring (1-Ar- moiety) on anti-inflammatory activity provides valuable guidance for the rational design and development of new highly active derivatives within this chemical series.

The outcomes of this research resulted in the granting of invention patent IAP 07531 and the publication of the following article: Azamatov A.A., Tursunkhodzhaeva F.M., Zhurakulov S.N., Boboev Z.D., Kuchimov K.F., Aytmuratova U.K., Ortikov I.S., Abdurazakova R.S., Vinogradova V.I., Abdullaev I.Z., et al. “Anti-Inflammatory Potential of 1-Aryl-6,7-Dimethoxy-1,2,3,4-Tetrahydroisoquinolines: Structure–Activity Relationship and COX-2 Binding.” Molecules. 2026;31:1956. https://www.mdpi.com/1420-3049/31/11/1956 

In collaboration with the Department of Organic Synthesis, a comprehensive study was carried out to evaluate the anti-inflammatory activity of 1,4-disubstituted 1H-1,2,3-triazole derivatives in experimental models of rheumatoid arthritis. The study aimed to assess the effects of these compounds on the key pathogenetic mechanisms of inflammation, their ability to suppress inflammatory responses, and their potential as promising pharmacological agents.

Within this research area, the pharmacological properties of 30 newly synthesized 1,4-disubstituted 1H-1,2,3-triazole derivatives were comprehensively investigated. Their acute toxicity, analgesic activity, and anti-inflammatory efficacy were evaluated, resulting in the identification of two lead candidate compounds with the most favorable pharmacological profiles. In addition, structure–activity and structure–toxicity relationships were established.

The results showed that most of the synthesized derivatives exhibited low acute toxicity (LD₅₀ > 5000 mg/kg) and a high safety profile following oral administration. For the first time, the anti-inflammatory activity of the lead candidate compounds was evaluated and compared with reference drugs used in clinical practice in collagen-, adjuvant-, and pristane-induced models of rheumatoid arthritis. The studied compounds demonstrated pronounced therapeutic efficacy that exceeded that of the reference drugs.

The effects of the candidate compounds on biochemical and hematological parameters were also investigated in experimental animals with rheumatoid arthritis. The findings confirmed their beneficial influence on the dynamics of these parameters and showed improvement in laboratory markers associated with the disease course. The candidate compounds were found to slow the development of destructive changes in cartilage tissue.

Morphological studies demonstrated that the investigated compounds possess cytoprotective, hepatoprotective, and chondroprotective properties. Importantly, when administered at recommended therapeutic doses, these compounds caused only minimal structural alterations in the gastric mucosa. Moreover, their use was associated with a lower risk of gastrointestinal bleeding compared with conventional nonsteroidal anti-inflammatory drugs (NSAIDs).

Thus, compounds of this series may be considered promising prototypes for the development of new anti-rheumatoid agents with complex pharmacological action, combining analgesic, anti-inflammatory, and chondroprotective effects with a high level of safety and good tolerability.

As a result of this research, invention patent No. IAP 7858 was obtained, and the PhD dissertation of Aytmuratova U.K. was successfully defended in the specialty 14.00.17 — Pharmacology and Clinical Pharmacology (Medical Sciences).

The obtained results are of significant theoretical and practical importance for further investigation of the pharmacological properties of novel biologically active derivatives of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 1,4-disubstituted 1H-1,2,3-triazole. They also contribute to elucidating the mechanisms underlying their anti-inflammatory and anti-rheumatic effects and provide a scientific basis for the development of innovative drugs for the treatment of inflammatory and rheumatic diseases.