This study investigated the anti-arthritic potential of novel mannich-based derivatives of 2-mercaptobenzimidazole (AK7 and AK9) in rats. The compounds were characterized by NMR and FTIR spectroscopies and their acute anti-inflammatory effects were measured by carrageenan (CRG)-induced paw edema model. The most potent doses of AK7 and AK9 were subsequently evaluated in the complete Freund’s adjuvant (CFA)–induced inflammatory arthritis model. AK7 and AK9 inhibited CRG-induced inflammation in a dose-dependent fashion and a similar reduction in CFA-induced paw inflammation was observed. Moreover, X-ray and histopathological analyses of AK7-treated animals displayed normal joint structure whereas AK9, despite of its anti-inflammatory effects, failed to protect against cartilage destruction. Interestingly, biochemical analysis revealed a better safety profile for AK7 than for AK9 and methotrexate. Both compounds suppressed mRNA levels of pro-inflammatory mediators (IRAK1, NF-κB1, TNF-α, IL1B) while only AK7 reduced the transcript levels of interstitial collagenase (MMP1). Molecular docking analysis of AK7 and AK9 with TNF-α and MMP1 also supported the experimental data. These findings clearly highlight the beneficial effects of AK7 in the prevention and/or treatment of inflammatory arthritis.

本研究调查了新型基于曼尼希的 2-巯基苯并咪唑衍生物（AK7 和 AK9）在大鼠体内的抗关节炎潜力。这些化合物通过 NMR 和 FTIR 光谱进行表征，并通过角叉菜胶 (CRG) 诱导的爪水肿模型测量其急性抗炎作用。随后在完全弗氏佐剂 (CFA) 诱导的炎症性关节炎模型中评估了 AK7 和 AK9 的最有效剂量。AK7 和 AK9 以剂量依赖性方式抑制 CRG 诱导的炎症，并且观察到 CFA 诱导的爪子炎症的类似减少。此外，AK7 治疗动物的 X 射线和组织病理学分析显示关节结构正常，而 AK9 尽管具有抗炎作用，但未能防止软骨破坏。有趣的是，生化分析显示 AK7 的安全性优于 AK9 和甲氨蝶呤。这两种化合物都抑制了促炎介质的 mRNA 水平（IRAK1、NF-κB1、TNF-α、IL1B ），而只有 AK7 降低了间质胶原酶（ MMP1）的转录水平。AK7 和 AK9 与 TNF-α 和 MMP1 的分子对接分析也支持了实验数据。这些发现清楚地突出了 AK7 在预防和/或治疗炎性关节炎方面的有益作用。