Sulphamethazine derivatives as immunomodulating agents: New therapeutic strategies for inflammatory diseases

Sulfamethazine (SMZ) (1) is an antibacterial sulfa drug which suppresses the synthesis of dihydrofolic acid. It is used for the treatment of infections in livestock; such as gastrointestinal, and respiratory tract infections. During the current study, synthesis, characterization, and evaluation of immunomodulatory activities of derivatives of sulfamethazine (SMZ) (3–39) was carried out. These derivatives were synthesized by the reaction of sulfamethazine with a range of acid chlorides. All the compounds were characterized by using modern spectroscopic techniques, such as 1H-, and 13C-NMR, EI-MS, and HRFAB-MS. Compounds 3–10, 14, and 15 were identified as new compounds. Immunomodulatory effect of compounds 3–39 on different parameters of innate immune response was evaluated, including the production of Reactive Oxygen Species (ROS) from human whole blood and isolated polymorphonuclear neutrophils (PMNs), nitric oxide (NO), and pro-inflammatory cytokine TNF-α. All the new compounds, except 14 and 15, showed a significant anti-inflammatory activity. Compounds 3–39 were also evaluated for their anti-bacterial activity and cytotoxicity (3T3 mouse fibroblast cell lines). All the compounds were found to be non-cytotoxic against normal cell lines.

磺胺二甲嘧啶（Sulfamethazine, SMZ）是一类磺胺类抗菌药物，可通过抑制二氢叶酸的合成发挥抗菌作用，临床用于治疗家畜胃肠道及呼吸道等部位的感染。本研究针对磺胺二甲嘧啶（SMZ）的3~39号衍生物开展了合成、结构表征及免疫调节活性评价工作。此类衍生物由磺胺二甲嘧啶与多种酰氯反应合成得到，所有目标化合物均采用现代波谱技术进行结构表征，包括氢谱（¹H-NMR）、碳谱（¹³C-NMR）、电子轰击质谱（EI-MS）及高分辨快原子轰击质谱（HRFAB-MS）。其中3~10号、14号及15号化合物为全新合成的化合物。本研究评价了3~39号化合物对天然免疫应答不同参数的免疫调节作用，包括检测人全血及分离的多形核中性粒细胞（polymorphonuclear neutrophils, PMNs）产生活性氧（Reactive Oxygen Species, ROS）的水平、一氧化氮（nitric oxide, NO）生成量及促炎细胞因子肿瘤坏死因子-α（TNF-α）的表达量。除14号和15号化合物外，其余全新化合物均表现出显著的抗炎活性。此外，本研究还评价了3~39号化合物的抗菌活性及细胞毒性（采用3T3小鼠成纤维细胞系），实验结果显示，所有受试化合物对正常细胞系均无细胞毒性。