Abstract：
Mycetoma is a neglected invasive infection endemic in tropical and subtropical regions, presenting as a chronic subcutaneous inflammatory mass that can spread to deeper structures, leading to deformities, disabilities, and potentially mortality. The current treatment of eumycetoma, the fungal form of mycetoma, involves antifungal agents, such as itraconazole, combined with surgical intervention. However, this approach has limited success, with low cure rates and a high risk of recurrence. This study addresses to the urgent need for more effective therapeutics by designing and synthesising 47 diversely pharmacomodulated imidazo [1,2-b]pyridazine derivatives using a simple synthetic pathway with good yields and purity. Of these, 17 showed promising in vitro activity against Madurella mycetomatis, the prime causative agent of eumycetoma, with IC50 ≤ 5 μM and demonstrated significantly lower cytotoxicity compared to standard treatments in NIH-3T3 fibroblasts. Notably, compound 14d exhibited an excellent activity with an IC50 of 0.9 μM, in the same order then itraconazole (IC50 = 1.1 μM), and achieved a favourable selectivity index of 16 compared to 0.8 for itraconazole. These promising results warrant further research to evaluate the clinical potential of these novel compounds as safer, more effective treatments for eumycetoma, thus addressing a profound gap in current therapeutic strategies.
摘要：
Mycetoma是一种被忽视的侵袭性感染，在热带和亚热带地区流行，表现为慢性皮下炎性肿块，可以扩散到更深的结构，导致畸形，残疾人,和潜在的死亡率。目前对大肠杆菌瘤的治疗，霉菌瘤的真菌形式，涉及抗真菌剂，例如伊曲康唑，结合手术干预。然而,这种方法成功有限，治愈率低，复发风险高。这项研究通过使用简单的合成途径设计和合成47种不同的药物调节的咪唑并[1,2-b]吖嗪衍生物，具有良好的产率和纯度，从而解决了对更有效疗法的迫切需要。其中,17显示了对mycetomatisMadurella的有希望的体外活性，Eumycetoma的主要病原体，IC50≤5μM，与NIH-3T3成纤维细胞的标准治疗相比，细胞毒性显着降低。值得注意的是,化合物14d表现出优异的活性，IC50为0.9μM，以相同的顺序，然后伊曲康唑（IC50=1.1μM），与伊曲康唑的0.8相比，选择性指数为16。这些有希望的结果值得进一步研究，以评估这些新型化合物的临床潜力，更有效的治疗eumycetoma，从而解决了当前治疗策略中的深刻差距。
