Emerging therapeutics: The imidazo[1,2-b]pyridazine scaffold as a novel drug candidate for eumycetoma, a neglected tropical disease

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.