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

• Published in: European journal of medicinal chemistry Vol. 277; p. 116720
• Main Authors: Elkheir, Lamis Yahia Mohamed, Delaye, Pierre-Olivier, Penichon, Mélanie, Eadie, Kimberly, Mohamed, Magdi Awadalla, Besson, Pierre, Chesnay, Adélaïde, Desoubeaux, Guillaume, Roger, Sébastien, van de Sande, Wendy Wilhelmina Johanna, Fahal, Ahmed Hassan, Enguehard-Gueiffier, Cécile
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 05.11.2024
• Subjects: Animals; Antifungal agents; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug discovery; Eumycetoma; Humans; imidazo[1,2-b]pyridazine; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Madurella - drug effects; Madurella mycetomatis; Mice; Microbial Sensitivity Tests; Molecular Structure; Mycetoma; Mycetoma - drug therapy; Neglected Diseases - drug therapy; Neglected tropical disease; NIH 3T3 Cells; Novel therapeutics; Pyridazines - chemical synthesis; Pyridazines - chemistry; Pyridazines - pharmacology; Structure-Activity Relationship; Madurella mycetomatis; Eumycetoma; Neglected tropical disease; Antifungal agents; Novel therapeutics; Drug discovery; Mycetoma; imidazo[1,2-b]pyridazine
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116720

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. [Display omitted] •Design and synthesis of 47 original imidazo [1,2-b]pyridazine derivatives.•Antifungal activity against M. mycetomatis, the major cause of eumycetoma.•17 compounds with in vitro IC50 ≤ 5 μM against Madurella mycetomatis.•Most active compound 14d with IC50 of 0.9 μM and selectivity index of 16.•Imidazo [1,2-b]pyridazines as potential candidates for treating eumycetoma.