Synthesis, Antifungal Evaluation, and Structure–activity Relationship of Chlorinated Imidazopyridinyl- phenylpropenone Derivatives against Aspergillus fumigatus

Background: Aspergillus fumigatus is the leading causative agent of invasive aspergillosis, a deadly opportunistic fungal infection in immunocompromised patients. The increasing emergence of azole-resistant strains necessitates the urgent development of new antifungal molecules. Objective: This study reports the synthesis, structural characterization, and evaluation of the antifungal activity of ten novel chlorinated chalcone-imidazo[1,2-a]pyridine hybrid derivatives against a clinical strain of A. fumigatus. Methods: The compounds were synthesized by Claisen-Schmidt condensation between acetylated imidazo[1,2-a]pyridine derivatives and various substituted aromatic aldehydes. Structural characterization was performed by ¹H and ¹³C NMR. Antifungal activity was determined by microplate scattering with calculation of minimum inhibitory concentrations (MICs). Results: Ten compounds were obtained with varying yields (45– 83%). Spectral analysis confirmed the formation of α,β-unsaturated structures with E geometry. The MICs ranged from 73.16 to 319.74 µM, with optimal activity for the 3-nitro derivative (MIC = 73.16 µM) and the Chlorinated derivatives (MIC = 75.48 µM). The 2-methoxyphenyl derivative (MIC = 76.50 µM) and the unsubstituted compound (MIC = 84.27 µM) show promising activity. Conclusion: Structure-activity relationship studies reveal the importance of lipophilicity and steric hindrance. These chalcone-imidazopyridine hybrids represent promising structures for the development of new antifungal agents against A. fumigatus.