Synthesis and Anti-Tubercular Activity of Novel Furan-Based Triazole-Acrylamide Hybrids: Experimental and Computational Insights.

Tuberculosis (TB) continues to pose a major global health challenge, particularly due to the rise of multidrug-resistant strains, necessitating the search for novel chemotypes with improved efficacy. In this work, a series of furan-based triazole-acrylamide hybrids (8a-8j) were designed and synthesized via a three-step sequence involving amidation, aryl azide preparation, and Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The structures of the synthesized compounds were confirmed through spectroscopic analyses, including attached proton test (APT) NMR. Biological screening against Mycobacterium tuberculosis H37Rv revealed promising activity, with the 4-bromo derivative (8e) exhibiting the highest potency (minimum inhibitory concentration [MIC] = 1.25 µg mL-1), followed by 4-CF3 (8f, 3.12 µg mL-1) and 4-F (8g, 6.25 µg mL-1). Structure-activity relationship analysis highlighted the beneficial role of electron-withdrawing and polarizable substituents at the para position of the phenyl ring. Molecular docking studies demonstrated strong binding affinities (up to -9.6 kcal mol-1 for 8e), correlating well with experimental MIC values, whereas density functional theory (DFT) analyses confirmed favorable electronic properties, including a narrow HOMO-LUMO gap and high softness for 8e, supporting its superior bioactivity.