A series of N-alkylfuran-2-carboxamide derivatives was easily prepared through direct acylation of diverse amine with 2-furoyl chloride. Using an E. coli reporter strain, all compounds were then examined as LuxR-regulated quorum sensing modulators for their agonistic or antagonistic activity. Compounds with a C8 or specially C6 alkyl chain with a comparable chain length with the natural ligand of LuxR were found to be antagonists with an IC50 value of 25 µM. Competition experiments between the N-hexylfuran-2-carboxamide with the natural ligand indicate that the LuxR activity could be restored with high concentration of LuxR ligand. Conformational analysis, docking simulations and protein-ligand affinity prediction suggest that furan-2-carboxamide derivatives interact within the LuxR binding site via H-bonds of the C=O oxygen atom with Tyr62 OH and of the amide NH with Asp79 carboxylate, Tyr62 and Asp79 being two important conserved residues in the LuxR family. The binding mode also suggests that the absence of the hydrogen bond with Trp66, normally observed for the amide retroisoster analogues having the lactone instead of the furyl moiety, is not deleterious to the ability to interact and induce inhibition.