A series of monosubstituted chalcones with potential anti-inflammatory activity have been rationally designed leading to a focused library of ligands 4a-j with ring-A substitution. Subsequent to drug-likeness and druggability assessments, the library members were synthesized in optimal yields and their structures were confirmed by IR, 1H NMR, 13C NMR and mass spectral analysis. Screening for anti-inflammatory activity revealed that most of the compounds were quite effective in containing inflammation with compound 4b being the most promising derivative.