In order to develop relatively small molecules as antimycobacterial agents, twenty-five chalcones were synthesized, their activity was evaluated, and quantitative structure-activity relationship (QSAR) was developed. The synthesis was based on the Claisen-Schimdt scheme and the resultant compounds were tested for antitubercular activity by luciferase reporter phage (LRP) assay. Compound C24 was found to be the most active (∼99%) in this series based on the percentage reduction in Relative Light Units at both 50 and 100 μg/ml levels, followed by compound C21. Four compounds at the 50 μg/ml and eight compounds at the 100 μg/ml showed activity above 90% level. QSAR model was developed between activity and spatial, topological, and ADME descriptors for the 50 μg/ml data. The statistical measures such as r, r2, q2, and F values obtained for the training set were in acceptable range and hence this relationship was used for the test set. The predictive ability of the model is satisfactory (q2 = 0.56) and it can be used for designing similar group of compounds. © 2007 Elsevier Ltd. All rights reserved.