Twenty three chalcones are synthesized and evaluated for antimycobacterial activity against M. tuberculosis H37Rv. Ortho chloro substitutions at A and B-ring favor activity. Compound 12 with chloro and hydroxyl substitution exhibits 98% reduction in relative light units at a concentration of 100μg/ml. Methylsulfonyl chalcones also exhibit very good activity. The requirements for the anti-infective activity are explored with 2D, 3D and group based QSAR studies. The 2D technique indicates the importance of volume, refractivity and molecular weight of the compounds on the activity. The 3DQSAR indicates less bulky (at R5) and more hydrophilic substituent groups (at R3) can improve the Antitubercular activity. The GQSAR technique indicates that hydrophilic groups in R3 or R5 positions can enhance activity. The oral bioavailability of all the molecules are between 30-70%.Compound 12 is mildly acidic, soluble in water,stable at pH<2 and does not violate the Lipinski's rule of 5. Hence it appears to be a strong drug candidate.