A series of novel natural product like 2-substiuted-3H-benzofurobenzofurans designed by molecular hybridization were synthesized in very good yields. The key reactions involved in the synthesis are iodination of 2-dibenzofuranol using iodine monochloride followed by palladium-copper catalyzed Sonagashira-coupling of 1-iododibenzofuran-2-ol with various alkyl and aryl acetylenes. Among the all 10 new compounds screened for in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv, 2-(4-methoxy-2-methyl phenyl)-3H-benzofuro[3,2-e]benzofuran (7c) was found to be most active with MIC 3.12 μg/mL and has shown lower cytotoxicity with good therapeutic index.