New sulfonamides 5/6 derived from 4-methoxyacetophenone 1 were synthesized by N-sulfonation reaction of ammonia (3) and aminopyrimidinone (4) with its sulfonyl chloride derivative 2. Sulfonamides 5 and 6 were used as precursors of two new series of chalcones 8a-f and 9a-f, which were obtained through Claisen-Schmidt condensation with aromatic aldehydes 7a-f. Compounds 5/6, 8a-d, 8f, 9a-d, and 9f were screened by the US National Cancer Institute (NCI) at 10 μM against sixty different human cancer cell lines (one-dose trial). Chalcones 8b and 9b satisfied the pre-determined threshold inhibition criteria and were selected for screening at five different concentrations (100, 10, 1.0, 0.1, and 0.01 μM). Compound 8b exhibited remarkable GI50 values ranging from 0.57 to 12.4 μM, with cytotoxic effects being observed in almost all cases, especially against the cell lines K-562 of Leukemia and LOX IMVI of Melanoma with GI50 = 0.57 and 1.28 μM, respectively. Moreover, all compounds were screened against Mycobacterium tuberculosis H37Rv, chalcones 8a-c and 9a-c were the most active showing MIC values between 14 and 42 μM, and interestingly they were devoid of antibacterial activity against Mycobacterium smegmatis and Staphylococcus aureus. These antituberculosis hits showed however low selectivity, being equally inhibitory to M. tuberculosis and mammalian T3T cells. The chalcone-sulfonamide hybrids 8a-f and 9a-f resulted to be appealing cytotoxic agents with significant antituberculosis activity.

Department of Chemistry and Biology Basic Sciences Division Universidad del Norte Barranquilla 081007 Colombia

Department of Chemistry and Biology Basic Sciences Division Universidad del Norte Barranquilla 081007 Colombia; Institute of Microbiology Czech Academy of Sciences Videnska 1083 142 20 Prague Czech Republic

Department of Inorganic and Organic Chemistry Universidad de Jaén Jaén 23071 Spain

Department of Medicine Health Sciences Division Universidad del Norte Barranquilla 081007 Colombia

Heterocyclic Compounds Research Group Department of Chemistry Universidad del Valle Cali A A 25360 Colombia

Heterocyclic Compounds Research Group Department of Chemistry Universidad del Valle Cali A A 25360 Colombia; Centre for Bioinformatics and Photonics CIBioFI Universidad del Valle Cali A A 25360 Colombia

Institute of Microbiology Czech Academy of Sciences BIOCEV Průmyslová 595 252 50 Vestec Czech Republic

Institute of Microbiology Czech Academy of Sciences Videnska 1083 142 20 Prague Czech Republic

Mycobacteria Laboratory National Health Institute Bogotá 111321 Colombia

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