Solvent-free synthesis of bacillamide analogues as novel cytotoxic and anti-inflammatory agents

Synthesis of fourteen analogues of bacillamide, a bioactive tryptamide alkaloid of marine origin, has been accomplished through a highly efficient convergent route. The present solvent-free protocol involves the formation of thiazole ring in the initial step followed by amide coupling between substituted ethyl 2-alkyliaryl/heteroaryliamino/aminoarylthiazole-4-carboxylates and tryptamine in presence of 2hydroxy-4,6-dimethylpyrimidine, a solid phase catalyst to yield N-[2-(1H-indo1-3-y1)ethyl]-2-alkyl/aryl/heteroaryl/amino/aminoarylthiazole-4-carboxamides as bacillamide analogues having structural variation at position-2 of thiazole ring. Bacillamide and its analogues were evaluated for their cytotoxic activity against three cancer cell lines (HCT-116, MDA-MD-231 and JURKAT cell lines) using colorimetric cell proliferation assay. Compounds 17a and 17b exhibited potent anti-cell proliferation activity with IC50 values in the range of similar to 3.0 mu M and similar to 0.1-0.6 mu M, respectively against these cell lines. Preliminary mechanism of action studies indicates that these compounds initiate caspase dependent apoptosis. Also, compounds 16d, 16f, 17a and 17d exhibited excellent anti-inflammatory activity comparable to well-known NSAID indomethacin and better to bacillamide, when evaluated using carrageenan induced rat hind paw oedema method. (C) 2016 Elsevier Masson SAS. All rights reserved.