Solvent-free synthesis of bacillamide analogues as novel cytotoxic and anti-inflammatory agents
- Eur J Med Chem. 2016 Nov 10:123:718-726. doi: 10.1016/j.ejmech.2016.07.033.
- 1. Department of Chemistry, Kurukshetra University, Kurukshetra, 136119, India.
- 2. Department of Chemistry, Kurukshetra University, Kurukshetra, 136119, India. Electronic address: [email protected].
- 3. Department of Natural Sciences, UH-Downtown, Houston, TX, 77002, USA.
- 4. Department of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra, 136119, India.
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-alkyl/aryl/heteroaryl/amino/aminoarylthiazole-4-carboxylates and tryptamine in presence of 2-hydroxy-4,6-dimethylpyrimidine, a solid phase catalyst to yield N-[2-(1H-indol-3-yl)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 ∼3.0 μM and ∼0.1-0.6 μM, 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.