Synthesis and investigations into the anticancer and antibacterial activity studies of ß-carboline chalcones and their bromide salts.

A series of sixteen ß-carbolines, bearing chalcone moiety at C-1 position, were prepared from easily accessible 1-acetyl-ß-carboline and various aldehydes under basic conditions followed by N2-alkylation using different alkyl bromides. The prepared compounds were evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. N2-Alkylated-ß-carboline chalcones 13a-i represented the interesting anticancer activities compared to N2-unsubstituted ß-carboline chalcones 12a-g. Off the prepared ß-carbolines, 13g exhibited broad spectrum of activity with IC50 values lower than 22.5 µM against all the tested cancer cell lines. Further, the N2-alkylated-ß-carboline chalcone 13g markedly induced cell death in MDA-MB-231 cells by AO/EB staining assay. The most cytotoxic compound 13g possessed a relatively high drug score of 0.48. Additionally, the prepared ß-carboline chalcones displayed moderate antibacterial activities against tested bacterial strains.

Design, synthesis and in vitro cytotoxicity studies of novel ß-carbolinium bromides.

A series of novel ß-carbolinium bromides has been synthesized from easily accessible ß-carbolines and 1-aryl-2-bromoethanones. The newly synthesized compounds were evaluated for their in vitro anticancer activity. Among the synthesized derivatives, compounds 16l, 16o and 16s exhibited potent anticancer activity with IC50 values of <10µM against tested cancer cell lines. The most potent analogue 16l was broadly active against all the tested cancer cell lines (IC50=3.16-7.93µM). In order to test the mechanism of cell death, we exposed castration resistant prostate cancer cell line (C4-2) to compounds 16l and 16s, which resulted in increased levels of cleaved PARP1 and AO/EB staining, indicating that ß-carbolinium salts induce apoptosis in these cells. Additionally, the most potent ß-carbolines 16l and 16s were found to inhibit tubulin polymerization.

Synthesis, evaluation and molecular modelling studies of 2-(carbazol-3-yl)-2-oxoacetamide analogues as a new class of potential pancreatic lipase inhibitors.

A series of twenty four 2-(carbazol-3-yl)-2-oxoacetamide analogues were synthesized, characterized and evaluated for their pancreatic lipase (PL) inhibitory activity. Porcine PL was used against 4-nitrophenyl butyrate (method A) and tributyrin (methods B and C) as substrates during the PL inhibition assay. Compounds 7e, 7f and 7p exhibited potential PL inhibitory activity (IC50 values of 6.31, 8.72 and 9.58µM, respectively in method A; and Xi50 of 21.85, 21.94 and 26.2, respectively in method B). Further, inhibition kinetics of 7e, 7f and 7p against PL, using method A, revealed their competitive nature of inhibition. A comparison of the inhibition profiles of the top three compounds in methods B and C, provided a preliminary idea of covalent bonding of the compounds with Ser 152 of PL. Molecular docking studies of the compounds 7a-x into the active site of human PL (PDB ID: 1LPB) was in agreement with the in vitro results, and highlighted probable covalent bond formation with Ser 152 apart from hydrophobic interactions with the lid domain. Molecular dynamics simulation of 7e complexed with PL, further confirmed the role of aromatic groups in stabilising the ligand (RMSD ⩽4Å). The present study led to the identification of 2-(carbazol-3-yl)-2-oxoacetamide analogues 7a-x as a new class of potential PL inhibitors.