Synthesis, Biological Evaluation and In silico Studies of Compounds Based on Tryptophan-Naproxen-Triazole Hybrids

A hybrid of three different frameworks e. g. tryptophan, naproxen and triazole has been explored for the identification of potential antibacterial / anticancer agents. A library of new compounds, designed based on this hybrid framework was synthesized via a multi-step sequence using the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) as the key reaction step. Thus the terminal alkyne obtained via the reaction of tryptophan ester with naproxen followed by N-propargylation of the indole ring was coupled with a range of organic azides to give the desired products (through the formation of triazole ring) in good to acceptable yields. The in vitro antibacterial screening of these compounds against S. aureus (Gram-positive) as well as E. coli and K. pneumoniae (Gram-negative) strains identified several hits with moderate to good activities with 4-(4-((3-(3-methoxy-2-(2-(6-methoxynaphthalen-2-yl)propanamido)-3-oxopropyl)-1H-indol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)benzoic acid (6 n) being the best (MIC similar to 25 mu g/mL across all the strains). Several compounds e. g. analogues containing a (4-chlorophenyl)amino)-2-oxoethyl moiety (6 e) and (4-nitrophenyl)amino)-2-oxoethyl moiety (6 h) attached to the triazole ring also showed cytotoxic activities when tested against A549 cancer cell line (IC50=39.35 and 28.52 mu g/mL, respectively).