Synthesis and Anti proliferative Activity of New N‐Pentylquinoxaline carboxamides and Their O‐Regioisomer

We have designed a series of quinoxalinepeptidomimetic derivatives based on our previous reported scaffold in attempt to find a promising lead compound. Quinoxaline derivatives; N‐alkyl‐3‐(3‐oxo‐4‐pentyl‐3,4‐dihydro‐quinoxalin‐2‐yl)‐propanamides and methyl 2‐[3‐(3‐oxo‐4‐pentyl‐3,4‐dihydro‐quinoxalin‐2‐yl)propanamido]alkanoates and their O‐regioisomers were prepared by alkylation of the ambient nucleophile methyl 3‐(3‐oxo‐3,4‐dihydroquinoxalin‐2‐yl)propanoate with pentyl bromide to give the corresponding N‐ and O‐pentylquinoxaline ester derivatives. The N‐ and O‐pentyl‐quinoxaline ester derivatives gave the desired products by the reaction with amines and amino acid esters via azide coupling method. We have examined the anti proliferative activity of the 35 different synthesized compounds on human HCT‐116 and HEK‐293 cell lines. Out of 35 screened derivatives, 14 active compounds exhibited inhibitory action on the HCT‐116 cells with IC50 values ranging from 0.43 mM to 2.62 mM. We have also examined the impact of these active compounds on cancer cells nucleus and caspase 3 activity, we have the found that active compounds also increased in the caspase 3 activity which led to programmed cell death of cancer cells. We have also examined the impact of 35 compounds on the normal and non‐cancerous cells (HEK‐293) and we have found these active compounds did not cause any cytotoxic effect on the normal cells. The article described the synthesis for series of O‐pentylquinoxaline peptide‐mimeticsand their anti proliferative activity in both HCT‐116 and HEK‐293 cells which showed IC50 values ranging from 0.43 mM to 2.62 mM. The active compounds also increased the caspase 3 activity which led to programmed cell death of cancer cells suggesting a mode of action through the signaling pathway. Those compounds have the advantage of being selective as evident from their effect on the normal and non‐cancerous cells (HEK‐293).