Structure–Activity Relationship and Pharmacokinetic Studies of 1,5-Diheteroarylpenta-1,4-dien-3-ones: A Class of Promising Curcumin-Based Anticancer Agents

Forty-three 1,5-diheteroaryl-1,4-pentadien-3-ones were designed as potential curcumin mimics, structurally featuring a central five-carbon dienone linker and two identical nitrogen-containing aromatic rings. They were synthesized using a Horner–Wadsworth–Emmons reaction as the critical step and evaluated for their cytotoxicity and antiproliferative activities toward both androgen-insensitive and androgen-sensitive prostate cancer cell lines and an aggressive cervical cancer cell line. Most of the synthesized compounds showed distinctly better in vitro potency than curcumin in the four cancer cell lines. The structure–activity data acquired from the study validated (1<i>E</i>,4<i>E</i>)-1,5-dihereroaryl-1,4-pentadien-3-ones as an excellent scaffold for in-depth development for clinical treatment of prostate and cervical cancers. 1-Alkyl-1<i>H</i>-imidazol-2-yl, ortho pyridyl, 1-alkyl-1<i>H</i>-benzo­[<i>d</i>]­imidazole-2-yl, 4-bromo-1-methyl-1<i>H</i>-pyrazol-3-yl, thiazol-2-yl, and 2-methyl-4-(trifluoromethyl)­thiazol-5-yl were identified as optimal heteroaromatic rings for the promising in vitro potency. (1<i>E</i>,4<i>E</i>)-1,5-Bis­(2-methyl-4-(trifluoromethyl)­thiazol-5-yl)­penta-1,4-dien-3-one, featuring thiazole rings and trifluoromethyl groups, was established as the optimal lead compound because of its good in vitro potency and attractive in vivo pharmacokinetic profiles