Novel Curcumin Mimics: Design, Synthesis, Biological Properties and Computational Studies of Piperidone‐Piperazine Conjugates
Mohamed A. Youssef, Siva S. Panda, Dalia R. Aboshouk, Mona F. Said, Ahmed El Taweel, Mohamed GabAllah, Walid Fayad, Ahmed F. Soliman, Ahmed Mostafa, Nehmedo G. Fawzy, Adel S. Girgis
Abstract
Abstract 3,5‐Di[( E )‐arylidene]‐1‐[3‐(4‐methylpiperazin‐1‐yl)alkyl]piperidin‐4‐ones 7 a−k were synthesized through dehydrohalogenation of 1‐(2‐chloroacyl)piperidin‐4‐ones 5 a−k with N ‐methylpiperazine ( 6 ). High antiproliferation potencies were observed by most of the synthesized agents against both HCT116 (colon) and MCF7 (breast) cancer cell lines relative to the standard references (sunitinib and 5‐fluorouracil). The synthesized agents are of dual activity against topoisomerases I and IIα however, with higher efficacy against topoisomerase IIα rather than topoisomerase I. Flow‐cytometry cell cycle studies support the observed antiproliferation properties and exhibit the capability of 1‐(2‐chloroacetyl)‐3,5‐bis[( E )‐4‐chlorobenzylidene]piperidin‐4‐one ( 5 e ) and 3,5‐bis[( E )‐4‐bromobenzylidene]‐1‐[2‐(4‐methylpiperazin‐1‐yl)acetyl]piperidin‐4‐one ( 7 g ) to arrest the HCT116 cell cycle progression at G1/S and G1 phases, respectively. Noticeable anti‐SARS‐CoV‐2 properties were observed by many synthesized agents. 3,5‐Bis[( E )‐4‐chlorobenzylidene]‐1‐[3‐(4‐methylpiperazin‐1‐yl)propanoyl]piperidin‐4‐one ( 7 f ) is the most effective anti‐SARS‐CoV‐2 synthesized with high SI. Applicability of the highly effective candidates synthesized as antitumor and anti‐SARS‐CoV‐2 is due to the safety observations against normal (RPE1 and VERO‐E6) cells. QSAR models validated internally and externally, support their possibility for optimizing more hits/leads.