3,7-bis-benzylidene hydrazide ciprofloxacin derivatives as promising antiproliferative dual TOP I & TOP II isomerases inhibitors

We report herein design and synthesis of a new series of 3,7-bis-benzylidenes of ciprofloxacin. Most of the target compounds revealed good cytotoxic activity; the most potent 4e and 4i achieved strong broad spectrum antiproliferative activity with comparable activity to Doxorubicin with IC50 (M-mu) of 1.21 +/- 0.02, 0.87 +/- 0.04, 1.21 +/- 0.02; 0.41 +/- 0.02, 0.57 +/- 0.06, 1.31 +/- 0.04 and 1.26 +/- 0.01, 1.79 +/- 0.04, 0.63 +/- 0.01 against leukemia cancer cell line HL-60 (TB), colon cancer cell line HCT-116 and breast cancer cell line MCF7, respectively. Moreover, the most potent derivative 4i induced apoptosis at G2/M phase Investigating the mechanism of action of compounds 4e, 4 h and 4i exhibited promising dual TOP I alpha and TOP IIB % inhibition comparable to Camptothecin and Etoposide; respectively. Docking of 4e, 4 h and 4i into the active site of topo I and II proteins compared to Camptothein and Etoposide revealed acceptable binding score and augmented enzyme assay data. Hence, 4e and 4i are promising targeted antiproliferative dual acting TOP I alpha TOP IIB inhibitors that require further optimization.