Design and Synthesis of ALK5 Inhibitors

A new series of imidazo[21-b][134]thiadiazoles 5(a-g) 6(a-g) 9(a-i) and 12(a-h) were synthesized. Among them 23 compounds 5a 5b 5e 5d 5f 5g 6a 6b 6c 6d 6e 9b 9d 9f 9g 9h 9i 12b 12c 12d 12e 12g and 12h were evaluated at National Cancer Institute for single dose in vitro primary cytotoxicity assay. Compound 5b 5e 6c 6d 6e 12c 12d and 12e were further screened for 5-log dose molar range as they have shown prominent cell growth inhibition at 10-5 M concentration against variety of cell lines. Compound 5e shows significant inhibition against Leukemia HL-60 cell line with GI50 of 0.0285 µM and highest selectivity towards the Leukemic Cancer cell line (selectivity ratio of 7.96) it also shows prominent ALK5 inhibition (IC50 = 0.0263 µM) and elective inhibition (91%) against KDR at10 µM. The binding mode of compound 5e by SP docking studies shows that it ?ts well into the active site cavity of ALK5 by forming broad and tight interactions. Lipinski’s rule and in silico ADME pharmacokinetic parameters are within the acceptable range defined for human use thereby indicating their potential as a drug-like molecules.