Synthesis, cytotoxicity, pharmacokinetic profile, binding with DNA and BSA of new imidazo[1,2-a]pyrazine-benzo[d]imidazol-5-yl hybrids
Iqubal Singh, Vijay Luxami, Kamaldeep Paul
Abstract
Abstract Novel derivatives possessing imidazo[1,2- a ]pyrazine and 1 H -benzo[ d ]imidazole scaffolds were synthesized using Suzuki-Miyaura cross-coupling reactions. In vitro anticancer activities against NCI-60 cancer cell panels were tested at 10 µ M concentration. The best results were obtained from substitution of two 1-cyclohexyl-1 H -benzo[ d ]imidazole groups present at C-6 and C-8 positions of imidazo[1,2- a ]pyrazine ( 31 ). Compound 31 was found to be cytotoxic against 51 cell lines and cytostatic against 8 cell lines with broad range of growth inhibitions (−98.48 to 98.86%). GI 50 value of compound 31 was found in the range of 0.80–2.87 µ M for 59 human cancer cell lines at five-dose concentration levels. DNA binding study of potent compound 31 was suggested that this compound was intercalated into DNA base pairs with binding constant of 1.25 × 10 4 M −1 . Compound 31 showed effective binding with bovine serum albumin (BSA) and presented binding constant value of 3.79 ×10 4 M -1 . Pharmacokinetic studies revealed that all compounds are following Lipinski’s rule of five and expected to be orally active.