Synthesis, Biological Evaluation, Molecular Docking and ADME Profiling of Methylpiperidin‐4‐ylphenyl‐nicotinamide Derivatives

In this paper, we designed, synthesized, and biologically screened a series of methyl‐piperidine‐phenyl‐nicotinamide derivatives with the aim of novel derivatives as effective anticancer agents. Compounds (9 a), (9 e) and (9 k) exhibited potent anticancer activity with an IC50 value of 5.9 μM, 5.9 μM and 5.0 μM, respectively using MV411 (Acute Myeloid Leukemia) and K562 (Chronic Myeloid Leukemia) cell line. Our docking studies show good binding affinity of these compounds for ABL1 kinase. Furthermore, these compounds exhibited a favourable in silico ADME profile with good solubility and low clearance in Human Liver Microsomes (HLM). These derivatives represent a promising approach to initiate the development of new anticancer drugs in oncology programs. In the present study a seris of methyl‐piperidine‐phenyl‐nicotinamide (9 c–9 n) derivatives were synthesized. In final step Suzuki Coupling between (9 b) (R)‐5‐Bromo‐N‐(3‐fluoro‐4‐(1‐methylpiperidin‐4‐yl) phenyl)‐6‐(3‐hydroxypyrrolidin‐1‐yl) nicotinamide and different boronic acid using Dichlorobis (triphenylphosphine) palladium (II) catalyst. The final molecule was confirmed by 1H NMR, 13C NMR and LCMS. Compounds (9 a), (9 e) and (9 k) exhibited potent anticancer activity with an IC50 value of 5.9 μM, 5.9 μM and 5.0 μM, respectively. Our docking studies show good binding affinity of these compounds for ABL1 kinase. Furthermore, these compounds exhibited a favourable in silico ADME profile with good solubility and low clearance in Human Liver Microsomes (HLM). These derivatives represent a promising approach to initiate the development of new anticancer drugs in oncology program.