Novel quinoline-4-carboxamide derivatives potentiates apoptosis by targeting PDK1 to overcome chemo-resistance in colorectal cancer: Theoretical and experimental results

A series of novel N,2-diphenyl-6-(aryl/heteroaryl)quinoline-4-carboxamide derivatives were designed and synthesized using the Suzuki coupling reaction and evaluated them for their anticancer activity. These compounds were screened for anti-colon cancer activity through <i>in-silico</i> studies by molecular docking and molecular dynamics studies. Furthermore, the density functional theory was used to determine the molecule's electrical properties. The molecular electrostatic potential map is used to evaluate the charge distribution on the molecule surface. Unveiling that the compound <b>7a</b> (binding energy of -10.2 kcal/mol) has good inhibition activity compared to other synthesized compounds (<b>7b-7j</b>) as well as the standard drug Gefitinib. The stability of the compound <b>7a</b> with the 1OKY protein was confirmed through molecular dynamics simulation studies, indicating potential anti-colon cancer activity against <i>phosphoinositide dependent protein kinase-1</i> (PDK1). The <i>in-silico</i> ADMET pharmacokinetic properties indicate adherence to Lipinski's rule of five for favorable safety profiles and the compound falls within the optimal range for physicochemical and pharmacokinetic properties, which is comparable to that of the standard medication drug Gefitinib. The synthesized library of compounds was further evaluated for their <i>in-vitro</i> anticancer potency against colon, pancreatic and breast cancer cells. The results demonstrated that the compounds effectively suppressed the proliferative potential of the screened cells in a concentration-dependent manner, as revealed by MTT assay. The anticancer potential of these molecules was further evaluated by acridine orange/PI, and Hoechst/PI which demonstrates the potential of molecules to induce apoptosis in cancer cells. Further investigations and optimization of these derivatives could lead to the development of effective anticancer strategies.