Abstract
As a continuation for our previous work, a novel set ofN-alkylindole-isatin conjugates (7,8a-c,9and10a-e) is here designed and synthesised with the prime aim to develop more efficient isatin-based antitumor candidates. Utilising the SAR outputs from the previous study, our design here is based on appending four alkyl groups with different length (ethyl and n-propyl), bulkiness (iso-propyl) and unsaturation (allyl) onN-1 of indole motif, with subsequent conjugation with differentN-unsubstituted isatin moieties to furnish the target conjugates. As planned, the adopted strategy achieved a substantial improvement in the growth inhibitory profile for the target conjugates in comparison to the reported leadVI. The best results were obtained withN-propylindole -5-methylisatin hybrid8awhich displayed broad spectrum anti-proliferative action with efficient sub-panel GI(50)(MG-MID) range from 1.33 to 4.23 mu M, and promising full-panel GI(50)(MG-MID) equals 3.10 mu M, at the NCI five-dose assay. Also, hybrid8awas able to provoke cell cycle disturbance and apoptosis in breast T-47D cells as evidenced by the DNA flow cytometry and Annexin V-FITC/PI assays. Furthermore, hybrid8aexhibited good inhibitory action against cell cycle regulator CDK2 protein kinase and the anti-apoptotic Bcl-2 protein (IC50= 0.85 +/- 0.03 and 0.46 +/- 0.02 mu M, respectively). Interestingly, molecular docking for hybrid8ain CDK2 and Bcl-2 active sites unveiled thatN-propyl group is involved in significant hydrophobic interactions. Taken together, the results suggested conjugate8aas a promising lead for further development and optimisation as an efficient antitumor drug.