Design and Synthesis of the Novel PI3K/mTOR Dual Inhibitors as Anticancer Agents

Abstract

Cancer is a chronic disease and the death occurring due to the cancer is increasing year by year. According to WHO statistics, breast cancer is the most dangerous type of cancer with high death rate. Several class I PI3K/mTOR dual inhibitors have entered different clinical research stages, such as gedatolisib, apitolisib, omipalisib, dactolisib and so on. However, all these inhibitors have varying degrees of adverse events and no PI3K/mTOR dual inhibitor has been successfully approved by FDA. Therefore, the development of PI3K/mTOR dual inhibitors with good clinical activity, few side effects, and low toxicity is extremely urgent. From the extensive literature review it was well understood that the PI3K/mTOR signalling has long been a therapeutic targeting pathway for development of breast cancer treatment. The aim of the present research work is to design and synthesise a novel PI3K/mTOR dual inhibitor for the treatment of breast cancer. 14 diversified structures were taken for the pharmacophore generation. Pharmacophore model was developed by using DISCOtech and refined by GASP module of Sybyl. The best model was selected which contain 1 hydrophobic, 2 donor site, 2 acceptor atoms. This model was further considered for the virtual screening. On virtual screening, 14420 molecules were retrieved which further filtered out counter ions, duplicate structures, bad fragments and Lipinski filtering. Total 7214 drug like molecules were obtained among them 35 compounds showed Qfit value greater than 95%. 58 derivatives of morpholino-pyrimidine were taken from various literature for 3D-QSAR studies. Two different alignments were performed. Among them distill-based alignment showed good result as compared to pharmacophore-based alignment. On the basis of contour maps favourable and unfavourable region were identified. Molecules were designed using rational-based drug design approach. Designed derivative were docked on PI3K and mTOR protein. Further, toxicity prediction and ADMET study of designed molecules was performed. Best docking score compounds were synthesized. Then further characterized synthesized compound using IR and mass.