Design synthesis and biological evaluation of some novel substituted pyrimidine and pyrimidinone derivatives as anticancer agents

Abstract

The present invention is related to some novel bipyrimidine analogues having a cyano moiety and the process for their preparation as potential anti-cancer agents (P 01-14). The compounds described in this invention are novel and new, and have the potential to be used against breast cancer as well as lung cancer. The invention also describes the process for the preparation of these novel compounds. A series of novel 2, 4, 5-Trisubstituted Pyrimidine derivatives (CS 01-15) were designed and synthesized to evaluate for Anticancer activity against cell line MCF7 (Breast Cancer) and A549 (Lung Cancer). All the synthesized molecules were confirmed by various spectroscopic studies. Some of the synthesized pyrimidine derivatives showed promising activity with IC50 values against standard drug Doxorubicin. All the synthesized molecules were subjected to molecular docking study using PyRx software (based on Auto Dock 4 and a genetic algorithm) against two standard drugs Lapatinib and Gefitinib (PDB ID: 3BBT). SAR of P Series shows that electron withdrawing group especially OCF3 (P-7) as well as electron donating group like methyl attached to phenyl group (P-10) more potency on MCF-7 cell line. Also we found that molecule having heterocyclic moiety indole (P-9) as well as p-methyl attached to phenyl (P-10) shows more potency on both MCF-7 and A549. While for A549 cell line molecules having N-methyl pyrazole attached to phenyl ring shows more potency. Interestingly almost all derivatives showed good docking score as compare to Gefitinib. Compounds CS-02, CS-04, CS-07, CS-10 and CS-11 showed moderate anticancer activity for both the cell lines having IC50 values in range from 12.06 µM to 22.45 µM. While compounds CS-06 and CS-03 showed moderate potency against A549 and MCF7 cell lines respectively.