DESIGN COMPUTATIONAL STUDY AND SYNTHESIS OF QUINAZOLINE ANALOGUES AS CYTOTOXIC AGENTS

Abstract

Synthesis of novel quinazoline derivatives was performed from reaction of N-benzoyl substituted piperazine-1-carbothioamide with 4-(2-chlormethyl) quinazoline-4-yloxy phenyl benzamide derivatives and screened for their in vitro cytotoxic activity by MTT assay. Docking study was performed for selection of best scored compound for synthesis based on minimized energetic compounds. The cell lines used were MCF 7 (Breast cancer cell), HCT 15 (Colon cancer cell line), and VERO (Normal epidermal kidney cell). Result of screening on cell line showed moderate to good cytotoxic activity for all the compounds. Compound GNU 02 (IC50 = 7.94 and#956;M, MCF), GNU 12 (IC50 = 8.43 and#956;M, HCT) and GNU 25 (IC50 = 9.41 and#956;M, HCT) was found to be most active compared to standard gefitinib (IC50 = 1.51 and#956;M HCT, IC50 =22.37 and#956;M MCF). Pharmacokinetic study was done based on computer software Molinspiration programme and proved best absorption, Distribution, Metabolism and Excretion profile of synthesized compounds. Some compounds which are not follow drug likeliness can developed by formulation development. Structure activity relationship of synthesized analogs suggested that the attachment of electron withdrawing groups like Nitro, Chloro gave better cytotoxic activity then unsubstituted phenyl and electron donating groups. Activity by substituted piperazine at 2nd position of thiazole linked with quinazoline scaffold gave better activity in the order of H gt CH3 gt C6H5. Our findings may impart new direction to medicinal chemists and biochemists for further investigations of quinazoline-thiazole containing cytotoxic agents. newline