Abstract

Novel angularly fused pyrido[3',2':4,5]furo[3,2-d]pyrimidines were synthesized using 3-amino-4- methyl-N-phenyl-6-substituted furo[2,3-b]pyridine-2-carboxamide and various aromatic carboxylic acids using microwave irradiation. The compounds were characterized and tested for in silico, in vitro and in vivo anticancer activities. The synthesized compounds were tested for receptor binding with dihydrofolate reductase and thymidylate synthase enzymes. Compounds pyrido[3',2':4,5]furo[3,2-d] pyrimidine-5, pyrido[3',2':4,5]furo[3,2-d]pyrimidine-6 and pyrido[3',2':4,5]furo[3,2-d]pyrimidine-7 showed effective binding with the target receptors through hydrogen bonding interactions. The 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide assay results revealed the cytotoxicity effect of compounds on Henrietta Lacks cervical cancer cell line, human breast cancer cell line and rat glioma cell line. Compounds, pyrido[3',2':4,5]furo[3,2-d]pyrimidine-5, pyrido[3',2':4,5]furo[3,2-d] pyrimidine-6 and pyrido[3',2':4,5]furo[3,2-d]pyrimidine-7 showed better acitivty on those cell lines with lesser half maximal inhibitory concentration values. So, they were selected for the in vivo anticancer study and in vitro deoxyribonucleic acid ladder assay. Pyrido[3',2':4,5]furo[3,2-d]pyrimidine-5 and pyrido[3',2':4,5]furo[3,2-d]pyrimidine-7 exhibited total tumor volume as 4.9±0.01 and 3.95±0.25 ml/mouse, respectively. Pyrido[3',2':4,5]furo[3,2-d]pyrimidine-5 and pyrido[3',2':4,5]furo[3,2-d] pyrimidine-6 markedly increased the mean survival time levels with an enhanced % increase in life span to 70.83 and 29.16, respectively. From the above results, it is concluded that compounds containing phenyl ring substituted with electron withdrawing groups such as 3-fluoro, 4-trifluoromethyl and 3,5-dimethoxy substitutions at the C-2 of pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4(3H)-one could be drug like candidates for further structural modification to enhance their biological activities.