Synthesis of indole-tethered [1,3,4]thiadiazolo and [1,3,4]oxadiazolo[3,2-a] pyrimidin-5-one hybrids as anti-pancreatic cancer agents

New indole-tethered [1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (8a -j) and [1,3,4]oxadiazolo[3,2-a]pyrimidin-5one hybrids (9a-e) were synthesized using [4+2] cycloaddition reactions of functionalized 1,3-diazabuta-1,3dienes with indole-ketenes. All molecular hybrids were structurally characterized by spectroscopic techniques (IR, NMR, and HRMS) and screened for their anti-pancreatic cancer activity in vitro. The [1,3,4]oxadiazolo[3,2a]pyrimidin-5-one hybrids (9a-e) showed stronger anti-pancreatic cancer activity than the [1,3,4]thiadiazolo [3,2-a]pyrimidin-5-one hybrids (8a-j) against the PANC-1 cell line. Compound 9d bearing an ortho-chlorophenyl moiety emerged as the most potent anti-pancreatic cancer agent with an IC50 value of 7.7 +/- 0.4 mu M, much superior to the standard drug Gemcitabine (IC50 > 500 mu M). The discovery of these [1,3,4]thiadiazolo and [1,3,4]oxadiazolo[3,2-a]pyrimidin-5-one hybrids elicits their potentials as pursuable candidates for pancreatic cancer chemotherapy.