2. Academic Validation
  3. 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

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

  • Bioorg Med Chem Lett. 2020 Nov 15;30(22):127544. doi: 10.1016/j.bmcl.2020.127544.
Lalitha Gummidi 1,  Nagaraju Kerru 1,  Paul Awolade 1,  Asif Raza 2,  Arun K Sharma 3,  Parvesh Singh 4
Affiliations

Affiliations

  • 1 School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, South Africa.
  • 2 Department of Pharmacology, Penn State Cancer Institute, CH72, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
  • 3 Department of Pharmacology, Penn State Cancer Institute, CH72, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA. Electronic address: asharma1@pennstatehealth.psu.edu.
  • 4 School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, South Africa. Electronic address: singhp4@ukzn.ac.za.
PMID: 32920143 DOI: 10.1016/j.bmcl.2020.127544
Abstract

New indole-tethered [1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (8a-j) and [1,3,4]oxadiazolo[3,2-a]pyrimidin-5-one hybrids (9a-e) were synthesized using [4+2] cycloaddition reactions of functionalized 1,3-diazabuta-1,3-dienes 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[3,2-a]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 µM, much superior to the standard drug Gemcitabine (IC50 > 500 µM). 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.

Keywords

Indole; Molecular hybridization; Pancreatic cancer; Pyrimidinone; [4+2] Cycloaddition reaction.

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