Ultrasound Mediated One-Pot, Three Component Synthesis, Docking and ADME Prediction of Novel 5-Amino-2-(4-chlorophenyl)-7-Substituted Phenyl-8,8a-dihydro-7H-(1,3,4)thiadiazolo(3,2-α)pyrimidine-6-carbonitrile Derivatives as Anticancer Agents

Molecules. 2016 Jul 29;21(8):894. doi: 10.3390/molecules21080894.

Abstract

Herein, we report an environmentally friendly, rapid, and convenient one-pot ultrasound-promoted synthesis of 5-amino-2-(4-chlorophenyl)-7-substituted phenyl-8,8a-dihydro-7H-(1,3,4)thiadiazolo(3,2-α)pyrimidine-6-carbonitrile derivatives. The in-vitro anticancer activities of these compounds were evaluated against four human tumor cell lines. Among all the synthesized derivatives, compound 4i, which has substituent 3-hydroxy-4-methoxyphenyl is found to have the highest GI50 value of 32.7 μM, 55.3 μM, 34.3 μM, 28.9 μM for MCF-7, K562, HeLa and PC-3 cancer cell lines respectively. A docking study of the newly synthesized compounds were performed, and the results showed good binding mode in the active site of thymidylate synthase enzyme. ADME properties of synthesized compounds were also studied and showed good drug like properties.

Keywords: 1,3,4-thiadiazolo(3,2-α)pyrimidine; ADME; docking; ultrasound-promoted synthesis.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • HeLa Cells
  • Humans
  • K562 Cells
  • MCF-7 Cells
  • Molecular Docking Simulation*
  • Neoplasm Proteins / antagonists & inhibitors*
  • Nitriles* / chemical synthesis
  • Nitriles* / chemistry
  • Nitriles* / pharmacology
  • Thymidylate Synthase / antagonists & inhibitors*
  • Ultrasonic Waves

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Neoplasm Proteins
  • Nitriles
  • Thymidylate Synthase