Unraveling the Alkaline Phosphatase Inhibition, Anticancer, and Antileishmanial Potential of Coumarin-Triazolothiadiazine Hybrids: Design, Synthesis, and Molecular Docking Analysis

Arch Pharm (Weinheim). 2016 Jul;349(7):553-65. doi: 10.1002/ardp.201500392. Epub 2016 May 23.

Abstract

A series of new coumarin-triazolothiadiazine hybrid compounds (5a-j) was designed and synthesized by using the molecular hybridization concept. The cyclocondensation reaction involves the coumarinyl 4-amino-1,2,4-triazole and a range of bromo-acetophenones, delivering the desired products in good yields. The structures of the synthesized compounds were established on the basis of spectro-analytical data. The prepared compounds were evaluated against alkaline phosphatase (ALP) where compound 5j incorporating bis-coumarinyl motifs at the 3- and 6-positions of the heteroaromatic core turned out to be a potent inhibitor with an IC50 value of 1.15 ± 1.0 µM. The synthesized compounds were also tested against Leishmania major and 5h was the lead member with an IC50 value of 0.89 ± 0.08 μM. Anticancer activity was also determined using kidney fibroblast (BHK-21) and lung carcinoma (H-157) cancer cell lines. Compound 5i showed highest cytotoxic potential against H-157 cells with an IC50 value of 1.01 ± 0.12 μM, which is an improved inhibition compared to the standards (vincristine and cisplatin) used in this assay. Molecular docking studies were carried out on the synthesized library of coumarin-triazolothiadiazine hybrids against ALP. Almost all of the compounds showed strong interactions with the key residues of the active site of the receptor. In case of compounds 5a-c, 5h, and 5j, docking results positively complemented the experimental screening. These results provided substantial evidence for the further development of these compounds as potent inhibitors of ALP.

Keywords: Coumarin; Cytotoxicity; Heterocycles; Leishmaniasis; Triazolothiadiazine.

MeSH terms

  • Alkaline Phosphatase / antagonists & inhibitors*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Coumarins / chemical synthesis
  • Coumarins / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Humans
  • Leishmania / drug effects*
  • Molecular Docking Simulation*
  • Structure-Activity Relationship
  • Thiadiazines / chemical synthesis
  • Thiadiazines / pharmacology*

Substances

  • Antineoplastic Agents
  • Coumarins
  • Thiadiazines
  • Alkaline Phosphatase