Design, Synthesis, Molecular Docking, ADMET, and Biological Studies of Some Novel 1,2,3-Triazole Linked Tetrazoles as...

1,2,3-Triazole-tetrazoles have received substantial attention because of their unique bioisosteric properties and an extraordinarily broad spectrum of biological activity, making them interesting for the drug design, and synthesis of a delightful class of widely investigated heterocyclic compounds. To address major health concerns, it is consequently important to devote ongoing effort to the identification and development of New Chemical Entities (NCEs) as possible anticancer medicines.

We began our initial investigation of the reaction between 5-(azidomethyl)-1H-pyrrolo[ 2,3-b]pyridine and 1-phenyl substituted-5-(prop-2-yn-1-ylthio)-1 H-tetrazole under click chemistry to give the corresponding triazole precursors and screened for their cytotoxicity reported by variations in therapeutic actions of the parent molecule. All of the prepared scaffolds were characterized by proton, carbon resonance spectroscopy, IR, and mass spectral techniques.

When tested for in vitro antitumor activity the prepared compounds 7e, 7h had a significant anticancer activity against human adenocarcinoma Hs766T cell line with IC₅₀ = 5.33, 4.92 μg/mL and Hs460 cell line with IC₅₀ = 4.82, 6.15 μg/mL respectively. Final scaffolds 7f, 7h, and 7j acquire the highest potential drug binding scores ΔG = -10.42, -8.80, -9.37 Kcal/, with amino acids residues Ala A:11 (2.195 A˚), Asp A:119 (1.991 A˚), Thr A:58 (1.890 A˚), Lys A:16 (1.253 A˚), Asp A:38 (2.013 A˚), Lys A:117 (2.046 A˚) respectively and process Lipinski's rule of five as good agents for oral bioavailability.

The molecular framework for the synthesis of novel Aza indole 1,2,3-triazole scaffolds coupled to tetrazole core was discovered in our study and evaluated for their anticancer activity.