Synthesis, antimicrobial, anti-proliferative activities, molecular docking and DFT studies of novel pyrazolo[5,1-c][1, 2, 4]triazine-3-carboxamide derivatives

Abstract

In this investigation, we studied the reactivity of 5-aminouracil (1) with ethyl cyanoacetate (2) utilizing microwave irradiation to afford the corresponding 2-cyano-N-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)acetamide (3) in excellent yield. The electrophilic azo-coupling reaction of acetamide 3 with aromatic diazonium salts afforded the corresponding hydrazone derivatives 4a–d. The Michael addition cyclization of hydrazone in pyridine to give pyrazolo[5,1-c][1, 2, 4]triazine-3-carboxamide 5a–d derivatives. The obtained compounds were elucidated against antimicrobial activity and antitumor activity breast cancer cells (MCF-7) and liver cancer cells (HepG2) utilized MTT assay. Compounds 5b, 5c and 5d revealed more inhibitory influence on MCF7 and HepG2 growth than the reference drug doxorubicin (Dox) after 48 h incubation. Furthermore, molecular docking studies were carried out on one of the most effective compound 4-amino-N-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-7-(4-fluorophenyl) pyrazole [5,1-c][1, 2, 4]triazine-3-carboxamide (5c) (TFC) with (PDB: 3t88), (PDB: 2wje) , (PDB: 4ynt), (PDB: 1tgh), (PDB: 4hdq) and (PDB: 3pxe) which attached with different proteins with different energies and shortage bond distance. Also; the comprehensive theoretical and experimental mechanical studies of compound TFC and TMC were compatible with FTIR and ¹H NMR spectral data. The optimized molecular structure of TFC with FTIR was examined via DFT/ B3LYP/6-31G (d) level.

Communicated by Ramaswamy H. Sarma

Keywords:

• Hydrazone
• pyrazolo[5,1-c][1
• 2
• 4]triazine-3-carboxamide
• antimicrobial
• antitumor activity
• docking studies
• computational calculations

Disclosure statement

No potential conflict of interest was reported by the author(s).