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

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 H-1 NMR spectral data. The optimized molecular structure of TFC with FTIR was examined via DFT/ B3LYP/6-31G (d) level.

Automated summary

In this study, a series of heterocyclic compounds were synthesized using microwave irradiation and their antimicrobial and antitumor activities were evaluated through experimental and theoretical studies. The compounds showed promising inhibitory effects against cancer cells, highlighting their potential as therapeutic agents.