From Bench to Bioactivity: Pyranopyrazole Synthesis, Anticancer, Antimicrobial Efficacy, DFT, Molecular Docking, and Molecular Dynamic Insights

Background: Heterocyclic compounds are prevalent in nature and essential to life. The synthesis and application of medium-sized ring heterocyclic compounds have gained prominence. Pyranopyrazole is one such compound that has a significant impact on biological and medicinal chemistry. It has attracted interest in agrochemical research due to its fungicidal, bactericidal, and herbicidal properties. Additionally, it exhibits various biological activities, including anti-inflammatory, analgesic, antidiabetic, antimicrobial, anticancer, and antimalarial effects. Furthermore, it has been explored for its potential in treating SARS-CoV-2. Objective: The study synthesized novel pyranopyrazole compounds and evaluated their anticancer efficacy against certain tumor cell lines (MCF-7, HeLa, and PC-3) and antimicrobial activities as deduced through molecular docking studies. Methods: A one-pot, four-component reaction involving ethyl acetoacetate (1), hydrazine hydrate (2), malononitrile or ethyl cyanoacetate (3a, b), and aromatic aldehydes (4a-c) in an ethanolic/piperidine solution was conducted, yielding pyranopyrazoles (5a-f) in moderate to good yields. Results: This study involved the synthesis of novel pyranopyrazole derivatives 5a-f and the evaluation of their anticancer and antimicrobial activities. These findings indicate that compound 5f is extremely active. It is more potent than 5-fluorourcail and ofloxacin, and it may also have new modes of action that are worth more research, while compound 4d has the highest antimicrobial activity. Molecular docking studies help us learn more about how these chemicals interact with biological targets like the TGF-βI receptor and the choline-binding domain, both of which play a key role in the growth of cancer. Conclusion: A series of novel pyranopyrazole derivatives 5a-f were synthesized and analyzed using spectral data. Compound 5f stands out as a lead molecule for more study and improvement due to its low IC50 value and high binding affinity. Based on how stable it is in molecular dynamics (MD) simulations and how its anticancer properties are linked to its binding affinities, it may be a strong TGF-βI receptor inhibitor.