Efficient synthesis, reactions, and biological activities of new thieno and furopyrazolo[3,4‐b]pyrazines and their related heterocycles

• Published in: Journal of the Chinese Chemical Society (Taipei) 2020-04, Vol.67 (4), p.658-673
• Main Authors: Zaki, Remon M., Kamal El‐Dean, Adel M., Radwan, Shaban M., Abd ul‐Malik, Mokhtar A.
• Format: Article
• Language: English
• Subjects: antimicrobial activity; anti‐inflammatory activity; pyrazolo[3,4‐b]pyrazine; synthesis; thienopyrazolopyrazine
• ISSN: 0009-4536; 2192-6549
• DOI: 10.1002/jccs.201900056

In the present investigation, a simple and straightforward methodology for the preparation of novel bifunctional thienopyrazolopyrazines 4a–d has been reported. Synthesis of thieno or furopyrazolopyrazines 5a,b,e,f was achieved by the reaction of o‐amino‐esters 4a,b,e,f with 2,5‐dimethoxytetrahydrofuran. The latter pyrrolyl derivatives 5a,b,e,f were used as starting intermediates for the synthesis of new pyrimido, pyrido, and pyrazino heterocycles fused to the thieno or furopyrazolopyrazine moiety. Furthermore, alkaline hydrolysis of the o‐amino‐ester 4a followed by acidification afforded the corresponding o‐amino carboxylic acid 15, which was used as a versatile precursor for the synthesis of other heterocyclic compounds fused to the thienopyrazolopyrazine ring system, namely: pyrimidine, oxazine, oxazepine, and pyridine derivatives 16–23. The chemical structures of the synthesized compounds were confirmed on the basis of elemental and spectral analyses (Fourier‐transform infrared spectroscopy [FT‐IR], 1H nuclear magnetic resonance [NMR], and mass spectroscopy [MS] in addition to 13C NMR for some of them). Moreover, from the biological screening, we found that most of the tested compounds exhibited promising antifungal, antibacterial, and anti‐inflammatory activities compared with the corresponding reference drugs. In the present work, we have provided an easy access for synthesis of new bi‐functional furo and thienopyrazolopyrazine heterocycles by a convenient and efficient methodology. Some of the newly synthesized compounds were evaluated for antimicrobial and anti‐inflammatory activities. Most of the tested compounds exhibited promising anti‐fungal, antibacterial and anti‐inflammatory importance.