ABSTRACT
In spite of various and extensive studies known for pyrazolo[1,5-a]pyrimidines the synthesis, in silico studies and biological evaluation of their 5-(het)aryl analogs remained underexplored. The TNF-α inhibitors on the other hand has considerable therapeutic potential for autoimmune and inflammatory diseases in addition to cancer, diabetes and possibly COVID-19. In the current study 5-aryl pyrazolo[1,5-a]pyrimidines were explored as potential inhibitors of TNF-α that was supported by the in silico studies. This class of compounds was accessed via a sonochemical synthesis involving the acid catalyzed cyclocondensation reaction of aminopyrazoles with acrylophenones in the presence of aerial oxygen. The study indicated that the overall rate of the reaction was enhanced by ultrasound in the absence of which a longer duration and higher temperature was necessary. The current catalyst/promoter/ligand free and scalable method afforded a range of compounds. Some of these compounds showed good inhibition of TNF-α in vitro where ester/amide moiety at the C-3 position played a key role in interacting with the protein dimer as suggested by the in silico studies. Indeed, these groups formed H-bonds with A: GLY121 and B: TYR151 residues of TNF-α dimer in silico. A brief SAR within the series and in silico ADME/toxicity prediction for best active compounds is presented. Compounds 3a-c were identified as initial hits for further pharmacological evaluations. A sonochemical method has been developed for the facile synthesis of pyrazolo[1,5-a]pyrimidines that were evaluated as potential inhibitors of TNF-α. [ABSTRACT FROM AUTHOR] Copyright of Polycyclic Aromatic Compounds is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
ABSTRACT
In spite of various and extensive studies known for pyrazolo[1,5-a]pyrimidines the synthesis, in silico studies and biological evaluation of their 5-(het)aryl analogs remained underexplored. The TNF-α inhibitors on the other hand has considerable therapeutic potential for autoimmune and inflammatory diseases in addition to cancer, diabetes and possibly COVID-19. In the current study 5-aryl pyrazolo[1,5-a]pyrimidines were explored as potential inhibitors of TNF-α that was supported by the in silico studies. This class of compounds was accessed via a sonochemical synthesis involving the acid catalyzed cyclocondensation reaction of aminopyrazoles with acrylophenones in the presence of aerial oxygen. The study indicated that the overall rate of the reaction was enhanced by ultrasound in the absence of which a longer duration and higher temperature was necessary. The current catalyst/promoter/ligand free and scalable method afforded a range of compounds. Some of these compounds showed good inhibition of TNF-α in vitro where ester/amide moiety at the C-3 position played a key role in interacting with the protein dimer as suggested by the in silico studies. Indeed, these groups formed H-bonds with A: GLY121 and B: TYR151 residues of TNF-α dimer in silico. A brief SAR within the series and in silico ADME/toxicity prediction for best active compounds is presented. Compounds 3a-c were identified as initial hits for further pharmacological evaluations. A sonochemical method has been developed for the facile synthesis of pyrazolo[1,5-a]pyrimidines that were evaluated as potential inhibitors of TNF-α. A sonochemical method has been developed for the facile synthesis of pyrazolo[1,5-a]pyrimidines that were evaluated as potential inhibitors of TNF-α.