Synthesis, characterization, antitubercular and anti-inflammatory activity of new pyrazolo[3,4-d]pyrimidines

Abstract

Aims and Objective: Copious proinflammatory cytokines including TNF-α and IL-1β are involved in progression of inflammation in human body. Inhibition of signaling mediated by proinflammatory cytokines offer effective in the treatment of inflammatory diseases. The treatment of dreadful infectious disease mycobacterium tuberculosis still remains a challenge owing to resistance to multiple drugs hence an urgent need for newer drugs. Pyrazolo[3,4-d]pyrimidines have been disclosed to possess numerous pharmacological activities including anti-inflammatory, antimicrobial and antitubercular activities. Here in we report the synthesis of pyrazolo[3,4-d]pyrimidines for anti-inflammatory and antitubercular activities. Materials and Methods: The targeted compounds having pyrazolo[3,4-d]pyrimidines 8a-m were synthesized in three step reactions with the formation of key intermediate 5-amino-4-cyno-1-phenyl pyrazole which upon cyclization resulted in 4amino pyrazolo[3,4-d]pyrimidine for subsequent benzoylation with substituted benzoyl chlorides to form 8a-m. Antiinflammatory activity of 8a-m was assessed at 25 mg/Kg dose and minimum inhibitory concentration against gram positive, gram negative and mycobacteria was also performed. Binding interactions were also measured in binding pocket of p38 kinase. Results: Four compounds 8a, 8b, 8e and 8i significant anti-inflammatory activity in rat paw edema model induced by carrageenan and among all 8b was potent with 80.6% activity. Numerous compounds exhibited potent activity against fungal strains than bacterial strains, compound 8k was most potent against gram negative bacteria Klebsiella pneumoniae. Compounds 8d, 8e and 8f exhibited antitubercular activity with MIC value of 6.25 μg/mL Conclusion: Substituted N-benzoylated amino pyrazolo[3,4-d]pyrimidines endowed significant and potent anti-inflammatory and antimicrobial activities. Molecular docking studies also revealed favorable interactions in active site of p38 kinase.

Food‐grade carrageenans and their implications in health and disease

“…Carrageenans are known to be potent inflammatory inducers. Carrageenan‐induced paw/pedal edema rodent models have been most frequently used for evaluating the anti‐inflammatory activity of numerous natural products (Kulkarni et al., 2020; Souto et al., 2011). λ‐Carrageenan‐induced pain models are also commonly used (X. Li et al., 2020).…”

Interaction Patterns of Pyrazolopyrimidines with Receptor Proteins

“…Pyrazolo­[4,3- d ]­pyrimidine derivatives inhibit hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) and thereby reduce renal anemia and show anti-inflammatory activities . Pyrazolo­[3,4- d ]­pyrimidines are the most studied isomer, which are reported to have anticancer activity, , antimicrobial activity, , anti-inflammatory activity , and activity toward adenosine receptors, xanthine oxidase, and growth factor receptor kinases . Specific carbon and nitrogen atoms of the pyrazolo­[3,4- d ]­pyrimidines scaffold, vital for its anticancer and antimicrobial activities, have also been identified. , As Pyp rings are privileged scaffolds in medicinal chemistry, which can bind to diverse receptors, the broad spectrum of medicinal properties documented for their derivatives is unsurprising. , …”

“…32 Pyrazolo [4,3-d]pyrimidine derivatives inhibit hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) and thereby reduce renal anemia 33 and show anti-inflammatory activities. 34 Pyrazolo [3,4-d]pyrimidines are the most studied isomer, which are reported to have anticancer activity, 8,11 antimicrobial activity, 35,36 anti-inflammatory activity 37,38 and activity toward adenosine receptors, 39 xanthine oxidase, 40 and growth factor receptor kinases. 21 Specific carbon and nitrogen atoms of the pyrazolo [3,4d] activities, have also been identified.…”

Pyrazolo[3,4‐d]pyrimidine‐based scaffolds as antibacterial agents: Synthetic strategies, reactions, and in vitro biological evaluation

“…Moreover, pyrazolo[3,4‐ d ]pyrimidine derivatives have attracted sizeable attention attributed to their versatile activities as anti‐inflammatory and neuroprotective, [ 17 ] antitubercular, [ 18 ] antimalarial, [ 19 ] and antidiabetic agents. [ 20 ]…”

“…[10][11][12] Hence, pyrazolo [3,4-d]pyrimidines exhibiting plenty of biological virtues such as antimicrobial, [13] antibacterial, [14,15] and Zika virus antiviral agents. [16] Moreover, pyrazolo [3,4-d]pyrimidine derivatives have attracted sizeable attention attributed to their versatile activities as anti-inflammatory and neuroprotective, [17] antitubercular, [18] antimalarial, [19] and antidiabetic agents. [20] Noteworthy, pyrazolo [3,4-d]pyrimidines emerged as vital pharmaceutically relevant molecules in view of their presence as part of several approved marketed drugs such as parsaclisib, ibrutinib (Imbruvica), allopurinol (Zyloric), umbralisib (Ukoniq).…”