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Synthesis, Characterization, Antitubercular and Anti-Inflammatory Activity of New Pyrazolo[3,4-d]Pyrimidines
Combinatorial Chemistry & High Throughput Screening ( IF 1.8 ) Pub Date : 2021-08-31 , DOI: 10.2174/1386207323999200918114905
Ravindra Kulkarni 1 , Krishna Kompalli 2 , Naveen Gaddam 2 , Chandrashekhar Venkaraddi Mangannavar 3 , Bikshupati Darna 4 , Achaiah Garlapati 5 , Dileep Kumar 1 , Baswaraju Machha 5
Affiliation  

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]pyrimidine scaffold 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 4-amino 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.



中文翻译:

新型吡唑并[3,4-d]嘧啶的合成、表征、抗结核和抗炎活性

目的和目的:包括TNF-α和IL-1β在内的大量促炎细胞因子参与了人体炎症的进程。抑制由促炎细胞因子介导的信号传导可有效治疗炎性疾病。由于对多种药物的耐药性,可怕的传染病结核分枝杆菌的治疗仍然是一个挑战,因此迫切需要更新的药物。吡唑并[3,4-d]嘧啶已被公开具有多种药理活性,包括抗炎、抗微生物和抗结核活性。在这里,我们报告了用于抗炎和抗结核活性的吡唑并[3,4-d]嘧啶的合成。

材料与方法:通过三步反应合成具有吡唑并[3,4-d]嘧啶骨架8a-m的靶向化合​​物,形成关键中间体5-氨基-4-cyno-1-苯基吡唑,环化后产生在 4-氨基吡唑并[3,4-d]嘧啶中,随后用取代的苯甲酰氯苯甲酰化形成 8a-m。在 25 mg/Kg 剂量下评估 8a-m 的抗炎活性,并且还进行了对革兰氏阳性、革兰氏阴性和分枝杆菌的最小抑制浓度。在 p38 激酶的结合口袋中也测量了结合相互作用。

结果:4种化合物8a、8b、8e和8i在角叉菜胶诱导的大鼠足部水肿模型中具有显着的抗炎活性,其中8b的活性为80.6%。许多化合物对真菌菌株表现出比细菌菌株更有效的活性,化合物 8k 对革兰氏阴性细菌肺炎克雷伯菌最有效。化合物8d、8e和8f具有抗结核活性,MIC值为6.25 μg/mL。

结论:取代的 N-苯甲酰氨基吡唑并[3,4-d]嘧啶具有显着而有效的抗炎和抗菌活性。分子对接研究还揭示了 p38 激酶活性位点的良好相互作用。

更新日期:2021-06-29
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