Synthesis, Anticancer Activity, and Computational Studies of Novel Imidazo[1′,2′:1,5]pyrazolo[3,4-b]pyridine Derivatives

IF 2 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY
Adel A. -H. Abdel-Rahman, Farag A. El-Essawy, Norah M. Almaneai, Mohamed N. El-Bayaa, Nader M. Boshta, Sabri Messaoudi, Wael A. El-Sayed
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Abstract

A series of novel functionalized pyrazolopyridine derivatives bearing arylidene side chains was synthesized through efficient heterocyclization methods. Additionally, alkyl-substituted imidazo-pyrazolopyridine (tetraazacyclopenta[a]indene) compounds and tetracyclic pyrazolopyridine–imidazopyrimidine hybrids (pentaazaindeno[1,2-a]inden-2-one) were prepared. The cytotoxicity of these compounds was assessed against human colorectal (HCT-116) and breast (MCF-7) cancer cell lines, revealing that compounds 9 and 16 have exhibited the most potent activity. Other derivatives showed selective cytotoxic effects toward one of the two cell lines. Molecular docking studies were conducted to explore the binding interactions of compounds 9 and 16 within the active site of EGFR (epidermal growth factor receptor). To further investigate the binding stability of compound 16, molecular dynamics (MD) simulations were performed using EGFR (PDB ID: 1M17), providing insight into the stability and structural integrity of the protein-ligand complex. Additionally, density functional theory (DFT) analysis was carried out to examine the electronic structure of compound 16, including its molecular orbitals and electrostatic potential. The HOMO–LUMO analysis supported the compound's electron-donating properties, aligning with its strong binding affinity and cytotoxic performance observed in the docking and MD studies.

Abstract Image

新型咪唑[1 ',2 ':1,5]吡唑[3,4-b]吡啶衍生物的合成、抗癌活性及计算研究
采用高效杂环化方法合成了一系列具有芳基侧链的新型功能化吡唑吡啶衍生物。此外,还制备了烷基取代咪唑-吡唑吡啶(四氮杂环五[a]茚)化合物和四环吡唑吡啶-咪唑嘧啶杂化物(五氮杂二[1,2-a]茚-2- 1)。这些化合物对人类结直肠癌(HCT-116)和乳腺癌(MCF-7)细胞系的细胞毒性进行了评估,结果显示化合物9和16表现出最有效的活性。其他衍生物对两种细胞系中的一种表现出选择性的细胞毒性作用。通过分子对接研究,探索化合物9和16在表皮生长因子受体(EGFR)活性位点内的结合相互作用。为了进一步研究化合物16的结合稳定性,我们使用EGFR (PDB ID: 1M17)进行了分子动力学(MD)模拟,以深入了解蛋白质-配体复合物的稳定性和结构完整性。此外,利用密度泛函理论(DFT)分析了化合物16的电子结构,包括分子轨道和静电势。HOMO-LUMO分析支持该化合物的供电子特性,与对接和MD研究中观察到的强结合亲和力和细胞毒性能一致。
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来源期刊
ChemistrySelect
ChemistrySelect Chemistry-General Chemistry
CiteScore
3.30
自引率
4.80%
发文量
1809
审稿时长
1.6 months
期刊介绍: ChemistrySelect is the latest journal from ChemPubSoc Europe and Wiley-VCH. It offers researchers a quality society-owned journal in which to publish their work in all areas of chemistry. Manuscripts are evaluated by active researchers to ensure they add meaningfully to the scientific literature, and those accepted are processed quickly to ensure rapid online publication.
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