Al-Mahadeen Mohammed M, Jaber Areej M, Zahra Jalal A, Al-Najjar Belal O, El-Abadelah Mustafa M, Khanfar Monther A
Chemistry Department, Faculty of Science, The University of Jordan, Amman, 11942, Jordan.
Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, 19328, Jordan.
Antiinflamm Antiallergy Agents Med Chem. 2025;24(2):127-138. doi: 10.2174/0118715230343474241009112335.
This study aimed at the synthesis of several spiro[benzofuran-3,3'-pyrroles] derivatives by a three-component reaction conducted by mixing DMAD, -bridgehead heterocycles, and benzofuran-2,3-diones in dichloromethane at room temperature for 24 h. Moreover, evaluation of their cytotoxicity affinities against FMS-like tyrosine kinase 3 was carried out.
The objective of this study was to use a one-pot, three-component reaction to synthesize a novel set of spiro[benzofuran-3,3'-pyrroles] derivatives.
A novel set of spiro[benzofuran-3,3'-pyrroles] ((11-13)a-e) was synthesized by a one-pot three-component reaction involving dimethyl acetylenedicarboxylate, -bridgehead heterocycles and benzofuran-2,3-diones in dichloromethane at room temperature for 24 h. The compounds were analyzed using NMR H, C, 2D-NMR (COSY, HMQC, HMBC), and HRMS. Docking simulations were conducted to elucidate the anticancer activity of synthesized compounds on FLT3 protein, with Gilteritinib as a reference for comparison.
This study demonstrated the successful design, synthesis, and biological evaluation of spiro[benzofuran-3,3'-pyrroles] derivatives as FLT3 inhibitors for AML treatment. The synthesized compounds demonstrated promising binding affinities and significant inhibitory activity against FLT3 kinase. The inhibitors (11a, 11b, 11c, 12d, and 12e) exhibited excellent selectivity profiles against FLT3. Particularly, compound 12e showed strong binding affinity and potent inhibitory activity (IC = 2.5 μM).
Fifteen new synthetic spiro[benzofuran-3,3'-pyrroles] were prepared, characterized, and evaluated for cytotoxicity affinities against FMS-like tyrosine kinase 3. Compound 12e showed strong binding affinity and potent inhibitory activity (IC = 2.5 μM), making it a promising candidate for further development as a therapeutic option for AML treatment. These findings lay the groundwork for further optimization and development of spiro[benzofuran-3,3'-pyrroles] derivatives as potential therapeutics for AML treatment. Further studies are needed to explore their efficacy and safety profiles in preclinical and clinical settings.
本研究旨在通过在室温下于二氯甲烷中将富马酸二甲酯（DMAD）、桥头杂环和苯并呋喃 - 2,3 - 二酮混合进行三组分反应，合成几种螺[苯并呋喃 - 3,3'-吡咯]衍生物。此外，还对它们针对FMS样酪氨酸激酶3的细胞毒性亲和力进行了评估。
本研究的目的是使用一锅法三组分反应合成一组新型的螺[苯并呋喃 - 3,3'-吡咯]衍生物。
通过在室温下于二氯甲烷中进行一锅法三组分反应，使乙酰基二羧酸二甲酯、桥头杂环和苯并呋喃 - 2,3 - 二酮反应24小时，合成了一组新型的螺[苯并呋喃 - 3,3'-吡咯]（（11 - 13）a - e）。使用核磁共振氢谱、碳谱、二维核磁共振谱（COSY、HMQC、HMBC）和高分辨质谱对化合物进行分析。进行对接模拟以阐明合成化合物对FLT3蛋白的抗癌活性，并以吉列替尼作为比较参考。
本研究证明了螺[苯并呋喃 - 3,3'-吡咯]衍生物作为用于急性髓系白血病（AML）治疗的FLT3抑制剂的成功设计、合成和生物学评估。合成的化合物表现出有前景的结合亲和力和对FLT3激酶的显著抑制活性。抑制剂（11a、11b、11c、12d和12e）对FLT3表现出优异的选择性。特别地，化合物12e显示出强结合亲和力和强效抑制活性（IC = 2.5 μM）。
制备了15种新的合成螺[苯并呋喃 - 3,3'-吡咯]，对其进行了表征，并评估了它们对FMS样酪氨酸激酶3的细胞毒性亲和力。化合物12e显示出强结合亲和力和强效抑制活性（IC = 2.5 μM），使其成为作为AML治疗的治疗选择进一步开发的有前景的候选物。这些发现为进一步优化和开发螺[苯并呋喃 - 3,3'-吡咯]衍生物作为AML治疗的潜在疗法奠定了基础。需要进一步研究以探索它们在临床前和临床环境中的疗效和安全性。
