Rafique Iqra, Maqbool Tahir, Rutjes Floris P J T, Irfan Ali, Jardan Yousef A Bin
Department of Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan.
Synthetic Organic Chemistry (SOC) Group, Radboud University, 6525 AJ Nijmegen, The Netherlands.
Pharmaceuticals (Basel). 2024 Oct 4;17(10):1326. doi: 10.3390/ph17101326.
Pyrazolo[3,4-]pyridine scaffolds have been heavily exploited in the development of nitrogen-containing heterocycles with numerous therapeutic applications in the field of medicinal and pharmaceutical chemistry. The present work describes the synthesis of eighteen biaryl pyrazolo[3,4-]pyridine ester (-) and hydrazide (-) derivatives via the Suzuki cross-coupling reaction. These derivatives were subsequently screened for their therapeutic potential to inhibit the diabetic α-amylase enzyme, which is a key facet of the development of anti-diabetic agents. Initially, the ethyl 4-(4-bromophenyl)-3-methyl-1-phenyl-1-pyrazolo[3,4-]pyridine-6-carboxylate was synthesized through a modified Doebner method under solvent-free conditions, providing an intermediate for further derivatization with a 60% yield. This intermediate was subjected to Suzuki cross-coupling, reacting with electronically diverse aryl boronic acids to obtain the corresponding pyrazolo[3,4-]pyridine ester derivatives (-). Following this, the biaryl ester derivatives (-) were converted into hydrazide derivatives (-) through a straightforward reaction with hydrazine monohydrate and were characterized using H-NMR, C-NMR, and LC-MS spectroscopic techniques. These derivatives were screened for their α-amylase inhibitory chemotherapeutic efficacy, and most of the biaryl ester and hydrazide derivatives demonstrated promising amylase inhibition. In the (-) series, the compounds , , , and exhibited excellent inhibition, with almost similar IC values of 5.14, 5.15, 5.56, and 5.20 μM, respectively. Similarly, in the series (-), the derivatives , , , , , , and displayed excellent anti-diabetic activities of 5.21, 5.18, 5.17, 5.12, 5.10, 5.16, and 5.19 μM, respectively. These in vitro results were compared with the reference drug acarbose (IC = 200.1 ± 0.15 μM), demonstrating better anti-diabetic inhibitory activity in comparison to the reference drug. The in silico molecular docking study results were consistent with the experimental biological findings, thereby supporting the in vitro pharmaceutical efficacy of the synthesized derivatives.
吡唑并[3,4 -]吡啶骨架在含氮杂环化合物的开发中得到了广泛应用，在药物化学和制药化学领域具有众多治疗应用。本工作描述了通过铃木交叉偶联反应合成十八种联芳基吡唑并[3,4 -]吡啶酯（-）和酰肼（-）衍生物。随后对这些衍生物抑制糖尿病α -淀粉酶的治疗潜力进行了筛选，这是抗糖尿病药物开发的一个关键方面。最初，通过改良的多布纳方法在无溶剂条件下合成了4 -（4 -溴苯基）-3 -甲基-1 -苯基-1 -吡唑并[3,4 -]吡啶-6 -羧酸乙酯，产率为60%，为进一步衍生化提供了中间体。该中间体进行铃木交叉偶联，与电子性质多样的芳基硼酸反应，得到相应的吡唑并[3,4 -]吡啶酯衍生物（-）。随后，通过与水合肼直接反应将联芳基酯衍生物（-）转化为酰肼衍生物（-），并使用H - NMR、C - NMR和LC - MS光谱技术进行表征。对这些衍生物的α -淀粉酶抑制化疗疗效进行了筛选，大多数联芳基酯和酰肼衍生物表现出有前景的淀粉酶抑制作用。在（-）系列中，化合物 、 、 和 表现出优异的抑制作用，IC值分别为5.14、5.15、5.56和5.20 μM，几乎相似。同样，在（-）系列中，衍生物 、 、 、 、 、 和 分别表现出5.21、5.18、5.17、5.12、5.10、5.16和5.19 μM的优异抗糖尿病活性。将这些体外结果与参考药物阿卡波糖（IC = 200.1 ± 0.15 μM）进行比较，表明与参考药物相比具有更好的抗糖尿病抑制活性。计算机辅助分子对接研究结果与实验生物学发现一致，从而支持了合成衍生物的体外药物疗效。
