New Indazole Derivatives as Potential Scaffolds for the Development of Anticancer, Antiviral, and Anti-tuberculosis Chemotherapeutic Compounds.

IF 3.5 4区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current medicinal chemistry Pub Date : 2025-09-05 DOI:10.2174/0109298673389070250822065247

Khandazhinskaya Anastasia, Kondrashova Evgenya, Sokhraneva Vera, Novikova Olga, Velikorodnaya Yulia, Gorshenin Andrey, Andreevskaya Sofia, Smirnova Tatyana, Moroz Maxim, Kirillov Ilya, Fedyakina Irina, Chizhov Alexandr, Kochetkov Sergey, Matyugina Elena

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引用次数: 0

Abstract

Introduction: Chemotherapy remains essential despite advances in immunotherapy, radiotherapy, and biological therapy. However, the wide range of chemical drugs is limited by a narrow therapeutic index, low selectivity, and the development of resistance. In this regard, new high-efficiency drugs are in extremely high demand. The indazole moiety, a scaffold found in many biologically active compounds, was selected for use in new drug design.

Methods: Six new indazole derivatives were synthesized via Suzuki-Miyaura coupling starting from bromoindazole. Their antiviral (against influenza A and SARS-CoV-2), antibacterial (against M. tuberculosis), and antiproliferative activities (against neuroblastoma, glioma, leukemia cell lines) were evaluated in vitro. Acute toxicity was assessed in mice of both sexes via single intragastric administration, with toxicometric parameters and pathomorphological changes studied.

Results: 6-(1H-pyrazol-4-yl)-1H-indazole (8) suppressed the reproduction of the influenza virus at non-toxic doses to the MDCK cells and showed cytotoxicity against cancer cell lines, with an IC50 between 4 and 14 μM. However, it exhibited significant acute toxicity in mice (LD50 40 mg/kg), causing systemic organ damage.

Discussion: Derivative 8 demonstrated promising antiviral and antiproliferative activities but exhibited considerable acute toxicity in vivo. The antiviral efficacy, although lower than oseltamivir, is meaningful and justifies further optimization and investigation. Its antibacterial activity against M. tuberculosis adds to its potential as a multifunctional agent.

Conclusion: While derivative 8 has shown potential as an antiviral and anticancer agent, its high toxicity highlights the need for further studies to define a safe and effective therapeutic window. Overall, the indazole scaffold remains a valuable platform for the development of new therapeutic compounds.

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新的吲哚唑衍生物作为抗癌、抗病毒和抗结核化疗化合物开发的潜在支架。

导言：尽管免疫治疗、放射治疗和生物治疗取得了进展，化疗仍然是必不可少的。然而，广泛的化学药物受到治疗指数窄、选择性低和耐药性发展的限制。在这方面，对新型高效药物的需求非常大。吲哚唑部分是许多生物活性化合物中发现的支架，被选择用于新药设计。方法：以溴茚达唑为起始原料，经Suzuki-Miyaura偶联法合成6个新的茚达唑衍生物。在体外评估了它们的抗病毒（抗甲型流感和SARS-CoV-2）、抗菌（抗结核分枝杆菌）和抗增殖活性（抗神经母细胞瘤、胶质瘤、白血病细胞系）。通过单次灌胃对雌雄小鼠的急性毒性进行了评估，并研究了毒性计量参数和病理形态学变化。结果：6-(1H-pyrazol-4-yl)- 1h -吲哚唑(8)对MDCK细胞无毒剂量抑制流感病毒的繁殖，对癌细胞显示细胞毒性，IC50在4 ~ 14 μM之间。然而，它对小鼠表现出明显的急性毒性（LD50 40 mg/kg），引起全身器官损伤。讨论：衍生物8显示出有希望的抗病毒和抗增殖活性，但在体内表现出相当大的急性毒性。抗病毒效果虽然低于奥司他韦，但有意义，值得进一步优化和研究。它对结核分枝杆菌的抗菌活性增加了它作为多功能药物的潜力。结论：虽然衍生物8显示出抗病毒和抗癌药物的潜力，但其高毒性突出表明需要进一步研究以确定安全有效的治疗窗口。总的来说，茚唑支架仍然是开发新的治疗性化合物的一个有价值的平台。

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来源期刊

Current medicinal chemistry 医学-生化与分子生物学

CiteScore

8.60

自引率

2.40%

发文量

468

审稿时长

3 months

期刊介绍： Aims & Scope Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews and guest edited thematic issues written by leaders in the field covering a range of the current topics in medicinal chemistry. The journal also publishes reviews on recent patents. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.