Design, Synthesis and Dual-Stage Antimalarial Evaluation of β-Carboline−Metronidazole Hybrids: Structure−Activity Relationship and Molecular Docking Correlations

IF 7.3 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2026-10-17 DOI:10.1021/acs.jmedchem.6c02225

Alka Raj Pandey,Suriya Pratap Singh,Rohini Nandi,Shabeer Ali H,Rama Krishna Rayiti,Shovan Ghosh,Gokul Krishnan Nagendran,Sathish Kumar Mudedla,Rabi Sankar Bhatta,Satish Mishra,Koneni V. Sashidhara

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引用次数: 0

Abstract

Abstract Malaria remains a major global health challenge, exacerbated by emerging drug-resistant Plasmodium strains. Herein, we report the design, synthesis, and dual-stage antimalarial evaluation of β-carboline−metronidazole hybrids. The synthesized hybrids, linked through ester and amide bonds, were evaluated in vitro against chloroquine-sensitive (Pf3D7) and resistant (PfK1) Plasmodium falciparum strains, as well as liver-stage Plasmodium berghei. Several compounds exhibited potent blood-stage inhibition (IC50 as low as 0.05 ± 0.02 μM), remarkable liver-stage activity surpassing primaquine, and favourable selectivity indices (>100). Notably, compound 8kkk achieved up to 95% suppression of parasitemia in P. berghei ANKA-infected Swiss mice at 50 mg/kg for four days. Pharmacokinetic studies revealed a distinct absorption and disposition profile. SAR analysis highlighted the importance of electronic nature and substitution pattern of the β-carboline scaffold, while molecular docking and fluorimetry analysis indicated strong binding to PfLDH. These findings suggest β-carboline−metronidazole hybrids as promising candidates for further development as dual-stage antimalarial agents.

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β-卡波林-甲硝唑杂合体的设计、合成及双阶段抗疟评价：构效关系和分子对接关系

疟疾仍然是一个主要的全球健康挑战，新出现的耐药疟原虫菌株加剧了这一挑战。在此，我们报道了β-卡波林-甲硝唑杂交体的设计、合成和双阶段抗疟评价。合成的杂种通过酯和酰胺键连接，在体外对氯喹敏感（Pf3D7）和耐药（PfK1）恶性疟原虫菌株以及肝期伯氏疟原虫进行了抗性评估。一些化合物表现出有效的血期抑制作用（IC50低至0.05±0.02 μM），显著的肝期活性超过伯氨喹，以及良好的选择性指数（>100）。值得注意的是，化合物8kkk在50 mg/kg的剂量下，对伯氏疟原虫感染的瑞士小鼠的寄生虫血症抑制率高达95%，持续4天。药代动力学研究揭示了其独特的吸收和处置特征。SAR分析强调了β-碳碱支架的电子性质和取代模式的重要性，而分子对接和荧光分析表明其与PfLDH有很强的结合。这些发现表明，β-卡波林-甲硝唑杂交体作为双阶段抗疟药有进一步开发的前景。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.