Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, 560107, Karnataka, India.
Department of Pharmaceutical Chemistry, National University of Science and Technology, PO 620, PC 130, Azaiba Bousher, Muscat, Sultanate of Oman.
Eur J Med Chem. 2023 Oct 5;258:115609. doi: 10.1016/j.ejmech.2023.115609. Epub 2023 Jun 30.
Leishmaniasis is a parasitic disease and categorised as a neglected tropical disease (NTD). Each year, between 70,0000 and 1 million new cases are believed to occur. There are approximately 90 sandfly species which can spread the Leishmania parasites (over 20 species) causing 20,000 to 30,000 death per year. Currently, leishmaniasis has no specific therapeutic treatment available. The prescribed drugs with several drawbacks including high cost, challenging administration, toxicity, and drug resistance led to search for the alternative treatment with less toxicity and selectivity. Introducing the molecular features like that of phytoconstituents for the search of compounds with less toxicity is another promising approach. The current review classifies the synthetic compounds according to the core rings present in the natural phytochemicals for the development of antileishmanial agents (2020-2022). Considering the toxicity and limitations of synthetic analogues, natural compounds are at the higher notch in terms of effectiveness and safety. Synthesized compounds of chalcones (Compound 8; IC: 0.03 μM, 4.7 folds more potent than Amphotericin B; IC: 0.14 μM), pyrimidine (compound 56; against L. tropica; 0.04 μM and L. infantum; 0.042 μM as compared to glucantime: L. tropica; 8.17 μM and L. infantum; 8.42 μM), quinazoline and (compound 72; 0.021 μM, 150 times more potent than miltefosine). The targeted delivery against DHFR have been demonstrated by one of the pyrimidine compounds 62 with an IC value of 0.10 μM against L. major as compared to the standard trimethoprim (IC: 20 μM). The review covers the medicinal importance of antileishmanial agents from synthetic and natural sources such as chalcone, pyrazole, coumarins, steroids, and alkaloidal-containing drugs (indole, quinolines, pyridine, pyrimidine, carbolines, pyrrole, aurones, and quinazolines). The efforts of introducing the core rings present in the natural phytoconstituents as antileishmanial in the synthetic compounds are discussed with their structural activity relationship. The perspective will support the medicinal chemists in refining and directing the development of novel molecules phytochemicals-based antileishmanial agents.
利什曼病是一种寄生虫病，被归类为被忽视的热带病（NTD）。据信，每年会出现 7 万至 100 万例新病例。大约有 90 种沙蝇物种可以传播利什曼原虫寄生虫（超过 20 种），每年导致 2 万至 3 万人死亡。目前，利什曼病没有特定的治疗方法。现有的治疗药物存在一些缺点，包括成本高、给药困难、毒性和耐药性，这导致人们寻找毒性和选择性较低的替代治疗方法。引入植物成分的分子特征，寻找毒性较低的化合物是另一种有前途的方法。本综述根据天然植物化学物质中的核心环对合成化合物进行分类，以开发抗利什曼病药物（2020-2022 年）。考虑到合成类似物的毒性和局限性，天然化合物在有效性和安全性方面处于更高水平。查耳酮（化合物 8；IC：0.03 μM，比两性霉素 B 强 4.7 倍；IC：0.14 μM）、嘧啶（化合物 56；对抗 L. tropica；0.04 μM 和 L. infantum；0.042 μM，与葡萄糖胺相比：L. tropica；8.17 μM 和 L. infantum；8.42 μM）、喹唑啉和（化合物 72；0.021 μM，比米替福新强 150 倍）的合成化合物。其中一种嘧啶化合物 62 对 DHFR 的靶向递送已得到证明，其对 L. major 的 IC 值为 0.10 μM，而标准药物三甲氧苄氨嘧啶（IC：20 μM）。该综述涵盖了来自合成和天然来源（如查耳酮、吡唑、香豆素、甾体和含生物碱药物（吲哚、喹啉、吡啶、嘧啶、咔啉、吡咯、奥罗内斯和喹唑啉）的抗利什曼病药物的药用重要性。本文讨论了在合成化合物中引入天然植物成分中的核心环作为抗利什曼病的方法及其结构活性关系。这一观点将支持药物化学家改进和指导基于植物化学物质的新型抗利什曼病药物的开发。
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