发现受天然产物启发的 3-Phenyl-1H-isochromen-1-ones 作为高效抗氧化剂和抗血小板剂：设计、合成、生物学评估、SAR 和计算机研究。,Current pharmaceutical design

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发现受天然产物启发的 3-Phenyl-1H-isochromen-1-ones 作为高效抗氧化剂和抗血小板剂：设计、合成、生物学评估、SAR 和计算机研究。
Current pharmaceutical design Pub Date : 2022-01-01 , DOI: 10.2174/1381612827666211116102031
Bharti R K Shyamlal ₁ , Manas Mathur ₂ , Dharmendra K Yadav ₃ , Irina V Mashevskaya ₄ , Mohamed El-Shazly _{5,

6} , Na'il Saleh ₇ , Sandeep Chaudhary _{1,

8}

Affiliation

Laboratory of Organic and Medicinal Chemistry (OMC Lab), Department of Chemistry, Malaviya National Institute of Technology Jaipur, Jawaharlal Nehru Marg, Jaipur 302017, India.
School of Agriculture, Suresh Gyan Vihar University, Mahal Road, Jagatpura, Jaipur 302017, India.
Gachon Institute of Pharmaceutical Sciences and Department of Pharmacy, College of Pharmacy, Gachon University of Medicine and Science, Incheon, 21936, South Korea.
Department of Organic Chemistry, Faculty of Chemistry, Perm State University, Bukireva Street, Perm 614990, Russian Federation.
Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, Organization of African, Unity Street, Cairo 11566, Egypt.
Department of Pharmaceutical Biology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.
Department of Chemistry, College of Science, United Arab Emirates (UAE) University, P.O. Box 15551, Al Ain, United Arab Emirates.
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Raebareli (NIPER-R), New Transit Campus, Sarojini Nagar, Lucknow UP 226002, India.

背景技术据报道，具有类似于1H-异色烯-1-酮的结构的几种天然/合成分子显示出有希望的抗氧化剂和血小板聚集抑制活性。异香豆素 (1H-2-benzopyran-1-one) 骨架，无论是整体还是作为分子框架的一部分，已被探索其抗氧化或抗血小板活性。引言根据文献，一种新的原型，即基于 3-苯基-1H-isochromen-1-ones 的化合物，已被合理化为具有抗氧化和抗血小板活性。因此，没有关于其通过环氧合酶-1 (COX-1) 酶或花生四烯酸 (AA) 诱导的血小板聚集抑制的报道。这促使我们研究 3-phenyl-1H-isochromen-1-ones 对抗氧化剂和抗血小板剂的影响。方法这项工作的目标是通过合成一系列类似物来鉴定新的基于 3-苯基-1H-isochromen-1-ones 的化合物，然后进行体外抗氧化以及 AA 诱导的抗血小板活性。然后，通过 SAR 和分子对接研究鉴定有效化合物。结果在所有合成的 3-苯基-1H-isochromen-1-ones 类似物中，有五种化合物的抗氧化活性是抗坏血酸的 7 倍至 16 倍。总之，十个 3-苯基-1H-isochromen-1-one 类似物在 2,2-diphenyl-1-picrylhydrazyl (DPPH) 测定中显示出抗氧化活性。几乎所有的 3-phenyl-1H-isochromen-1-one 类似物都表现出强效的 AA 诱导的抗血小板活性；与阿司匹林相比，它们中很少有人表现出高出 7 倍的活性。更远，计算机分析验证了湿法结果。结论我们公开了第一个详细研究，将 3-苯基-1H-isochromen-1-one 类似物鉴定为高效抗氧化剂和抗血小板剂。该文章描述了具有药学特权的生物活性 3-phenyl-1H-isochromen-1-one 一类杂环的支架设计、合成、生物评价、构效关系和计算机研究。

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Discovery of Natural Product Inspired 3-Phenyl-1H-isochromen-1-ones as Highly Potent Antioxidant and Antiplatelet Agents: Design, Synthesis, Biological Evaluation, SAR and In Silico Studies.

BACKGROUND Several natural/synthetic molecules having a structure similar to 1H-isochromen- 1-ones have been reported to display promising antioxidants and platelet aggregation inhibitory activity. Isocoumarin (1H-2-benzopyran-1-one) skeleton, either whole or as a part of the molecular framework, has been explored for its antioxidant or antiplatelet activities. INTRODUCTION Based on the literature, a new prototype, i.e., 3-phenyl-1H-isochromen-1-ones based compounds, has been rationalized to possess both antioxidant as well as antiplatelet activities. Consequently, no reports are available regarding its inhibition either by cyclooxygenase-1 (COX-1) enzyme or by arachidonic acid (AA)-induced platelet aggregation. This prompted us to investigate 3-phenyl-1H-isochromen-1-ones towards antioxidant and antiplatelet agents. METHODS The goal of this work was to identify new 3-phenyl-1H-isochromen-1-ones based compounds via synthesis of a series of analogues, followed by performing in vitro antioxidant as well as AA-induced antiplatelet activities. Then, identification of potent compounds by SAR and molecular docking studies was carried out. RESULTS Out of all synthesized 3-phenyl-1H-isochromen-1-ones analogues, five compounds showed 7-fold to 16-fold more highly potent antioxidant activities than ascorbic acid. Altogether, ten 3-phenyl-1H-isochromen- 1-one analogues displayed antioxidant activities in 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. Almost all the 3-phenyl-1H-isochromen-1-one analogues exhibited potent AA-induced antiplatelet activity; few of them displayed 7-folds more activity as compared to aspirin. Further, in silico analysis validated the wet results. CONCLUSION We disclose the first detailed study for the identification of 3-phenyl-1H-isochromen-1-one analogues as highly potent antioxidant as well as antiplatelet agents. The article describes the scaffold designing, synthesis, bioevaluation, structure-activity relationship, and in silico studies of a pharmaceutically privileged bioactive 3-phenyl-1H-isochromen-1-one class of heterocycles.

更新日期：2021-11-15

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