Bharti Rajesh Kumar Shyamlal, Manas Mathur, Dharmendra K. Yadav, Irina V. Mashevskaya, Mohamed El-Shazly, Na'il Saleh* and Sandeep Chaudhary*
Background: Several natural/synthetic molecules having 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 molecular framework, have been explored for their antioxidant or antiplatelet activities.
Introduction: Based on literature, a new prototype i.e., 3-phenyl-1H-isochromen-1-ones based compounds have 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 to identify new 3-phenyl-1H-isochromen-1-ones based compounds via synthesis of a series of analogues and performing in vitro antioxidant as well as AA-induced antiplatelet activities and then, identification of potent compounds by SAR and molecular docking studies.
Results: Out of all synthesized 3-phenyl-1H-isochromen-1-ones analogues, five compounds showed 7-folds to 16-folds 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 pharmaceutically privileged bioactive 3-phenyl-1H-isochromen-1-one class of heterocycles.
3-Phenyl-1H-isochromen-1-one, Sonogashira coupling, 6-endo-dig cyclization, Antioxidant, DPPH, Antiplatelet, Arachidonic acid, Structure-Activity Relationship
Laboratory of Organic and Medicinal Chemistry (OMC Lab), Department of Chemistry, Malaviya National Institute of Technology Jaipur, Jawaharlal Nehru Marg, Jaipur-302017, School of Agriculture, Suresh Gyan Vihar University, Mahal Road, Jagatpura, Jaipur-302017, Gachon Institute of Pharmaceutical Sciences and Department of Pharmacy, College of Pharmacy, Gachon University of Medicine and Science, Incheon, 21936, Department of Organic Chemistry, Faculty of Chemistry, Perm State University, Bukireva Street, Perm 614990, Department of Pharmaceutical Biology, Faculty of Pharmacy and Biotechnology, The German University in Cairo, Cairo, Department of Chemistry, College of Science, United Arab Emirates (UAE) University, P.O. Box 15551, Al Ain, Laboratory of Organic and Medicinal Chemistry (OMC Lab), Department of Chemistry, Malaviya National Institute of Technology Jaipur, Jawaharlal Nehru Marg, Jaipur-302017