title: Platelet protective efficacy of 3,4,5 trisubstituted isoxazole analogue by inhibiting ROS-mediated apoptosis and platelet aggregation.
abstract: Thrombocytopenia is a major hematological concern in oxidative stress-associated pathologies and chronic clinical disorders, where premature platelet destruction severely affects the normal functioning of thrombosis and hemostasis. In addition, frequent exposure of platelets to chemical entities and therapeutic drugs immensely contributes in the development of thrombocytopenia leading to huge platelet loss, which might be fatal sometimes. Till date, there are only few platelet protective molecules known to combat thrombocytopenia. Hence, small molecule therapeutics are extremely in need to relieve the burden on limited treatment strategies of thrombocytopenia. In this study, we have synthesized a series of novel 3,4,5 trisubstituted isoxazole derivatives, among which compound 4a [4-methoxy-N'-(5-methyl-3-phenylisoxazole-4-carbonyl) benzenesulfonohydrazide] was found to significantly ameliorate the oxidative stress-induced platelet apoptosis by restoring various apoptotic markers such as ROS content, cytosolic Ca(2+) levels, eIF2-α phosphorylation, mitochondrial membrane depolarization, cytochrome c release, caspase activation, PS externalization, and cytotoxicity markers. Additionally, compound 4a dose dependently inhibits collagen-induced platelet aggregation. Hence, compound 4a can be considered as a prospective molecule in the treatment regime of platelet activation and apoptosis and other clinical conditions of thrombocytopenia. Further studies might ensure the use of compound 4a as a supplementary therapeutic agent to treat, thrombosis and CVD-associated complications. Over all, the study reveals a platelet protective efficacy of novel isoxazole derivative 4a with a potential to combat oxidative stress-induced platelet apoptosis.
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysuru, Karnataka, 570006, India.|Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysuru, 570 006, India.
authors.forename: Swamy
authors.initials: S
authors.lastname: Jagadish
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysuru, Karnataka, 570006, India.
authors.forename: Narasimhamurthy
authors.initials: N
authors.lastname: Rajeev
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysuru, 570 006, India.
authors.forename: Somanathapura K
authors.initials: SK
authors.lastname: NaveenKumar
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysuru, Karnataka, 570006, India.|Department of Chemistry Regional Institute of Education, Manasagangotri, Mysuru, 570 006, India.
authors.forename: Kothanahally S
authors.initials: KS
authors.lastname: Sharath Kumar
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysuru, 570 006, India.
authors.forename: Manoj
authors.initials: M
authors.lastname: Paul
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysuru, Karnataka, 570006, India.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Hegde
authors.affiliation: Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Bengaluru, 560 056, India.
authors.lastname: Basappa
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysuru, Karnataka, 570006, India.
authors.forename: Marilinganadoddi P
authors.initials: MP
authors.lastname: Sadashiva
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysuru, 570 006, India. ksgbaboo@gmail.com.|Department of Studies and Research in Biochemistry, Tumkur University, Tumkur, Karnataka, 572 103, India. ksgbaboo@gmail.com.
authors.forename: Kesturu S
authors.initials: KS
authors.lastname: Girish
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysuru, Karnataka, 570006, India. rangappaks@gmail.com.
authors.forename: Kanchugarakoppal S
authors.initials: KS
authors.lastname: Rangappa
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000187:drug effects; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors
chemical_list: D007555:Isoxazoles; D017382:Reactive Oxygen Species; D005954:Glucosephosphate Dehydrogenase; D005723:gamma-Glutamyltransferase; D020169:Caspases; D005978:Glutathione; D002118:Calcium; D019803:Glutathione Disulfide
keywords: Caspases; Isoxazoles derivative; Oxidative stress; Platelet aggregation; Platelet apoptosis