Non‐peptide‐based new class of platelet aggregation inhibitors: Design, synthesis, bioevaluation, SAR, and in silico studies

Abstract

A series of 2-oxo-2-phenylethylidene linked 2-oxo-benzo[1,4]oxazine analogues 17a-x and 18a-o, incorporated with a variety of electron-withdrawing as well as electron-donating groups at ring A and ring C, were synthesized under greener conditions in excellent yields (up to 98%). These analogues 17a-x and 18a-o were evaluated for their arachidonic acid (AA)-induced platelet aggregation inhibitory activities in comparison with the standard reference aspirin (IC = 21.34 ± 1.09 µg/mL). Among all the screened compounds, eight analogues, 17i, 17x, 18f, 18g, 18h, 18i, 18l, and 18o, were identified as promising platelet aggregation inhibitors as compared to aspirin. In addition, cytotoxic studies in 3T fibroblast cell lines by MTT assay of the promising compounds (17i, 17x, 18f-18i, 18l, and 18o) were also performed and the compounds were found to be non-toxic in nature. Furthermore, the results on the AA-induced platelet aggregation inhibitory activities of these compounds (17i, 17x, 18f-18i, 18l, and 18o) were validated via in silico molecular docking simulation studies. To the best of our knowledge, this is the first report of the identification of non-peptide-based functionalized 2-oxo-benzo[1,4]oxazines as platelet aggregation inhibitors.

Synthesis, Bioevaluation, Structure-Activity Relationship and Docking Studies of Natural Product Inspired (Z)-3-benzylideneisobenzofuran-1(3H)-ones as Highly Potent antioxidants and Antiplatelet agents

“…Similarly, to study the binding modes of the five active molecules (28k, 28s, 28f, 28l and 28j) in the cyclooxygenase-1 (COX-1) enzyme against platelet aggregation inhibitory activity, we performed molecular docking study with aspirin (reference compound) on COX-1 domain antiplatelet target (PDB ID: 2OYE) using Surflex-Dock using the reported procedure (see details in supporting information) 37 .…”

Discovery of Aporphine Analogues as Potential Antiplatelet and Antioxidant Agents: Design, Synthesis, Structure–Activity Relationships, Biological Evaluations, and in silico Molecular Docking Studies

“…In our endeavor to develop non‐peptide‐based antiplatelet agents; we recently reported that the inhibition of cyclooxygenase‐1 (COX‐1) was the key target in the development of novel platelet aggregation inhibitors . As acetylsalicylic acid, tirofiban, sulfinpyrazone, and clopidogrel are well‐established potent platelet‐aggregation inhibitors that contain amide/sulfonamide moieties and as natural/semisynthetic aporphine analogues 3 – 7 were reported to show promising antioxidant activities, we envisaged that aporphines having these scaffolds would also show potent activities.…”

“…The molecular docking studies were performed by using SYBYL‐X 2.1.1 software (Tripos International) . The crystal structures of the antiplatelet target (PDB ID: https://www.rcsb.org/structure/2OYE) and antioxidant target (PDB ID: https://www.rcsb.org/structure/3MNG) co‐crystallized with indomethacin (ligand ID: IM8) and dithiothreitol (ligand ID: DID), respectively, were used for the molecular docking studies.…”

Synthesis of 1,4-benzothiazinones from acylpyruvic acids or furan-2,3-diones and o-aminothiophenol

“…Because of their availability in gram-scale quantities, these compounds were thoroughly investigated for the possibility of practical use. Particularly, some enaminones I and II were found to show antioxidant [ 3 ], antimycotic [ 7 – 8 ], antimycobacterial [ 9 – 10 ], anti-Alzheimer’s disease (JNK3 inhibitors) [ 11 ], platelet aggregation inhibitory [ 12 ], antimicrobial [ 7 ] and analgesic [ 13 ] activities. Enaminones II were reported as potential Cu 2+ chemosensors [ 14 ], and their BF 2 chelates, as multicolor fluorescence complexes, some of which exhibited aggregation-induced emission (AIE) properties [ 15 ].…”