AUTHOR=Sharma Vashundhra , Jaiswal Pradeep K. , Saran Mukesh , Yadav Dharmendra Kumar , Saloni  , Mathur Manas , Swami Ajit K. , Misra Sanjeev , Kim Mi-hyun , Chaudhary Sandeep 

TITLE=Discovery of C-3 Tethered 2-oxo-benzo[1,4]oxazines as Potent Antioxidants: Bio-Inspired Based Design, Synthesis, Biological Evaluation, Cytotoxic, and in Silico Molecular Docking Studies

JOURNAL=Frontiers in Chemistry

VOLUME=6

YEAR=2018

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2018.00056

DOI=10.3389/fchem.2018.00056

ISSN=2296-2646

ABSTRACT=<p>The discovery of C-3 tethered 2-oxo-benzo[1,4]oxazines as potent antioxidants is disclosed. All the analogs <bold>20a-20ab</bold> have been synthesized via “on water” ultrasound-assisted irradiation conditions in excellent yields (upto 98%). All the compounds have been evaluated for their <italic>in vitro</italic> antioxidant activities using DPPH free radical scavenging assay as well as FRAP assay. The result showed promising antioxidant activities having IC<sub>50</sub> values in the range of 4.74 ± 0.08 to 92.20 ± 1.54 μg/mL taking ascorbic acid (IC<sub>50</sub> = 4.57 μg/mL) as standard reference. In this study, compounds <bold>20b</bold> and <bold>20t</bold>, the most active compound of the series, showed IC<sub>50</sub> values of 6.89 ± 0.07 μg/mL and 4.74 ± 0.08 μg/mL, respectively in comparison with ascorbic acid. In addition, the detailed SAR study shows that electron-withdrawing group increases antioxidant activity and vice versa. Furthermore, in the FRAP assay, eight compounds (<bold>20c</bold>, <bold>20j</bold>, <bold>20m</bold>, <bold>20n</bold>, <bold>20r</bold>, <bold>20u</bold>, <bold>20z</bold>, and <bold>20aa</bold>) were found more potent than standard reference BHT (C<sub>0.5FRAP</sub> = 546.0 ± 13.6 μM). The preliminary cytotoxic study reveals the non-toxic nature of active compounds <bold>20b</bold> and <bold>20t</bold> in non-cancerous 3T<sub>3</sub> fibroblast cell lines in MTT assay up to 250 μg/mL concentration. The results were validated <italic>via</italic> carrying out <italic>in silico</italic> molecular docking studies of promising compounds <bold>20a</bold>, <bold>20b</bold>, and <bold>20t</bold> in comparison with standard reference. To the best of our knowledge, this is the first detailed study of C-3 tethered 2-oxo-benzo[1,4]oxazines as potential antioxidant agents.</p>