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

Abstract

For the first time, a series of highly potent natural product inspired substituted (Z)-3benzylideneisobenzofuran-1(3H)-ones 28a-t, embraced with electron-withdrawing groups (EWG) and electron-donating groups (EDG) at site I and site II, were prepared and assessed for their in vitro antioxidant activities (DppH free radical scavenging assay) and arachidonic acid (AA)-induced antiplatelet activities using ascorbic acid (IC 50 = 4.57 µg/mL) and aspirin (ic 50 = 21.34 µg/mL), as standard references, respectively. In this study, compounds 28f-g, 28k-l and 28q have shown high order of in vitro antioxidant activity. Infact, 28f and 28k were found to show 10-folds and 8-folds more antioxidant activity than ascorbic acid, respectively and was found to be the most active analogues of the series. Similarly, Compounds 28c-g, 28k-l, 28o and 28q-t were recognized as highly potent antiplatelet agents (upto 6-folds) than aspirin. furthermore, in silico studies of the most active antioxidants 28f, 28k and 28l and very active antiplatelet molecules 28f, 28k, 28l and 28s were carrying out for the validation of the biological results. This is the first detailed study of the discovery of several (Z)-3-benzylideneisobenzofuran-1(3H)-ones as highly potent antioxidants and antiplatelet agents. Isobenzofuran-1(3 H)-one, commonly known as "phthalide" is found in many naturally-occurring and pharmaceuticals important molecules 1. This benzo-fused heterocyclic class of compounds are blended with several pharmacological properties such as anti-tumor 2 , anti-HIV 3 , anti-allergic 4 , antifungal 5 , antidiabetic 6 , antispasmodic 7 , anti-inflammatory 8 , pesticidal 9 , COX-2 inhibitor 10 , insecticidal 11 , anti-microbial 12 , herbicidal 13 , and anti-cancer 14 etc. Several naturally occurring as well as synthetic molecules having isobenzofuran-1(3H)-ones have also been classified as promising antioxidants 1-7 (Fig. 1) 15-18. Similarly, several natural and synthetic molecules 7-15 show promising platelet aggregation inhibitors 15 (Fig. 1). Relevant to the present study, natural product inspired isobenzofuran-1(3 H)-ones are known to be potential antioxidant (7) and antiplatelet agents (7, 12-15) 15,19-21. Earlier, Teng and his co-workers carried out extensive platelet aggregation inhibitory studies on butylidenephthalide 7 triggered by various inducers such as Arachidonic acid (AA), Adenosine diphosphate (ADP), platelet activation factor (PAF), etc. as well as the inhibition of thromboxane B2 (TXB2) formation caused by AA, collagen, ionophore A23187 and thrombin 20. In this study, 7 showed significantly higher inhibitory

Mechanistic Insight into Binding of Huperzine A with Human Serum Albumin: Computational and Spectroscopic Approaches

“…Many studies have used the MD simulation approach to investigate ligand binding with proteins [ 7 , 19 , 20 , 21 ]. All-atom MD simulations were carried out for the docked complex of HSA–HpzA and compared with those for the free state of HSA.…”

A New 7‐Azaindole Structure Analog: Molecular Docking, Synthesis and Preliminary Biological Activity in Vitro for Anticancer

“…Table 1 showed the results of molecular docking of pexidartinib and other 7‐azaindole analogs with CSF‐1R. Molecular docking scores for all compounds were positive, and higher scores indicated higher affinity of the compounds to the CSF‐1R target [34] . The results of molecular docking studies showed that the scores of all compounds except compound P2 were higher than 10.20 points of pexidartinib, and the score of compound P6 was second only to P1 , but the synthesis of compound P6 would have a higher raw material cost and very lower yield compared to compound P1 .…”

Discovering Tuberosin and Villosol as Potent and Selective Inhibitors of AKT1 for Therapeutic Targeting of Oral Squamous Cell Carcinoma

“…AMES toxicity helps to assess the probable carcinogenic effect of a compound through the use of the bacteria S. typhi . It is an effective and reliable method to estimate the genotoxicity of the compound and its propensity to reverse the mutations at the selected target in the bacterial strain [ 54 , 55 , 56 ]. We selected GI absorption, BBB permeation, CYP2D inhibitor, OCT2 substrate, AMES, and hepatotoxicity to finalize the compounds that showed the most promising results for effective molecules.…”