Research Articles

2018  |  Vol: 4(4)  |  Issue: 4 (July- August)  |
Synthesis, docking, characterization and anti-inflammatory activity of novel phosphodiesterase-4 inhibitors

Amit Girdhar*1, 2, Shikha Raheja1, 2, Deepti Pandita3, Vandana Kharb4, Viney Lather5

 1IKG Punjab Technical University, Jalandhar, Punjab, India

2Jan Nayak Ch. Devi Lal Memorial College of Pharmacy, Sirsa, Haryana, India

3Amity Institute of Molecular Medicine & Stem Cell Research, Amity University, Noida, Uttar Pradesh, India 

4Sachdeva College of Pharmacy, Mohali, Punjab, India

5Amity Institute of Pharmacy, Amity University, Noida, Uttar Pradesh, India

*Address for Corresponding Author

Amit Girdhar

Jan Nayak Ch. Devi Lal Memorial College of Pharmacy, Sirsa-125055 Haryana, India


Objective: Phosphodiesterase-4 (PDE4) is the key enzyme involved in the hydrolysis of cyclic adenosine monophosphate to adenosine monophospahte in inflammatory and immunomodulatory cells, is the important target for treatment of various inflammatory conditions such as asthma, chronic obstructive pulmonary disease, rhinitis, dermatitis, multiple sclerosis, and rheumatoid arthritis. The objective of present study was to synthesize and evaluate various PDE4 inhibitors as potential anti-inflammatory agents. Materials and Methods: Coumarin belongs to a group of benzopyrones, and consists of a benzene ring joined to a pyrone nucleus. In the present study, the substituted coumarins were synthesized by reaction of substituted phenols and ethyl acetoacetate in the presence of concentrated sulphuric acid using substitution with aromatic & aliphatic groups. 7-hydroxy-4-methyl coumarin was reacted in the presence of sodium hydroxide with commercially available aliphatic & aromatic acids and halides to obtain the proposed esters & ketones. The compounds were evaluated by docking study in the binding site of PDE4 protein using AutoDock Vina and their dock scores were calculated. The newly synthesized compounds were further screened for the anti-inflammatory activity using carrageenan induced rat paw edema method. Results: Based on the docking studies, the compounds with good binding interactions with PDE4B enzyme were selected for evaluation of anti-inflammatory activity. The anti-inflammatory activity was measured by calculating the volume displaced and percent inhibition of edema and was further analyzed by two-way ANOVA. The value of anti-inflammatory activity indicated that some compounds exhibited good anti-inflammatory activities. Aromatic compound displayed appreciable anti-inflammatory activity compared to the standard drug (Rolipram). It was found that substitution with electronegative or aromatic groups enhanced the anti-inflammatory activity while substitution with aliphatic groups showed poor binding affinity for the enzyme as well as poor anti-inflammatory activity. Conclusion: Aromatic substituent’s (Benzene, Phenol, Chlorobenzene & Benzoyl chloride) showed significant binding affinity in docking studies and also displayed good anti-inflammatory activities when compared to aliphatic groups (Propionyl chloride, Acetyl chloride, n-propyl, Carboxamide).

Keywords: PDE4B, inflammation, coumarin, phosphodiesterase, docking

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