Insights of Novel Anti-Inflammatory Drugs Targeting Phosphodiesterase and Their Characterization: An In-Silico and In-Vitro Approach

Inflammation is a bodily response to injury, infection or destruction characterized by heat, redness, pain, swelling and disturbed physiological functions. Inflammation is a normal protective response to tissue injury caused by physical trauma, noxious chemical or microbial agents. It is triggered by the release of chemical mediators from injured tissues and migrating cells. The present study was focused to evaluate the possible in-vitro anti-inflammatory effect of synthesized compounds against the denaturation of protein along with in-silico approach. Many of the existing drugs, for example, Tetomilast, oglemilast and ciliomilast are potent anti-inflammatory agents, they do have serious side effects. Many other standard drugs of today also, have other types of unwanted effects one important being drug resistance. Thus, newer agents without such undesirable side effects and better potency are the need of the day. This work, thus, was undertaken to study a few novel compounds synthesis, characterization and biological activity of methoxydibenzofuran-1,3-thiazole carboxamide derivatives and a series of ten aryl amine derivatives (i.e. 4a-j) were produced targeting Phospodiesterases(PDE). The inhibition of the PDEs in the cell effectively elevates the intracellular cAMP level. This in turn inhibits the release of inflammatory mediators (TNF-α, interleukin-2, interleukin -12) and act as an anti-inflammatory drug. All compounds were confirmed by melting point, FTIR, 1H-NMR and High resolution Mass spectroscopy and their structure was determined. Then a series of assessments to the generated molecules were carried out, including assessments of drug-likeness, bioactivity and synthetic accessibility. The result of short term in-vitro anti-inflammatory screening against protein denaturation method shows a moderate inhibitory effect. Among these particularly compounds 4d, 4e, 4f, 4g, 4h and 4i showed promising activity when compared to standard drug diclofenac sodium at lowest concentration of 100 µg/ml and the percentage of inhibition are found to be 26.70, 35.86, 27.16, 27.60, 38.54 and 32.57 µg/ml respectively, where the standard drug diclofenac sodium was 25.31 µg/ml. Likewise, in-silico approaches are highly helpful in understanding the molecular mechanism of the protein-ligand interactions to bring the pragmatic features of protein functions through structural analysis. The design of inhibitors selectively targeting PDE4 with high affinity and specificity was observed in 4d, 4e, 4g and 4h compounds showing the binding energies in the range of inhibition. From the in-silico and in-vitro studies it is conformed that the compound 4e shows significant inhibition with respect to other derived compounds and the standard diclofenac sodium. It is evident from our analysis and the prompts a novel inhibition of drug candidates along with the available drugs present. Therefore, the structure based designed drug shows the inhibition at the binding site scaffold of the protein PDE4B and along with mutational studies on these residues could be highly effective in further study. The synthetized drugs are further carried out for in-vivo studies and clinical trials.