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Hybrid Pharmacophores as Anti-inflammatory Agents

1136 words (5 pages) Essay in Chemistry

29/01/18 Chemistry Reference this

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CHAPTER VII

SUMMARY AND CONCLUSION

The Synthesis of molecules that are important in the control of ageing diseases is very important in the present decades. The compounds like Diarylsulfonylurea-chalcone may act as anti-inflammatory agents that may be linked as network to several diseases.

The synthetic compounds have the abilities to act as preventive compounds having therapeutic action. In the present decade, one can consider synthetic products in preventing aging diseases via anti-inflammation. Hence there is a need to discover novel synthetic compounds that are deemed in prevention and treatment of diseases showing tremendous impact on health care systems.

As a part of our research program aimed at search for new hybrid pharmacophores as anti-inflammatory agents, we are interested to have α,β-unsaturatedketone linker to the diarylsulfonylurea basic nucleus to give a series of diarylsulfonylurea-chalcone hybrids. Therefore, in the present study an attempt has been made to design, synthesize and characterize some new diarylsulfonylurea-chalcone hybrids.

Drug Discovery and drug development is a knowledge base, expensive and time intense method. Scientific advancements throughout the past 20 years have modified the manner pharmaceutical analysis generate novel bioactive molecules. Advances in machine/computer aided techniques and in parallel support of hardware have enabled in silico strategies, and particularly structure-based drug style technique, to speed up new target choice through identification of hits for the optimization of lead compounds within the drug discovery method. Genomics, proteomics, bioinformatics and, chemo informatics have gained vast quality Associate in development became an integral a part of the commercial and educational analysis, directive drug style and discovery. Virtual screening emerged as a crucial tool in our quest to access novel drug like compounds (Wermuth et al., 1998, Allen, 2002).

Rational in silico drug style are often tired 2 ways in which ligand-based or structure-based are analyzed for compound activity. With the supply of the 3D structure of a biological target, it’s possible to use a structure-based approach to judge and predict the binding mode of a matter inside the situation of the receptor with tying up strategies. Currently it’s a well-liked technique used for increasing the speed of drug coming up with method. This was created attainable by the supply of the many super molecule structures that helped in developing tools to know the structure operate relationships, machine-controlled tying up and virtual screening. Moreover, once no 3D structural data regarding target proteins with their receptor website is obtainable ligand-based style is applied. The ligand-based approach starts with a bunch of ligands binding to a similar receptor with a similar mechanism. These four completely different methods supported the previous information of the targets 3D structure and therefore the ligands binding to that square measure predominant (Van, 2007; Kier, 1967).

Chalcones are considered as precursors of flavonoidsand isoflavonoids in edible plants thatshowa variousarray ofmedical specialtyactivities. Chalcones are new class of glycosidase (α-amylase, α-glucosidase, and β-amylase) inhibitors that shows non-competitive inhibition acts against α-glucosidase. The effect of chalcones in hyperglycemic-normal rats on serum glucose-lowering properties highlighting the novel compounds showing strong anti-hyperglycemic properties (Damazio et al., 2009).

Sulfonylureas were only drugs used to stimulate the insulin secretion in patients with type 2 diabetes or D2M. Diarylsulfonylurea (DSU) is a novel anticancer molecule because has unique chemical structure with broad-spectrum antisolid-tumor activity in preclinical models. The sulfonylurea inhibits the eosinophil survival in a method similar to lidocaine.

Anti-inflammation is the biological process of the diseases that links to the pathways related to aging diseases. A substance that reduces inflammation are linked to cancer, diabetes, etc., are anti-inflammatory compounds used to reduce the risk of age related diseases.

In the present investigation, the LPID approach is now applied to the database of 25 compounds virtually designed for finding ‘best fit’ (hit identification) against selected anti-inflammatory protein drug target (5-Lipoxygenase (5-LO)). The compounds appear out of these molecular docking studies with least binding energy against target protein were prepared by using standard conventional methods of synthesis and subjected for corresponding in vitro and in vivo studies. By this means, it is possible to understand how the compounds interact with the selected anti-inflammatory target protein. The results promising out of this study can be used to identify a new class of potential anti-inflammatory agents with selective 5-LO inhibitory activity.

A set of 25 diarylsulfonylurea-chalcone hybrids 4a-4y were subjected to ligand-protein inverse docking simulation using software Molegro Virtual Docker v 5.0. These compounds were docked against selected anti-inflammatory drug target (i.e. Human 5-Lipoxygenase PDB Code: 3V99). The results of these studies could help in preliminary confirmation of inhibitory activity against 5-lipoxygenase. The result of the docking interactions between the selected compounds and protein target, data in shows that compound 4g was accomplished best binding efficiency against 5-lipoxygenase with Moldock Score (-193.641) with 3 hydrogen bond interactions and the corresponding interacting residues are Asn 554, Ser 608 and Ala 606 these hydrogen bonds not only relevant for the binding 4g to 3V99 to exhibit highly selective and potent binding affinity. Moreover, from the data given in it appears that the co-crystallized ligand arachidonic acid and positive standard abietic acid showed no hydrogen bond interactions with the active binding site residues indicating the importance of steric interactions and electrostatic interactions for their observed 5-lipoxygenase inhibitory activity.

The key intermediary in the current study 1-(3-acetylphenyl)-3-tosylurea was synthesized by reaction of 3-aminoacetophenone with methylchloroformate under basic conditions at 0 °C temperature to give methyl-3-acetylphenylcarbamate followed by the reaction with toluene sulphonamide and on the other hand subsequent Claisen-Schmidt condensation of the intermediate with appropriate aromatic/heteroaromatic aldehydes in ethanolic KOH solution to give the corresponding diarylsulfonylurea-chalcone hybrids (4a4y) in good yield

The investigation of the compounds(4a-4y) in vitro 5-LO inhibitory activity screening data revealed that the compounds 4r and 4o demonstrated comparatively the most potent inhibitory activity, with IC50 values of 7.88±0.14 µg/mL and 11.77±0.21 µg/mL, respectively.

An in silico toxicity tests can be conducted for diarylsulfonylurea-chalcone hybrids 4o, 4q, 4r, 4t, 4y and standard (Aceclofenac) to predict the toxicity nature using Lazar server. All the compounds are predicted as non-toxic. From the in vitro 5-LO inhibitory activity data, five potent diarylsulfonylurea-chalcone hybrids compounds (mentioned above) which displayed significant activity has been selected for further anti-inflammatory activity studies by using in vivo bioassay model i.e. Carrageenan-induced rat paw oedema method. The results of the assessment have been viewed by taking Aceclofenac as the standard drug.

Finally the work concludes that all the compounds displayed were shown remarkable anti-inflammatory activity.

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