Design, synthesis and in vivo evaluation of 1,4-dioxo-2-butenyl aryl amine derivatives as a promising anti-inflammatory drug prototype

[Display omitted] •Virtual screening provided 4 candidates potentially able to strongly inhibit COX isoenzymes in inflammatory process.•Compounds (1–4) reduced pain in the inflammatory phase response.•Compound 4 inhibited the involvement of PGs in the formation of paw edema.•Compounds 2 and 4 reduce...

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Published in:	Bioorganic chemistry Vol. 124; p. 105754
Main Authors:	da Silveira, Ingridhy O.M.F., Moslaves, Iluska S.B., Muller, Jéssica A.I., Hortelan, Cristiane R.W., Juliano Oliveira, Rodrigo, Okuyama, Tatiane T., Fernandes, Juliana, Badenoch, Bretton, Janaína de Campos, Luana, Almeida, Leandro D., Mohammad, Jiyan, Martins, Allana C.F., Beatriz, Adilson, da Silva Júnior, Eufrânio N., Cristina Toffoli-Kadri, Mônica, da Silva Gomes, Roberto
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-07-2022
Subjects:	1,4-Dioxo-2-butenyl derivatives Analgesic effects Anti-inflammatory effects Dipyrone Docking Analgesic effects Dipyrone Docking 1,4-Dioxo-2-butenyl derivatives Anti-inflammatory effects
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Summary:	[Display omitted] •Virtual screening provided 4 candidates potentially able to strongly inhibit COX isoenzymes in inflammatory process.•Compounds (1–4) reduced pain in the inflammatory phase response.•Compound 4 inhibited the involvement of PGs in the formation of paw edema.•Compounds 2 and 4 reduced the cellular recruitment of PMN to the inflammatory site.•Compounds 1, 3 and 4 reduced the neurogenic phase of pain. Inflammation is a natural response of the organism to an infection, trauma, or cellular stress. Pain is the first symptom of acute and chronic inflammation. The standard class of medication to treat inflammatory pain is the nonsteroidal anti-inflammatory drug (NSAID). These drugs are associated with severe side effects such as gastric ulcers, gastritis, or internal bleeding. One of NSAIDs, Dipyrone® (metamizole) is largely used in many European and South American countries despite its dubious effectivity and its withdrawal from the market of several countries. Here, aiming to identify a new anti-inflammatory drug prototype based on Dipyrone® structure, a set of 27 molecules were virtually screened, and 4 compounds containing the active metabolite 4-aminoantipyrine and 1,4-dioxo-2-butenyl fragment were selected for docking, synthesis, and biological evaluation. The selection was based on the number of H-bonds and π- π stacking interactions between the inhibitor and the amino acids within the binding site of the enzyme. Carrageenan-induced paw edema, acetic acid-induced writhing, and formalin assays were used to evaluate inflammation and pain response. The selected compounds 1–4 inhibited the involvement of biogenic amines in the formation of paw edema. Compounds 1–4 also reduced pain in the inflammatory response phase. It has to be noted that 4-AA may cause agranulocytosis, which should be borne in mind when developing drug candidates of similar structure. Our new drug prototypes based on 4-aminoantipyrine and 1,4-dioxo-2-butenyl moieties open a gate for developing a prototype of nonsteroidal anti-inflammatory drugs.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0045-2068 1090-2120
DOI:	10.1016/j.bioorg.2022.105754