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

Silveira, Ingridhy Ostaciana Maia Freitas da; Moslaves, Iluska Senna Bonfá; Muller, Jéssica de Araújo Isaías; Hortelan, Cristiane R. W.; Okuyama, Tatiane Teibel; Fernandes, J.M.; Badenoch, Bretton; Campos, Luana Janaína de; Almeida, Leandro Duarte de; Mohammad, Jiyan; Martins, Allana C. F.; Beatriz, Adilson; Júnior, Eufrânio N. da Silva; Toffoli-Kadri, Mônica Cristina; Gomes, Roberto da Silva

doi:10.1016/j.bioorg.2022.105754

Cited by 4 publications

(3 citation statements)

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“…We showed that ZIM could be involved in inhibiting the inflammatory response, the involvement of Prostaglandins in the formation of edema, and reducing the recruitment of polymorphonuclear cells and the neurogenic phase of pain, making ZIM a good anti-inflammatory prototype . However, it is the first time ZIM has been reported as an efficient genotoxic agent since ZIM induced an increase in the frequency of both genomic and chromosomal damage.…”

Section: Discussionmentioning

confidence: 97%

“…The reaction of 1 with sodium acetate and acetic anhydride provided the maleimide 3 . Finally, the 4+2 cycloaddition reaction of 3 and cyclopentadiene provided the polycyclic compound 4 with a 3 h overall reaction time (Scheme B) …”

Section: Discussionmentioning

confidence: 99%

“…Building on our earlier work, ,, we first synthesized ZIM , a norbornene dicarboximide based on the 1,4-dioxo-butenyl/4-aminoantipyrine scaffold. We then evaluated the synthesized ZIM in a mouse model for its genotoxic and apoptotic potential alone and in combination with three chemotherapeutic agents currently used in clinical settings (cisplatin- CIS , doxorubicin- DOX , and cyclophosphamide- CYP ).…”

Section: Introductionmentioning

confidence: 99%

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ZIM, a Norbornene Derived from 4-Aminoantipyrine, Induces DNA Damage and Cell Death but in Association Reduces the Effect of Commercial Chemotherapeutics

Oliveira

Silveira

Neves

et al. 2022

Chem. Res. Toxicol.

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Cancer incidence is increasing, and the drugs are not very selective. These drugs cause adverse effects, and the cells become resistant. Therefore, new drugs are needed. Here, we evaluated the effects of ZIM, a candidate for chemotherapy, and 4-AA alone and in association with commercial chemotherapeutic agents. Subsequently, the results of ZIM and 4-AA were compared. Male Swiss mice were treated with doses of 12, 24, or 48 mg/kg ZIM or 4-AA alone or in association with cisplatin (6 mg/kg), doxorubicin (16 mg/kg), and cyclophosphamide (100 mg/kg). Biometric parameters, DNA damage (comet and micronuclei), cell death, and splenic phagocytosis were evaluated. DNA docking was also performed to confirm the possible interactions of ZIM and 4-AA with DNA. 4-AA has been shown to have low genotoxic potential, increase the frequency of cell death, and activate phagocytosis. ZIM causes genomic and chromosomal damage in addition to causing cell death and activating phagocytosis. In association with chemotherapeutical agents, both 4-AA and ZIM have a chemopreventive effect and, therefore, reduce the frequency of DNA damage, cell death, and splenic phagocytosis. The association of 4-AA and ZIM with commercial chemotherapeutic agents increased the frequency of lymphocytes compared to chemotherapeutic agents alone. Molecular docking demonstrated that ZIM has more affinity for DNA than 4-AA and its precursors (1 and 2). This was confirmed by the lower interaction energy of the complex (−119.83 kcal/mol). ZIM can break the DNA molecule and, therefore, its chemotherapeutic effect can be related to DNA damage. It is considered that ZIM has chemotherapeutic potential. However, it should not be used in combination with cisplatin, doxorubicin, and cyclophosphamide as it reduces the effects of these drugs.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%