pyridazinone derivatives
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Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5992
Author(s):  
Aurélie Moniot ◽  
Julien Braux ◽  
Camille Bour ◽  
Christine Guillaume ◽  
Fabien Lamret ◽  
...  

Osteosarcoma is a rare primary bone cancer that mostly affects children and young adults. Current therapeutic approaches consist of combining surgery and chemotherapy but remain unfortunately insufficient to avoid relapse and metastases. Progress in terms of patient survival has remained the same for 30 years. In this study, novel pyridazinone derivatives have been evaluated as potential anti-osteosarcoma therapeutics because of their anti-type 4 phosphodiesterase activity, which modulates the survival of several other cancer cells. By using five—four human and one murine osteosarcoma—cell lines, we demonstrated differential cytotoxic effects of four pyridazinone scaffold-based compounds (mitochondrial activity and DNA quantification). Proapoptotic (annexin V positive cells and caspase-3 activity), anti-proliferative (EdU integration) and anti-migratory effects (scratch test assay) were also observed. Owing to their cytotoxic activity in in vitro conditions and their ability to limit tumor growth in a murine orthotopic osteosarcoma model, our data suggest that these pyridazinone derivatives might be hit-candidates to develop new therapeutic strategies against osteosarcoma.


2021 ◽  
Vol 141 ◽  
pp. 111878
Author(s):  
Katarzyna Potyrak ◽  
Benita Wiatrak ◽  
Edward Krzyżak ◽  
Łukasz Szczukowski ◽  
Piotr Świątek ◽  
...  

2021 ◽  
Vol 14 (3) ◽  
pp. 183
Author(s):  
Mehmet Abdullah Alagöz ◽  
Zeynep Özdemir ◽  
Mehtap Uysal ◽  
Simone Carradori ◽  
Marialucia Gallorini ◽  
...  

Novel twenty−three 3(2H)−pyridazinone derivatives were designed and synthesized based on the chemical requirements related to the anti−proliferative effects previously demonstrated within this scaffold. The introduction of a piperazinyl linker between the pyridazinone nucleus and the additional (un)substituted phenyl group led to some compounds endowed with a limited cytotoxicity against human gingival fibroblasts (HGFs) and good anti−proliferative effects against gastric adenocarcinoma cells (AGS) as evaluated by MTT and LDH assays, using doxorubicin as a positive control. Successive analyses revealed that the two most promising representative compounds (12 and 22) could exert their effects by inducing oxidative stress as demonstrated by the hydrogen peroxide release and the morphological changes (cell blebbing) revealed by light microscopy analysis after the haematoxylin−eosin staining. Moreover, to further assess the apoptotic process induced by compounds 12 and 22, Bax expression was measured by flow cytometry. These findings enlarged our knowledge of the structural requirements in this scaffold to display valuable biological effects against cancerous cell lines.


2021 ◽  
Vol 12 (4) ◽  
pp. 584-592
Author(s):  
Ingrid Allart-Simon ◽  
Aurélie Moniot ◽  
Nicolo Bisi ◽  
Miguel Ponce-Vargas ◽  
Sandra Audonnet ◽  
...  

This work describes the development of pyridazinone derivatives bearing an indole moiety as PDE4B inhibitors and their evaluation as anti-inflammatory agents.


2020 ◽  
Vol 17 (2) ◽  
pp. 171-186
Author(s):  
Magda M.F. Ismail ◽  
Dalia H.S. Soliman ◽  
Mona H. Abd Elmoniem ◽  
Ghehad A.R. Abdel Jaleel

Background: Hypertension, one of the most common cardiovascular diseases that can cause coronary disease, stroke, myocardial infarction, and sudden death, it is the major contributor to cardiac failure as well as renal insufficiency. Objectives: As there are many cardio-active pyridazinone-base derivatives in clinical use, therefore, we aimed to synthesize a new series of pyridazin-3-ones and evaluate their vasorelaxant activity. Methods: A new series of synthesized compounds were carried out first by the synthesis of 6- flouroarylpyridazinones by cyclization of 3-(4-flourobenzoyl) propionic acid with hydrazine hydrate or arylhydrazines to provide the corresponding pyridazinone derivatives 2a-d. Mannich reaction was performed using morpholine or piperidine formaldehyde to obtain compounds 3a,b. On the other hand, reaction of 2a with various chloroacetamide intermediates, in dimethylformamide and potassium carbonate as a catalyst, afforded the target compounds 5a-c. The aromatic acid hydrazide intermediates 6a-g were prepared in 50-90% yield, by reacting to the prepared esters with hydrazine hydrate under reflux in ethanol. The two compounds 8a,b were prepared via condensation of 7a,b with ethyl chloroacetate in dry acetone. Finally, the target 2,4,6-trisubstituted pyridazinones 9a-c derivatives were obtained by the reaction of 7a with the appropriate aromatic aldehyde or substituted acetophenones. The new compounds were then evaluated for their vasorelaxant properties using isolated thoracic rat aortic rings. In addition, a homology model was built and molecular modeling simulation of these compounds into the active sites of the newly created α1a-adrenoceptor model was performed in order to predict and rationalize their affinities toward this receptor. Results: Among these compounds; 5a was the most potent, it exhibited approximately two-times the activity of prazosin (IC50 = 0.250, 0.487 mmol, respectively) also, fourteen compounds were more potent than prazosin.


Author(s):  
Oya Unsal Tan ◽  
Keriman Ozadali Sari

Azolo[ d]pyridazinone is a privileged structure and versatile pharmacophore whose derivatives are associated with diverse biological activities, in particular antidiabetic, antiasthmatic, anticancer, analgesic, anti-inflammatory, antithrombotic, antidepressant and antimicrobial activities. The importance of this scaffold against some targets like PDE, COX and DPP-4 has been reviewed in detail previously. In the present review, we have summarized comprehensive information on azolo[ d]pyridazinone derivatives investigated by many researchers for their diverse pharmacological activities, structure–activity relationship and molecular modeling studies since 2000. The review may lead scientists in the research fields of organic synthesis, medicinal chemistry and pharmacology to the strategic design and development of azolo[ d]pyridazinone-based drug candidates in the future.


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