PUBLICATION
Anti-Inflammatory Activity and Cheminformatics Analysis of New Potent 2-Substituted 1-Methyl-5-Nitroindazolinones
- Authors
- Siverio-Mota, D., Andujar, I., Marrero-Ponce, Y., Giner, R.M., Mendoza, C.D., Paba, G.M., Vicet-Muro, L., Cordero-Maldonado, M.L., de Witte, P.A.M., Crawford, A.D., Veitia, M.S., Perez-Jimenez, F., Aran, V.J.
- ID
- ZDB-PUB-180124-1
- Date
- 2018
- Source
- Current topics in medicinal chemistry 17(30): 3236-3248 (Journal)
- Registered Authors
- Cordero-Maldonado, Maria Lorena
- Keywords
- SARANEA software, TPA-induced mouse ear edema., anti-inflammatory compound, nitroindazolinones, structure-activity relationship, zebrafish
- MeSH Terms
-
- Animals
- Anti-Inflammatory Agents, Non-Steroidal/chemistry
- Anti-Inflammatory Agents, Non-Steroidal/pharmacology*
- Cyclooxygenase 2/metabolism
- Cyclooxygenase 2 Inhibitors/chemistry
- Cyclooxygenase 2 Inhibitors/pharmacology*
- Dose-Response Relationship, Drug
- Humans
- Indazoles/chemistry
- Indazoles/pharmacology*
- Informatics*
- Lipopolysaccharides/antagonists & inhibitors
- Lipopolysaccharides/pharmacology
- Molecular Structure
- Nitric Oxide/antagonists & inhibitors
- Nitric Oxide/biosynthesis
- Nitric Oxide Synthase Type II/antagonists & inhibitors
- Nitric Oxide Synthase Type II/metabolism
- Nitro Compounds/chemistry
- Nitro Compounds/pharmacology*
- Structure-Activity Relationship
- Tumor Necrosis Factor-alpha/antagonists & inhibitors
- Zebrafish
- PubMed
- 29357800 Full text @ Curr. Top. Med. Chem.
Citation
Siverio-Mota, D., Andujar, I., Marrero-Ponce, Y., Giner, R.M., Mendoza, C.D., Paba, G.M., Vicet-Muro, L., Cordero-Maldonado, M.L., de Witte, P.A.M., Crawford, A.D., Veitia, M.S., Perez-Jimenez, F., Aran, V.J. (2018) Anti-Inflammatory Activity and Cheminformatics Analysis of New Potent 2-Substituted 1-Methyl-5-Nitroindazolinones. Current topics in medicinal chemistry. 17(30):3236-3248.
Abstract
After the identification of the anti-inflammatory properties of the VA5-13l (2-benzyl-1-methyl-5-nitroindazolinone) in previous investigations, some analogous compounds of them were designed, synthesized and evaluated in two anti-inflammatory methods: LPS-enhanced leukocyte migration assay in zebrafish and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema. Of the products evaluates (3, 6, 8, 9 and 10) showed the lower values of relative leukocyte migration at 30 µM (0.14, 0.07, 0.10, 0.13 and 0.07, respectively), while in ear edema and myeloperoxidase activity methods, all the compounds reduced inflammation, only 4 and 16 yielded unsatisfactory results. The relationship linking structure and activity (SAR analysis) was determinate by using SARANEA software. The importance of the 5-Nitro group of the indazole ring for the activity was evident, showered modest reduction of it when of benzyl (Bn) is changed by alkyl group. A substituted Bn moiety at N2 (R) is the best substituent (5-10); nevertheless, if methylene group of Bn is deleted, the activity is affected. Also introduction of halogen atoms mainly at positions 3 or 4 of the benzyl moiety (6 and 10) leads in general to strong activities. In fact, compounds 7 and 8 (R = 4-FBn or 4-ClBn, respectively) exhibit results satisfactory in vivo tests and appear promising. The production of IL-6 at all doses assayed was significantly reduced, except with 16. Nonetheless, the production of TNF-α was significantly inhibited only by this chemical (16) at concentration of 50 µM. On the other hand, compound 2 was the one that mostly inhibited the expression of COX-2 and iNOS. From these results, it can be concluded that the inhibition in the release of cytokines can be one of the mechanisms of action responsible for the anti-inflammatory effect for 2-benzyl derivates while other 2-alkyl derivatives can inhibit production of NO. Therefore, nitroindazolinone chemical prototype could be an interesting structural group with anti-inflammatory purposes in the therapeutic.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping