Title:Anti-Inflammatory Activity and Cheminformatics Analysis of New Potent 2-Substituted 1-Methyl-5-Nitroindazolinones
Volume: 17
Issue: 30
Author(s): Dany Siverio-Mota, Isabel Andujar, Yovani Marrero-Ponce*, Rosa M. Giner*, Claudia Diaz-Mendoza, Ganiveth Manjarrez Paba, Liliana Vicet-Muro, Maria Lorena Cordero-Maldonado , Peter A. M. de Witte, Alexander D. Crawford *, Maite Sylla-Iyarreta Veitia , Facundo Perez-Jimenez and Vicente J. Aran*
Affiliation:
- Unidad de Investigacion de Diseno de Farmacos y Conectividad Molecular, Departamento de Quimica Física, Facultad de Farmacia, Universitat de Valencia,Spain
- Departamento de Farmacologia, Facultad de Farmacia, Universitat de Valencia, Valencia,Spain
- Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Herestraat 49, 3000 Leuven,Belgium
- Instituto de Quimica Medica, CSIC, c/Juan de la Cierva 3, 28006 Madrid,Spain
Keywords:
SARANEA software, Structure-activity relationship, Nitroindazolinones, Anti-inflammatory compound, Zebrafish,
TPA-induced mouse ear edema.
Abstract: After the identification of the anti-inflammatory properties of VA5-13l (2-benzyl-1-
methyl-5-nitroindazolinone) in previous investigations, some of its analogous compounds 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. The products evaluated (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,
and showed modest reduction when 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 satisfactory results in 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.
