3-Aminothiophene-2-Acylhydrazones: Non-Toxic, Analgesic and Anti-Inflammatory Lead-Candidates

Abstract

Different chemotypes are described as anti-inflammatory. Among them the N-acylhydrazones (NAH) are highlighted by their privileged structure nature, being present in several anti-inflammatory drug-candidates. In this paper a series of functionalized 3-aminothiophene-2-acylhydrazone derivatives 5a-i were designed, synthesized and bioassayed. These new derivatives showed great anti-inflammatory and analgesic potency and efficacy. Compounds 5a and 5d stand out in this respect, and were also active in CFA-induced arthritis in rats. After daily treatment for seven days with 5a and 5d (50 µmol/Kg), by oral administration, these compounds were not renal or hepatotoxic nor immunosuppressive. Compounds 5a and 5d also displayed good drug-scores and low risk toxicity calculated in silico using the program OSIRIS Property Explorer.

Crystal Structures of 1-Aryl-1H- and 2-Aryl-2H-1,2,3-triazolyl Hydrazones. Conformational Consequences of Different Classical Hydrogen Bonds

“…In Figure 3b Index ranges bond (E C=N and Z C=N ), making four possible arrangements in all about the C(O)−NH−N=CH-aryl fragment. [32][33][34][35] While the triazolyl ring is planar in all compounds, none of the compounds is planar overall. The deviation from planarity is relatively small for the 2H-1,2,3-triazolyl compounds, 2a, 2b and 3, as shown by the angles between the aryl rings in Table 3, and very much larger for 1a and 1b (see Figure 4).…”

Synthesis, X-ray diffraction study and pharmacological evaluation of 3-amino-4-methylthiophene-2-acylcarbohydrazones

“…and 7b (Ar = 4-nitro-phenyl; ID 50 = 2,6 µmol/kg in acetic acid-induced writhing model, p.o.) (Da Silva et al 2014), the methylation effect was deleterious for the antinociceptive profile of the methylated counterparts 8a (Ar = phenyl) and 8c (Ar = 4-nitro-phenyl). On the other hand, regarding the aromatic ring linked to the imine carbon, the introduction of more hydrophobic and bulky aromatic systems such as 4-biphenyl (8j) and 2-naphthyl (8l), not yet explored for the previously described 3-aminothiophene-2-acylhydrazones, proved to be useful for the optimization of the antinociceptive effect within the series.…”

“…The intermolecular interactions can be observed between atoms N (9) Considering the previously described analgesic and anti-inflammatory properties of 3-aminothiophene-2-acylhydrazones 7a and 7b (Da Silva et al 2014), we decided in a first approach to study the antinociceptive profiles of the methylated analogues 8a-t using the classical writhing test. In this animal model, peripheral pain is induced in mice by a parenteral administration of acetic acid.…”

“…Starting from the synthetic precursor methyl 3-amino-4-methylthiophene-2-carboxylate (9), the key intermediate 3-amino-4-methylthiophene-2-carbohydrazide (10) was prepared by hydrazinolysis reaction. With intermediate 10 in hands, the NAH derivatives 8a-t were obtained by classical condensation with functionalized aldehydes under acid catalysis (Da Silva et al 2014, Lacerda et al 2012. The target compounds (8a-t) were prepared in good yields, between 42.4 and 95.5%, and were analyzed by HPLC, MS, IR, 1 H-NMR and 13 C-NMR.…”

“…Several NAH compounds are well-known inhibitors of relevant inflammation targets, including cyclooxygenases (COX) (Gundogdu-Hizliates et al 2014, Ünsal-Tan et al 2010, inducible nitric oxide synthase (iNOS) (Moldovan et al 2011, Tiperciuc et al 2013) and the p38 mitogenactivated protein kinase (p38 MAPK) (Lacerda et al 2012). Examples of promising analgesic and anti-inflammatory NAH lead candidates (1-7) are depicted in Figure 1, highlighting the 3-aminothiophene-2-acylhydrazone derivatives (7a and 7b), which have recently been described by our research group as non-toxic, analgesic and antiinflammatory candidates (Da Silva et al 2014).…”