Targeting Inflammation with Conjugated Cinnamic Amides, Ethers and Esters

Abstract

Background: Cinnamic acid is a key intermediate in shikimate and phenylpropanoid pathways. It is found both in free form, and especially in the form of esters in various essential oils, resins and balsams which are very important intermediates in the biosynthetic pathway of several natural products. The cinnamic derivatives play a vital role in the formation of commercially important intermediate molecules which are necessary for the production of different bioactive compounds and drugs. Different substitutions on basic moiety lead to various biological activities. Furthermore, combination of appropriate pharmacophore groups with cinnamic acid derivatives were developed to give hybrids in order to find out promising drug candidates as inhibitors of multiple biological targets associated with inflammation. We found interesting to continue our efforts to design and synthesise three series of novel cinnamic acid-based hybrids: a) nitrooxy esters of cinnamic acid, b) ethers and c) amides of cinnamic acids with arginine, as pleiotropic candidates against multiple targets of inflammation. Methods: The synthesis of cinnamic was established by a Knoevenagel-Doebner condensation of the suitable aldehyde either with malonic acid in the presence of pyridine and piperidine, or with phenylacetic acid in the precence of triethylamine in acetic anhydride. The synthesis of the corresponding esters was conducted in two steps. The ethers were synthesized in low yields, with 1,2 – dibromoethane in dry acetone, in the presence of K2CO3, to give oily products. The corresponding cinnamic amides were synthesised in a single step. The synthesised hybrids were tested as lipoxygenase (LOX) and cyclooxygenase (COX) inhibitors in vitro. In silico docking was applied to all the novel derivatives. Several molecular properties of the hybrids were calculated in order to evaluate their drug likeness. Results: A number of esters, ethers and amides of selected cinnamic acids, either phenyl substituted or not, has been synthesised and subjected to modelling studies. The compounds were studied in vitro/in vivo for their inhibitory activities on cox and lox, and as antioxidants. Log P values of all the title compounds except of 3a (5.38) were found to be less than 5 and are in agreement to Lipinski’s rule of five, suggesting satisfactory permeability across cell membrane. The molecular modelling study seems to be in accordance with the experimental results for LOX and COX-2. The result of antioxidant activity for amide 3b supports the anti-lox activity. Compound 5d presents the higher in vivo anti-inflammatory. Conclusion: According to the experimental findings compounds 3b and 5d can be used as lead compounds for the design of new molecules to target inflammation.

Development of Novel Pyrrole Derivatives and Their Cinnamic Hybrids as Dual COX-2/LOX Inhibitors

“…In the present study, the new 3,4-disubstituted pyrrole derivatives and pyrrolecinnamate hybrids were evaluated in vitro for their antioxidant activity and their ability to inhibit soybean lipoxygenase and cyclooxygenase-2, in comparison to the well-known reference compounds trolox, nordihydroguaiaretic acid (NDGA) [30], and indomethacin [51]. For the sake of comparison, the previously published results of 4, 8 [31], 9 [27], and cinnamic acid's biological data [30] are also included (Table 2) The biological results are discussed in relation to the physicochemical properties of the molecules, e.g., the molecular volume (MV) and molar refractivity (MR) of the aromatic substituents Ar 1 and Ar 2 and ClogP and R M values.…”

“…For the sake of comparison, the previously published results of 4, 8 [31], 9 [27], and cinnamic acid's biological data [30] are also included (Table 2) The biological results are discussed in relation to the physicochemical properties of the molecules, e.g., the molecular volume (MV) and molar refractivity (MR) of the aromatic substituents Ar 1 and Ar 2 and ClogP and R M values. to inhibit soybean lipoxygenase and cyclooxygenase-2, in comparison to the well-known reference compounds trolox, nordihydroguaiaretic acid (NDGA) [30], and indomethacin [51]. For the sake of comparison, the previously published results of 4, 8 [31], 9 [27], and cinnamic acid's biological data [30] are also included (Table 2) The biological results are discussed in relation to the physicochemical properties of the molecules, e.g., the molecular volume (MV) and molar refractivity (MR) of the aromatic substituents Ar 1 and Ar 2 and ClogP and RM values.…”

Hybrids as NO Donors

“…A new series of synthetic cinnamic acid derivatives (Figure 3) incorporating a nitro group were evaluated as anti-inflammatory and antioxidant agents by Fotopoulos et al [34]. The new molecules tested as possible inhibitors of soybean LOX and ovine COX-2.…”

Ethyl (E)-(3-(4-((4-bromobenzyl)oxy)phenyl)acryloyl)glycinate

“…In light of the above, continuing our efforts in the design of cinnamic hybrids [5], we report the synthesis of a new cinnamic acid-glycine hybrid combining two pharmacophore units in a single molecule. Earlier studies [6] showed that (E)-(3-(4-((4-bromobenzyl)oxy)…”