Background:
Coumarins exhibit a plethora of biological activities, e.g. antiinflammatory
and anti-tumor. Molecular hybridization technique has been implemented in the design
of novel coumarin hybrids with several bioactive groups in order to obtain molecules with
better pharmacological activity and improved pharmacokinetic profile.
Objective:
Therefore, we tried to gather as many as possible biologically active coumarin hybrids
referred in the literature till now, to delineate the structural characteristics in relation to the activities
and to have a survey that might help the medicinal chemists to design new coumarin hybrids
with drug-likeness and varied bioactivities.
Results:
The biological activities of the hybrids in most of the cases were found to be different
from the biological activities presented by the parent coumarins. The results showed that the hybrid
molecules are more potent compared to the standard drugs used in the evaluation experiments.
Conclusion:
Conjugation of coumarin with varied pharmacophore groups/druglike molecules responsible
for different biological activities led to many novel hybrid molecules, with a multitarget
behavior and improved pharmacokinetic properties.
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.
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