Simple chalcones and bis-chalcones ethers as possible pleiotropic agents

Abstract

The synthesis, the antioxidative properties and the lipoxygenase (LOX) and acetylcholinesterase (AChE) inhibition of a number of 4-hydroxy-chalcones diversely substituted as well as of a series of bis-chalcones ether derivatives are reported. The chalcones derivatives were readily produced using a Claisen-Schmidt condensation in a ultra sound bath in good yields. The structures of the synthesized compounds were confirmed by spectral and elemental analysis. Their lipophilicity is experimentally determined by reversed-phase thin-layer chromatography method. Most of them are potent in vitro inhibitors of lipid peroxidation and of LOX. Compounds b2 and b3 were found to be the most potent LOX and AChE inhibitors among the tested derivatives with a significant anti-lipid peroxidation profile. The results led us to propose these enone derivatives as new multifunctional compounds against Alzheimer's disease. The results are discussed in terms of structural and physicochemical characteristics of the compounds. Moreover, the pharmacokinetic profile of these compounds was investigated using computational methods.

Small Multitarget Molecules Incorporating the Enone Moiety

“…1 H-NMR spectroscopy revealed through integration the right analogy of aromatic and C H = protons. The results are consistent with the proposed ( Ε ) structures and are in agreement with our previous findings [29]. All the derivatives were taken in satisfactory yields (over 70%).…”

“…Subsequent reaction of dii , for which a 3C-ether link was employed between the two 4-hydroxyacetophenone units, with the aromatic aldehydes of Figure 2 under Claisen-Schmidt conditions afforded chalcones c ( 1 – 13 ) is shown in Figure 4. Finally, prompted by the encouraging results of our previous work on bis -etherified chalcone c3 [29], which resulted from the reaction of the 4-dimethylamino(phenyl)acrylaldehyde with dii , and exhibited a very potent anti-lipid peroxidation activity (100%), a series of the corresponding bis -etherified double chalcones e ( i – vii ) were synthesized in a similar manner, as shown in Figure 5. These molecules were anticipated to reveal the effect of the carbon chain length of the bis -ether between the two 4-dimethylamino(phenyl)acryl-derived chalcone units.…”

“…A number of chalcone derivatives have been obtained and evaluated herein as pleitropic potential antioxidant agents, inhibitors of AChE and Lipoxygenase in vitro. Among them we included also a1 – 4 , c1 – 4 and dii for which earlier we performed a number of in vitro assays [29]. For the sake of comparison, we include them in the tables and in the discussion, and simultaneously we investigate their behavior in some additional assays.…”

“…Herein, we continue our efforts [29] to design and synthesize small biologically active molecules and for this scope, the chalcone structural template was exploited as a privileged scaffold for the design of multi-target agents. The synthesis of simple chalcones a1 – 4 , of the bis -etherified chalcones c1 – 4 and of the intermediate ether dii , as well as their antioxidant activities (DPPH, AAPH, ABTS •+ ), cytotoxicity, and inhibition against lipoxygenase and acetylcholinesterase have been already published [29]. Several substituted aromatic and heteroaromatic aldehydes have been used in order to evaluate the effect of steric and electronic parameters on the biological activity and to optimize the activities through systematic modification of the substituents.…”

ss-NMR and single-crystal X-ray diffraction in the elucidation of a new polymorph of bischalcone (1E,4E)-1,5-bis(4-fluorophenyl)penta-1,4-dien-3-one

“…However, releasing a new drug onto the market is challenging and demands many expensive and time-consuming steps. Only 20% of all new compounds are candidates for clinical trials and just 10% of those are registered (Liargkova et al, 2016). Because of this, the search for potential drug candidates is a trend nowadays, enabling the design of useful molecular libraries in order to reduce high research costs.…”