It appears that these curcumin analogues interacted with Soybean Lipoxygenase SLOX in the same way with an allosteric binding mode

It appears that these curcumin analogues interacted with Soybean Lipoxygenase SLOX in the same way with an allosteric binding mode. 3h. No inhibition for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 was noticed. According to the Ames test, all the hybrids induced mutagenicity with the exception of 3d. Efforts were conducted a) to correlate the in vitro results with the most important physicochemical properties of the structural components of the molecules and b) to clarify the correlation of actions among them to propose a possible mechanism of action. Docking studies were performed on soybean lipoxygenase (LOX) and showed hydrophobic interactions with amino acids. Docking studies on acetylcholinesterase (AChE) exhibited: (a) hydrophobic interactions with TRP281, LEU282, TYR332, PHE333, and TYR336 GLPG0492 and (b) -stacking interactions with TYR336. isomers [23,53]. The olefinic double bond was found to possess stereo chemistry. The NH absorptions were not observed for most of the compounds in series 1. The findings were in agreement with earlier publication [40]. The compounds 1kCn and 1q were prepared by the condensation of the appropriate ketone and arylaldehyde under basic conditions in ethanol using GLPG0492 microwave (MW) irradiation to afford the target curcumin analogues. Compounds 1k, 1l, 1m, and 1n had been synthesized earlier under different experimental conditions [54,55,56,57]. We used a different synthetic procedure, and the structures of the known compounds were verified according to literature spectral data, elemental analysis, or mps. In all cases, our synthetic technique was simpler. Lawessons reagent is usually a moderate and convenient thionating agent for ketones, esters, and amides that allows for the preparation of thioketones, thioesters, and thioamides in good yields. Compounds 1g and 1a were transformed to the corresponding 1o and 1p using the Lawessons reagent [58]. Mild conditions were used. It seems that the volume of PTPRC Substituent A influenced the yield of the reaction. Thus, compound GLPG0492 1o resulted in a higher yield % (71%) compared to the results provided by 1p. Spectrometric data supported the given structures (Physique 6). Open in a separate window Physique 6 Miscellaneous curcumin analogues. The synthesis of cinnamic acids 2aCc was established by the KnoevenagelCDoebner condensation of the suitable aldehyde with malonic acid in the presence of pyridine and piperidine as we have earlier reported [37]. The structural characterization of the new curcumin analogues 3aCh was based on their spectral data and elemental analyses. For example, the IR spectra of compounds revealed an absorption band at 1669C1659 cm? characteristic to carbonyl group of the curcumin analogue and to the amide group of the hybrid. Their 1H-NMR spectra revealed two signals at 7.67C7.96 ppm assignable to vinylic protons of benzylidenes. The survey of the 13C-NMR spectra of title compounds revealed that this carbonyl carbon GLPG0492 was displayed downfield at >189 ppm and the amidic carbonyl group at >165 ppm. The LCCMS results pointed to the presence of [M + CH3OH]+, [M + CH3OH + Na]+, and [M + Na]+. The physicochemical properties of the novel derivatives are given in the experimental section. 2.2. Physicochemical Studies 2.2.1. Experimental Determination of Lipophilicity as RM Values Since lipophilicity is usually described as a major physicochemical parameter that affects ligandCtarget binding interactions, solubility, ADME (absorption, distribution, bioavailability, metabolism, and elimination), and toxicological effects, we considered it important to experimentally determine this property as RM values. The RPTLC (reverse phase thin layer chromatography) method, which has been characterized as a secure, rapid, and appropriate technique for expressing lipophilicity, was applied (Table 1) [37]. We tried to correlate the milog P values, the theoretically calculated lipophilicity in one equation, with the RM.