Synthesis And Structure-activity Relationship Study Of 2-(4-methoxyphenoxy) Propionic Acid Derivatives With Sweetness Inhibitory Activity

2-(4-methoxyphenoxy)propionic acid(HPMP)is a potent sweetness inhibitor,which has been approved for use by many countries and areas,including China,the United States,Europe and Singapore.HPMP can help reduce the sweetness of food and improve the edible quality,but the structure-activity relationship for sweetness inhibitory activity of HPMP remains unclear.Therefore,according to the demand of the National Natural Science Foundation of China(No.31972010),the structure of HPMP was modified in this paper and an electronic tongue method was established for the evaluation of sweetness inhibition.The sweetness inhibitory activities of HPMP derivatives were investigated and the influence of specific structural changes on the sweetness inhibitory activity was explored,aiming at providing a theoretical guidance for the development of novel sweetness inhibitors and the improvement of sweetness inhibition mechanism.The main research contents are listed as followed.The structure of HPMP was modified from three aspects,namely replacing the hydrophobic group at para-position of the aromatic ring,adding substituents at other positions of the aromatic ring and changing the carbon chain between the aromatic ring and the carboxyl group.Through Williamson reaction,a total of eleven derivatives in three series were synthesized.All derivatives were confirmed by Fourier transform infrared spectroscopy,nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.After searching the Scifinder and Reaxys databases,one of them was found to be a new compound which has not been reported in the literatures.An evaluation method based on the electronic tongue was established in order to accurately analyze the sweetness inhibitory activities of HPMP derivatives.It was found that the electronic tongue had a certain selectivity for the evaluation of sweeteners.The sweeteners such as sucrose,fructose,glucose,xylitol,sorbitol and erythritol,which elicited a positive response of electronic tongue,were selected as research carriers.And the sweetness inhibitory activities of HPMP on six kinds of sweeteners were analyzed by both electronic tongue and sensory evaluation.The results showed that the electronic tongue could objectively reflect the sweetness inhibitory effects of HPMP on six kinds of sweeteners.Compared with sensory evaluation,the results of electronic tongue had a smaller error and higher accuracy.The prediction models of sweetness inhibitory effects were preliminarily established using electronic tongue.It revealed that there was a good linear correlation between the results of electronic tongue and sensory evaluation.For all prediction models,the determination coefficients were greater than 0.9,which indicated that the electronic tongue could be an effective evaluation tool for sweetness inhibition.The sweetness inhibitory activities of three series of HPMP derivatives were investigated by electronic tongue.The results showed that:(1)When the para-position of the aromatic ring was modified with different hydrophobic groups,the corresponding derivatives could inhibit the sweetness of sugars and sugar alcohols.It was speculated that the space volume of the hydrophobic substituents on the para-position was a significant property affecting the sweetness inhibitory effect.When the para-carbon of the aromatic ring bore different alkoxy groups,the sweetness inhibitory activity gradually decreased with the increase of the volume of substituents.The derivatives modified with smaller hydrophobic groups,such as methyl group and chlorine atom,had a similar sweetness inhibitory potency to HPMP.(2)When the hydrophobic groups were added to other positions of the aromatic ring,the corresponding derivatives still maintained a good sweetness inhibitory activity,but their sweetness inhibitory effects were not remarkably improved,which may be attributed to the enhanced steric hindrance of the aromatic ring.The derivatives with added chlorine atom or methyl group at the ortho-position had a similar sweetness inhibitory ability to HPMP,while the derivative with added methoxy group at the meta-position had a slightly weaker sweetness inhibitory effect than HPMP.(3)When the carbon chain between the aromatic ring and the carboxylic acid was modified,not all derivatives could inhibit the sweetness.The existence of the branched chain between the aromatic ring and the carboxylic acid may be crucial for sweetness inhibition.When the branched chain was missing,the sweetness inhibitory activity decreased significantly as the chain length between the aromatic ring and the carboxyl group increased.However,when the branched chain was present,the sweetness inhibitory effect also tended to be slightly weakened with the increase of branched chain length.