Synthesis of heterosulfamates. Search for structure-taste relationships

Abstract

Thirty one new sodium heterosulfamates, RNHSO 3 Na, where the R portion contains mainly thiazole, benzothiazole, thiadiazole and pyridine ring structures, have been synthesized and their taste portfolios have been assessed. A database of 132 heterosulfamates (both open-chain and cyclic) has been formed by combining these new compounds with an existing set of 101 heterosulfamates which were previously synthesized and for which taste data are available.Simple descriptors have been obtained using (i) measurements with Corey-Pauling-Koltun (CPK) space-filling models giving x, y and z dimensions and a volume V CPK , (ii) calculated first order molecular connectivities ( 1 χ v ) and (iii) the calculated Spartan program parameters to obtain HOMO, LUMO energies, the solvation energy E solv and V SPARTAN . The techniques of linear (LDA) and quadratic (QDA) discriminant analysis and Tree analysis have then been employed to develop structure-taste relationships (SARs) that classify the sweet (S) and non-sweet (N) compounds into separate categories. In the LDA analysis 70 % of the compounds were correctly classified (this compares with 65 % when the smaller data set of 101 compounds was used) and in the QDA analysis 68 % were correctly classified (compared to 80 % previously). TheTree analysis correctly classified 81 % (compared to 86 % previously). An alternative Tree analysis derived using the Cerius2 program and a set of physicochemical descriptors correctly classified only 54 % of the compounds.

Structure−Taste Relationships for Disubstituted Phenylsulfamate Tastants Using Classification and Regression Tree (CART) Analysis

“…Five of the predictors, namely, x, y, z, V CPK , and V Spartan , that are used are various measures of size and volume, and we have used these because the bulkiness of the R moiety in RNHSO 3 -Na has been shown to be important in developing structuretaste relationships for the sulfamates (7,19,20). The electronic properties HOMO and LUMO show electron-rich areas such as lone pairs and regions susceptible to nucleophilic attack, respectively.…”

“…Recently we have been looking at the effects on taste of changes in the sulfamate −NHSO 3 Na () moiety, and for many years several laboratories have been studying the structure−taste relationships of sulfamates RNHSO 3 Na, where the R moiety has included alicyclic, aliphatic, heterocyclic, and hetero and aryl groups ( − ). In the case of the latter type we have recently published reliable structure−taste relationships for monosubstituted X-phenylsulfamates () ( Figure ) using over 80 compounds and a wide range of substituents (X) in the ortho-, meta-, and para-positions.…”

A QSTR-Based Expert System to Predict Sweetness of Molecules

“…The curated TastesDB dataset consisted of 649 molecules divided into two subsets of 435 sweet and 214 non-sweet (133 tasteless and 81 bitter) compounds, respectively (Table S1 ). QSTR studies regarding the prediction of the sweetness receptor-mediated taste were conducted by considering only homogeneous families of sweeteners (Iwamura, 1980 ; Kier, 1980 ; Spillane and McGlinchey, 1981 ; Takahashi et al, 1982 , 1984 ; Spillane et al, 1983 , 1993 , 2000 , 2002 , 2003 , 2006 , 2009 ; Miyashita et al, 1986a , b ; van der Wel et al, 1987 ; Okuyama et al, 1988 ; Spillane and Sheahan, 1989 , 1991 ; Drew et al, 1998 ; Kelly et al, 2005 ), limiting their ability to predict the sweetness of other kinds of sweeteners. In order to generalize the predictiveness of the QSTR-based expert system, we used a dataset that covered a large chemical space of both sweet and non-sweet molecules.…”

“…Several Quantitative Structure-Taste Relationships (QSTRs) for predicting the sweetness of chemicals were proposed in the past years and are summarized in Table 1 . The earlier work included compounds such as perillartine and aniline derivatives (Iwamura, 1980 ; van der Wel et al, 1987 ), sweet and bitter aldoxime derivatives (Kier, 1980 ), perillartine derivatives, aspartyl dipeptides, and carbosulfamates (Takahashi et al, 1982 , 1984 ; Miyashita et al, 1986a , b ; Okuyama et al, 1988 ), as well as sulfamate derivatives (Spillane and McGlinchey, 1981 ; Spillane et al, 1983 , 1993 , 2000 , 2002 , 2003 , 2006 , 2009 ; Spillane and Sheahan, 1989 , 1991 ; Drew et al, 1998 ; Kelly et al, 2005 ). Moreover, two QSTR models to discriminate sweet, tasteless and bitter compounds have been proposed (Rojas et al, 2016a ).…”

Synthesis and antiproliferative activity of imidazo[2,1- b ][1,3,4]thiadiazole derivatives

“…The starting 2-amino-5-substituted-1,3,4-thiadiazoles were prepared according to the literature, [21][22][23] whereas the various phenacyl bromides are commercially available or prepared by bromination of the corresponding ketones in glacial acetic acid. The 2-aralkyl/alkyl/-6-aryl-imidazo[2,1-b] [1,3,4]thiadiazole derivatives (5-8, 10 and 11) were subjected to electrophilic substitution at position 5 with bromine in the presence of sodium acetate in acetic acid to obtain the 5-bromo derivatives 13-18 in good yield.…”