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A computer-aided predictions of antioxidant activities were performed with the Prediction Activity Spectra of Substances (PASS) program. Antioxidant activity of compounds 1, 3, 4 and 5 were studied using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and lipid peroxidation assays to verify the predictions obtained by the PASS program. Compounds 3 and 5 showed more inhibition of DPPH stable free radical at 10−4 M than the well-known standard antioxidant, butylated hydroxytoluene (BHT). Compound 5 exhibited promising in vitro inhibition of Fe2+-induced lipid peroxidation of the essential egg yolk as a lipid-rich medium (83.99%, IC50 16.07 ± 3.51 µM/mL) compared to α-tocopherol (α-TOH, 84.6%, IC50 5.6 ± 1.09 µM/mL). The parameters for drug-likeness of these BHT analogues were also evaluated according to the Lipinski’s “rule-of-five” (RO5). All the BHT analogues were found to violate one of the Lipinski’s parameters (LogP > 5), even though they have been found to be soluble in protic solvents. The predictive polar surface area (PSA) and absorption percent (% ABS) data allow us to conclude that they could have a good capacity for penetrating cell membranes. Therefore, one can propose these new multipotent antioxidants (MPAOs) as potential antioxidants for tackling oxidative stress and lipid peroxidation processes.

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The rates of the hydrolyses of N-(o-hydroxyphenyl)phthalimide (1) and N-(o-methoxyphenyl)phthalimide (2), studied at different pH, show that the hydrolysis of 1 involves intramolecular general base (IGB) assistance where the o-O- group of ionized 1 acts as IGB and H2O as the reactant. The rate enhancement due to the IGB-assisted reaction of H2O with ionized 1 is>8x10(4)-fold. Pseudo-first-order rate constant for the reaction of water with 2 is approximately 2x10(3)-fold smaller than the first-order rate constant (0.10 s-1) for pH-independent hydrolysis of 1 within the pH range of 9.60-10.10. Second-order rate constants (kOH) for hydroxide ion-assisted hydrolysis of ionized 1 and 2 are 3.0 and 29.1 M-1 s-1, respectively. The solvent deuterium kinetic isotope effect (dKIE) on the rate of alkaline hydrolysis of 1 and 2 reveals that the respective values of kOH/kOD are 0.84 and 0.78, where kOD represents the second-order rate constant for DO--assisted cleavage of these imides (1 and 2). The value of kwH2O/kdD2O is 2.04, with kwH2O and kdD2O representing pseudo-first-order rate constants for the reactions of ionized 1 with H2O and D2O, respectively.

BackgroundTamarindus indica L. (T. indica) or locally known as “asam jawa” belongs to the family Leguminosae. T. indica seeds as by-products from the fruits were previously reported to contain high polyphenolic content. However, identification of their bioactive polyphenols using recent technologies is less well researched but nonetheless important. Hence, it was the aim of this study to provide further information on the polyphenolic content and antioxidant activities as well as to identify and quantify its bioactive polyphenols.MethodsT. indica seeds were extracted with methanol and were then fractionated with different compositions of hexane, ethyl acetate and methanol. Polyphenolic contents were measured using Folin-Ciocalteu assay while antioxidant activities were measured using DPPH radical scavenging and ferric reducing (FRAP) activities. The cytotoxic activities of the crude extract and the active fraction were evaluated in HepG2 cells using MTT assay. The cells were then pre-treated with the IC20 concentrations and induced with H2O2 before measuring their cellular antioxidant activities including FRAP, DPPH, lipid peroxidation, ROS generation and antioxidant enzymes, SOD, GPx and CAT. Analyses of polyphenols in the crude extract and its active fraction were done using UHPLC and NMR.ResultsAmongst the 7 isolated fractions, fraction F3 showed the highest polyphenolic content and antioxidant activities. When HepG2 cells were treated with fraction F3 or the crude extract, the former demonstrated higher antioxidant activities. F3 also showed stronger inhibition of lipid peroxidation and ROS generation, and enhanced activities of SOD, GPx and CAT of HepG2 cells following H2O2-induced oxidative damage. UHPLC analyses revealed the presence of catechin, procyanidin B2, caffeic acid, ferulic acid, chloramphenicol, myricetin, morin, quercetin, apigenin and kaempferol, in the crude seed extract of T. indica. UHPLC and NMR analyses identified the presence of caffeic acid in fraction F3. Our studies were the first to report caffeic acid as the active polyphenol isolated from T. indica seeds which likely contributed to the potent antioxidant defense system of HepG2 cells.ConclusionResults from this study indicate that caffeic acid together with other polyphenols in T. indica seeds can enhance the antioxidant activities of treated HepG2 cells which can provide protection against oxidative damage.

Pseudo-first-order rate constants (k(obs)) for alkaline hydrolysis of N-benzylphthalimide (1) show a nonlinear decrease with the increase in [C(m)E(n)]T (total concentration of Brij 58, m = 16, n = 20 and Brij 56, m = 16, n = 10) at constant [CH(3)CN] and [NaOH]. These nonionic micellar effects, within the certain typical reaction conditions, have been explained in terms of the pseudophase micellar (PM) model. The values of micellar binding constants (KS) of 1 are 1.04 x 10(3) M(-1) (at 1.0 x 10(-3) M NaOH) and 1.08 x 10(3) M(-1) (at 2.0 x 10(-3) M NaOH) for C(16)E(20) as well as 600 M(-1) (at 7.6 x 10(-4) M NaOH) and 670 M(-1) (at 1.0 x 10(-3) M NaOH) for C(16)E(10) micelles. The pseudo-first-order rate constants (kM) for hydrolysis of 1 in C(16)E(20) micellar pseudophase are approximately 90-fold smaller than those (kW) in water phase. The values of kM for hydrolysis of 1 in C(16)E(10) micelles are almost zero. Kinetic coupled with UV spectral data reveals significant irreversible nonionic micellar binding of 1 molecules in the micellar environment of nearly zero hydroxide ion concentration at >or=0.14 M C(16)E(20) and 1.0 x 10(-3) M NaOH while such observations could not be detected at or=3 x 10(-3) M C(16)E(10) and 7.6 x 10(-4) M NaOH, while the rate of hydrolysis of 1 is completely ceased at >or=0.05 M C(16)E(10) and 7.6 x 10(-4) M NaOH. The rate of hydrolysis of 1 at 5.0 x 10(-2) and 8.8 x 10(-2) M C(16)E(10) and 1.0 x 10(-3) M NaOH reveals the formation of presumably phthalic anhydride, whereas such observation was not observed in the C(16)E(20) micellar system under similar experimental conditions.

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The apparent second-order rate constant (k OH) for hydroxide-ion-catalyzed conversion of 1 to N-(2'-methoxyphenyl)phthalamate (4) is approximately 10(3)-fold larger than k OH for alkaline hydrolysis of N-morpholinobenzamide (2). These results are explained in terms of the reaction scheme 1 --> k(1obs) 3 --> k(2obs) 4 where 3 represents N-(2'-methoxyphenyl)phthalimide and the values of k(2obs)/k(1obs) vary from 6.0 x 10(2) to 17 x 10(2) within [NaOH] range of 5.0 x 10(-3) to 2.0 M. Pseudo-first-order rate constants (k(obs)) for alkaline hydrolysis of 1 decrease from 21.7 x 10(-3) to 15.6 x 10(-3) s(-1) with an increase in ionic strength (by NaCl) from 0.5 to 2.5 M at 0.5 M NaOH and 35 degrees C. The values of k obs, obtained for alkaline hydrolysis of 2 within [NaOH] range 1.0 x 10(-2) to 2.0 M at 35 degrees C, follow the relationship k(obs) = kOH[HO(-)] + kOH'[HO (-)] (2) with least-squares calculated values of kOH and kOH' as (6.38 +/- 0.15) x 10(-5) and (4.59 +/- 0.09) x 10(-5) M (-2) s(-1), respectively. A few kinetic runs for aqueous cleavage of 1, N'-morpholino-N-(2'-methoxyphenyl)-5-nitrophthalamide (5) and N'-morpholino-N-(2'-methoxyphenyl)-4-nitrophthalamide (6) at 35 degrees C and 0.05 M NaOH as well as 0.05 M NaOD reveal the solvent deuterium kinetic isotope effect (= k(obs) (H 2) (O)/ k(obs) (D 2 ) (O)) as 1.6 for 1, 1.9 for 5, and 1.8 for 6. Product characterization study on the cleavage of 5, 6, and N-(2'-methoxyphenyl)-4-nitrophthalimide (7) at 0.5 M NaOD in D2O solvent shows the imide-intermediate mechanism as the exclusive mechanism.