Azhar Ariffin

Understanding the chemistry behind the antioxidant activities of butylated hydroxytoluene (BHT): a review.

Hindered phenols find a wide variety of applications across many different industry sectors. Butylated hydroxytoluene (BHT) is a most commonly used antioxidant recognized as safe for use in foods containing fats, pharmaceuticals, petroleum products, rubber and oil industries. In the past two decades, there has been growing interest in finding novel antioxidants to meet the requirements of these industries. To accelerate the antioxidant discovery process, researchers have designed and synthesized a series of BHT derivatives targeting to improve its antioxidant properties to be having a wide range of antioxidant activities markedly enhanced radical scavenging ability and other physical properties. Accordingly, some structure-activity relationships and rational design strategies for antioxidants based on BHT structure have been suggested and applied in practice. We have identified 14 very sensitive parameters, which may play a major role on the antioxidant performance of BHT. In this review, we attempt to summarize the current knowledge on this topic, which is of significance in selecting and designing novel antioxidants using a well-known antioxidant BHT as a building-block molecule. Our strategy involved investigation on understanding the chemistry behind the antioxidant activities of BHT, whether through hydrogen or electron transfer mechanism to enable promising anti-oxidant candidates to be synthesized.

Butylated hydroxytoluene analogs: synthesis and evaluation of their multipotent antioxidant activities.

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.

Use of a bis-lithium amide base in asymmetric metallation of tricarbonyl(η6-1,3-dihydroisobenzothiophene)chromium(0)

Abstract Enantiomerically enriched tricarbonyl(η 6 -arene)chromium complexes derived from tricarbonyl(η 6 -1,3-dihydroisobenzothiophene)chromium(0) can be obtained in up to 95% ee by means of an enantioselective metallation reaction using the bis-lithium amide base 8 .

Correlation of antioxidant activities with theoretical studies for new hydrazone compounds bearing a 3,4,5-trimethoxy benzyl moiety

A new series of antioxidants, namely imines bearing the well-known free radical scavenger group 3,4,5-trimethoxybenzyloxy, was designed and synthesized. Theoretical calculations based on density functional theory (DFT) were performed to understand the antioxidant activities. Experimental studies evaluating the antioxidant activities of the compounds using DPPH and FRAP assays verified the predictions obtained by DMOL3 based on DFT.1. The DPPH radical scavenging activities depended on the substitution pattern of the aromatic aldehyde, with both the substitution type and position showing significant effects. Compounds 7b, 7c and 7d, which contain a phenolic hydroxyl group at the para position to the imine as well as, additional electron donating groups at the ortho-position to this hydroxyl group, exhibited IC₅₀ values of 62, 75 and 106 μg/mL, respectively, and potent antioxidant activities against DPPH, which were better than that of the reference compound BHT. With the exception of compounds 7a and 7h with a phenolic hydroxyl group at the ortho position, all of the investigated compounds exhibited ferric reducing activities above 1000 μM. Correlation analysis between the two antioxidant assays revealed moderate positive correlation (r = 0.59), indicating differing antioxidant activities based on the reaction mechanism. Therefore, imines bearing a 3,4,5-trimethoxybenzyloxy group can be proposed as potential antioxidants for tackling oxidative stress.

Suggested Improved Method for the Ing‐Manske and Related Reactions for the Second Step of Gabriel Synthesis of Primary Amines

Abstract This work demonstrates an improvement in the Ing‐Manske and related procedures by the increase of pH of the reaction mixture after the complete disappearance of N‐substituted phthalimide. Hydrazinolysis of N‐phenylphthalimide (1a) gave 80% of the desired primary amines after 5.3 h in the absence of added NaOH. The reaction time was reduced to 1.6 h and 1.2 h when 1 eq. and 5 eq. of NaOH were added to the reaction mixture after the complete disappearance of 1a. Hydroxyaminolysis of N‐(4‐ethylphenyl)phthalimide (1b) gave 80% of the desired primary amines after 7.5 h of reaction time (at added [NaOH] = 0). When 10 eq. and 20 eq. of NaOH were added to the reaction mixture after the disappearance of 1b, the reaction time was reduced to 4 h and 2 h, respectively. Methylaminolysis of N‐(2‐ethylphenyl)phthalimide (1c) gave 80% of the desired primary amines after 1.7 h (at added [NaOH] = 0). The reaction time was reduced to 1 h and 0.7 h when 1 eq. and 25 eq. of NaOH were added to the reaction mixture after the complete disappearance of 1c.

Triplet states and energy back transfer of carbazole derivatives

Intermolecular interactions among π conjugated semiconducting molecules often give rise to totally different optical behaviours between the solid state and dilute phases. Phosphorescence spectra observed in the solid state are often lowered compared with dilute forms resulting in the red-shift of the phosphorescence spectra. Here, we demonstrate that this red-shift can be reduced by introducing side groups. We also show that such a shift is a function of interchromophoric distance with fast exponential decay. Furthermore, we show conclusively that triplet exciton transfer between the hosts and the bis[2-(4F,6-difluorophenyl)pyridinato-C2,N](picolinato)iridium(III) can be described in terms of the Boltzmann factor using triplet energies obtained from the solid state. These results will have implications in molecular design that utilizes triplet excitons such as organic light emitting diodes and singlet fission solar cells.

Rational Design and Synthesis of New, High Efficiency, Multipotent Schiff Base-1,2,4-triazole Antioxidants Bearing Butylated Hydroxytoluene Moieties

A new series of multipotent antioxidants (MPAOs), namely Schiff base-1,2,4-triazoles attached to the oxygen-derived free radical scavenging moiety butylated hydroxytoluene (BHT) were designed and subsequently synthesized. The structure-activity relationship (SAR) of the designed antioxidants was established alongside the prediction of activity spectra for substances (PASS). The antioxidant activities of the synthesized compounds 4–10 were tested by the DPPH bioassay. The synthesized compounds 4–10 inhibited stable DPPH free radicals at a level that is 10−4 M more than the well-known standard antioxidant BHT. Compounds 8–10 with para-substituents were less active than compounds 4 and 5 with trimethoxy substituents compared to those with a second BHT moiety (compounds 6 and 7). With an IC50 of 46.13 ± 0.31 µM, compound 6 exhibited the most promising in vitro inhibition at 89%. Therefore, novel MPAOs containing active triazole rings, thioethers, Schiff bases, and BHT moieties are suggested as potential antioxidants for inhibiting oxidative stress processes and scavenging free radicals, hence, this combination of functions is anticipated to play a vital role in repairing cellular damage, preventing various human diseases and in medical therapeutic applications.

Polyphenols from the extract and fraction of T-indica seeds protected HepG2 cells against oxidative stress

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.

N-Acetyl-2-hydroxy-N'-[methoxy(1-methylindol-2-yl)methyl]benzohydrazide.

In the crystal structure of the title Schiff-base, C20H21N3O4, the amino group forms an N—H⋯O hydrogen bond to the acetyl group of an adjacent molecule, forming a zigzag chain. The 2-hydroxy group is internally hydrogen bonded to the amido group though an O—H⋯O hydrogen bond.

N'-(3,5-Di-tert-butyl-4-hydroxy-benzyl-idene)-2-hydroxy-benzohydrazide methanol solvate.

The asymmetric unit of the title compound, C(22)H(28)N(2)O(3)·CH(4)O, consists of two independent Schiff base mol-ecules and two independent methanol solvent mol-ecules. In one Schiff base mol-ecule, the 2-hydr-oxy group forms an intra-molecular hydrogen bond with the amide O atom, whereas in the other Schiff base mol-ecule, the 2-hydr-oxy-substituted benzene ring is oriented so that the 2-hydr-oxy group serves as hydrogen-bond acceptor for the amide NH group. In the crystal structure, Schiff base mol-ecules inter-act with methanol solvent to furnish a hydrogen-bonded chain.