Huda, Salah Kareem (2016) Synthesis and antioxidant activity of conjugated oligo-aromatic compounds containing a 3,4,5-trimethoxybenzyl substituent / Huda Salah Kareem. PhD thesis, University of Malaya.
Abstract
The main aim of the thesis was the synthesis, characterization and investigation of new synthetic compounds bearing the well-known 3,4,5-trimethoxybenzyloxy free radical scavenger group. The compounds are aimed as potential antioxidants to reduce free radical-induced cell damage. Theoretical calculations obtained by DMOL3 based on density functional theory (DFT) were used to rationalize the antioxidant activities. The theoretical investigation emphasized on a hydrogen atom transfer (HAT) mechanism. Therefore, the bond dissociation energy (BDE) for the most active (weakest) X-H bond (where X= O, N, S) in each molecule was compared. The key compound, 4-(3,4,5-trimethoxybenzyloxy)benzohydrazide, was synthesized by reacting hydrazine hydrate with ethyl 4-(3,4,5-trimethoxybenzyloxy) benzoate. It was converted into series of hydrazone and thiosemicarbazide derivatives. Besides, reaction of the hydrazide with carbon disulfide furnished 5-(4-(3,4,5-trimethoxybenzyloxy) phenyl)-1,3,4-oxadiazole-2-(3H)-thione, which was subsequently converted into a series of s-alkylated derivatives. Treatment of the thiosemicarbazide with 4N NaOH led to a series of 1,2,4-triazoles, for a thiosemicarbazide with an electron-withdrawing nitro- group, which led to the hydrolysis of the thiosemicarbazide instead. All synthesized compounds were characterized by IR, NMR and mass spectral analyses. The free radical scavenging activities of the synthesized compounds were investigated by DPPH and FRAP assays, using ascorbic acid and BHT as references. The DPPH radical scavenging activity, which is applicable to reaction based on both HAT and single electron transfer (SET), depended on the type and the position of substituents of the compounds at the varied aromatic group. iv Hydrazone derivatives with a hydroxyl group at the para position and additional electron donating groups (EDGs) at the ortho position of the phenyl ring of the aldehyde component, showed high free radical scavenging activities. In contrast, electron withdrawing groups (EWGs) decreased the activity. Some of the compounds exhibited potent antioxidant activities that were equal to or better than the reference compound BHT. One of the 1,3,4,-oxadizole derivatives exhibited a strong scavenging effect on the DPPH radical, due to the exchangeable proton between the –NH and –SH groups in the oxadiazole ring. However, S-alkylation of this compound eliminated this activity. The thiosemicarbazides exhibited stronger inhibitory effects on the DPPH radical than the reference compounds, ascorbic acid and BHT. The most active compound bore a strong electron withdrawing nitro group at the para position of the phenyl group. Cyclization of the thiosemicarbazides reduced the radical scavenging abilities. The FRAP assay showed different trends than the DPPH radical scavenging results. Some of the compounds exhibited high activities in the FRAP assay while showing low activity in the DPPH assay. High FRAP activities were obtained for acid hydrazide as well as one of the hydrazone derivatives. Most of the investigated compounds exhibited low activities in the FRAP assay. Thiosemicarbazides were highly active in both antioxidant assays, i.e. DPPH and FRAP. Therefore they deserve attention in the synthesis of bioactive compounds.
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