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Fulltext Conjugated Oligo-Aromatic Compounds Bearing a 3,4,5-Trimethoxy Moiety: Investigation of Their Antioxidant Activity Correlated with a DFT Study

Kareem HS, Nordin N, Heidelberg T, Abdul-Aziz A, Ariffin A

Molecules, 2016 Feb 17;21(2).
PMID: 26901175 DOI: 10.3390/molecules21020224

A series of heterocyclic compounds bearing the well-known free radical scavenging 3,4,5-trimethoxybenzyloxy group, was synthesized. The key compound 4-(3,4,5-trimethoxybenzyl-oxy)benzohydrazide was converted into thiosemicarbazide derivatives, which were subsequently cyclized with NaOH to provide 1,2,4-triazole derivatives. Alternative treatment of the acid hydrazide with carbon disulfide in the presence of KOH led to the corresponding 1,3,4-oxadiazole and various alkylated derivatives. The newly synthesized compounds were purified and the structures of the products were elucidated and confirmed on the basis of their analytical and spectral data. Their antioxidant activities were evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH(•)) and Ferric Reducing Antioxidant Power (FRAP) assays. The thiosemicarbazide derivatives were highly active in both antioxidant assays with the lowest IC50 value for DPPH radical scavenging. Theoretical calculations based on density functional theory (DFT) were performed to understand the relative importance of NH, SH and CH hydrogens on the radical scavenging activities of these compounds.
Fulltext Respiratory diphtheria in three paediatric patients

Lee JK, Huda S, Francis A, Aisai, Jusoh M

Med J Malaysia, 1999 Sep;54(3):377-82.
PMID: 11045069

From August till November 1998, the Paediatric and Anaesthetic Units of Hospital Kuala Terengganu managed three patients from Kuala Terengganu District who were ventilated for respiratory diphtheria. Their ages were 5, 4 and 7 years old and their immunisation for diphtheria were not complete. All three patients presented with respiratory distress and were ventilated for upper airway obstruction. Their treatment included intravenous penicillin and diphtheria antitoxin. One patient died of cardiogenic shock with secondary pneumonia. Pharyngeal and tonsillar swabs of all three patients grew toxigenic Corynebacterium diphtheriae biotype mitis. There were 765 throat cultures taken from contacts. The confirmed positive cultures grew 2 toxigenic and 3 non-toxigenic Corynebacterium diphtheriae biotype mitis and surprisingly, 10 non-toxigenic biotype gravis. A prevalence study is needed to document the endemicity of diphtheria in Kuala Terengganu and to determine the carrier rate of both biotypes. Steps have been taken to increase the immunisation coverage in children. The giving of regular booster doses of diphtheria toxoid to the adult population should be considered.
Correlation of antioxidant activities with theoretical studies for new hydrazone compounds bearing a 3,4,5-trimethoxy benzyl moiety

Kareem HS, Ariffin A, Nordin N, Heidelberg T, Abdul-Aziz A, Kong KW, et al.

Eur J Med Chem, 2015 Oct 20;103:497-505.
PMID: 26402727 DOI: 10.1016/j.ejmech.2015.09.016

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.
Activation of Intrinsic Apoptosis and G1 Cell Cycle Arrest by a Triazole Precursor, N-(4-chlorophenyl)-2-(4-(3,4,5-trimethoxybenzyloxy)benzoyl)-hydrazinecarbothioamide in Breast Cancer Cell Line

Arulnathan SB, Leong KH, Ariffin A, Kareem HS, Cheah KKH

Anticancer Agents Med Chem, 2020;20(9):1072-1086.
PMID: 32188392 DOI: 10.2174/1871520620666200318100051

BACKGROUND: Oxadiazoles, triazoles, and their respective precursors have been shown to exhibit various pharmacological properties, namely antitumour activities. Cytotoxic activity was reported for these compounds in various cancer cell lines.
AIM AND OBJECTIVES: In this study, we aim at investigating the mechanism of apoptosis by N-(4-chlorophenyl)-2-(4- (3,4,5-trimethoxybenzyloxy)benzoyl)-hydrazinecarbothioamide, a triazole precursor, henceforth termed compound P7a, in breast cancer cell line, MCF-7. We first screen a series of analogues containing (3,4,5-trimethoxybenzyloxy) phenyl moiety in breast cancer cell lines (MCF-7 and MDA-MB-231) to select the most cytotoxic compound and demonstrate a dose- and time-dependent cytotoxicity. Then, we unravel the mechanism of apoptosis of P7a in MCF-7 as well as its ability to cause cell cycle arrest.
METHODS: Synthesis was performed as previously described by Kareem and co-workers. Cytotoxicity of analogues containing (3,4,5-trimethoxybenzyloxy)phenyl moiety against MCF-7 and MDA-MB-231 cell lines was evaluated using the MTS assay. Flow cytometric analyses was done using Annexin V/PI staining, JC-1 staining and ROS assay. The activity of caspases using a chemoluminescence assay and western blot analysis was conducted to study the apoptotic pathway induced by the compound in MCF-7 cells. Lastly, cell cycle analysis was conducted using flow cytometry.
RESULTS: Upon 48 hours of treatment, compound P7a inhibited the proliferation of human breast cancer cells with IC50 values of 178.92 ± 12.51μM and 33.75 ± 1.20μM for MDA-MB-231 and MCF-7, respectively. Additionally, compound P7a showed selectivity towards the cancer cell line, MCF-7 compared to the normal breast cell line, hTERT-HME1, an advantage against current anticancer drugs (tamoxifen and vinblastine). Flow cytometric analyses using different assays indicated that compound P7a significantly increased the proportion of apoptotic cells, increased mitochondria membrane permeabilisation and caused generation of ROS in MCF-7. In addition, cell cycle analysis showed that cell proliferation was arrested at the G1 phase in the MCF-7 cell line. Furthermore, upon treatment, the MCF-7 cell line showed increased activity of caspase-3/7, and caspase-9. Lastly, the western blot analysis showed the up-regulation of pro-apoptotic proteins along with up-regulation of caspase-7 and caspase-9, indicating that an intrinsic pathway of apoptosis was induced.
CONCLUSION: The results suggest that compound P7a could be a potential chemotherapeutic agent for breast cancer.
Fulltext Antioxidant and hepatorenal protective effects of bee pollen fractions against propionic acid-induced autistic feature in rats

Al-Salem HS, Al-Yousef HM, Ashour AE, Ahmed AF, Amina M, Issa IS, et al.

Food Sci Nutr, 2020 Sep;8(9):5114-5127.
PMID: 32994972 DOI: 10.1002/fsn3.1813

In the brain, propionic acid (PA) can cross cell membranes and accumulate within cells, leading to intracellular acidification, which may alter neurotransmitter release (NT), communication between neurons, and behavior. Such elevation in levels of PA constitutes a neurodevelopmental metabolic disorder called propionic acidemia, which could clinically manifest as autism. The purpose of this study was to investigate the protective effects of different fractions of bee pollen (BP) on PA-induced autism in rats, and to evaluate their effects on the expression of liver and renal biomarkers. Groups of rats received treatments of different fractions of BP at a dose of 250 mg/kg of body weight/day for a period of 1 month. Normal control group I and group II were orally administered with phosphate-buffered saline and propionic acid, respectively, for 3 days. BP contains various health-promoting phenolic components. Different fractions of BP administered pre- and post-treatment with PA showed significant reduction in the levels of liver and renal biomarkers (p S-transferase (GST), catalase CAT), and ascorbic acid (VIT C) was observed. Supplementation with BP significantly reduced biochemical changes in the liver, kidneys, and brain of rats with PA-induced toxicity. It exhibited protective effects against oxidative damage and reactive oxygen species produced by PA-induced adverse reactions in rats. Taken together, our study shows that BP possesses protective effects in PA-induced liver and kidney damage.
Fulltext Treatment of MOG antibody associated disorders: results of an international survey

Whittam DH, Karthikeayan V, Gibbons E, Kneen R, Chandratre S, Ciccarelli O, et al.

J Neurol, 2020 Dec;267(12):3565-3577.
PMID: 32623595 DOI: 10.1007/s00415-020-10026-y

INTRODUCTION: While monophasic and relapsing forms of myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD) are increasingly diagnosed world-wide, consensus on management is yet to be developed.
OBJECTIVE: To survey the current global clinical practice of clinicians treating MOGAD.
METHOD: Neurologists worldwide with expertise in treating MOGAD participated in an online survey (February-April 2019).
RESULTS: Fifty-two responses were received (response rate 60.5%) from 86 invited experts, comprising adult (78.8%, 41/52) and paediatric (21.2%, 11/52) neurologists in 22 countries. All treat acute attacks with high dose corticosteroids. If recovery is incomplete, 71.2% (37/52) proceed next to plasma exchange (PE). 45.5% (5/11) of paediatric neurologists use IV immunoglobulin (IVIg) in preference to PE. Following an acute attack, 55.8% (29/52) of respondents typically continue corticosteroids for ≥ 3 months; though less commonly when treating children. After an index event, 60% (31/51) usually start steroid-sparing maintenance therapy (MT); after ≥ 2 attacks 92.3% (48/52) would start MT. Repeat MOG antibody status is used by 52.9% (27/51) to help decide on MT initiation. Commonly used first line MTs in adults are azathioprine (30.8%, 16/52), mycophenolate mofetil (25.0%, 13/52) and rituximab (17.3%, 9/52). In children, IVIg is the preferred first line MT (54.5%; 6/11). Treatment response is monitored by MRI (53.8%; 28/52), optical coherence tomography (23.1%; 12/52) and MOG antibody titres (36.5%; 19/52). Regardless of monitoring results, 25.0% (13/52) would not stop MT.
CONCLUSION: Current treatment of MOGAD is highly variable, indicating a need for consensus-based treatment guidelines, while awaiting definitive clinical trials.