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Fulltext 3,4,5-Trihydr-oxy-N'-(2-hydr-oxy-5-nitro-benzyl-idene)benzohydrazide mono-hydrate

Abdul Alhadi AA, Ali HM, Ng SW

Acta Crystallogr Sect E Struct Rep Online, 2009;65(Pt 4):o908.
PMID: 21582611 DOI: 10.1107/S1600536809010563

The benzohydrazide mol-ecule of the title compound, C(14)H(11)N(3)O(7)·H(2)O, is planar (r.m.s. deviation = 0.068 Å). The benzohydrazide mol-ecule and the uncoordinated water mol-ecule inter-act through O-H⋯O hydrogen bonds; these together with O-H⋯N and N-H⋯O hydrogen bonds form a three-dimensional network.
Fulltext N'-(5-Chloro-2-hydroxy-benzyl-idene)-3,4,5-trihydroxy-benzohydrazide dihydrate

Abdul Alhadi AA, Ali HM, Ng SW

Acta Crystallogr Sect E Struct Rep Online, 2009;65(Pt 4):o910.
PMID: 21582613 DOI: 10.1107/S1600536809010812

The benzohydrazide mol-ecule in the title dihydrate, C(14)H(11)ClN(2)O(5)·2H(2)O, is non-planar, with the two aromatic rings at either side of the -C(=O)-NH-N=CH- unit forming a dihedral angle of 29.7 (2)°. The benzohydrazide mol-ecule is linked to the water mol-ecules by O-H⋯O and N-H⋯O hydrogen bonds, with other O-H⋯O hydrogen bonds leading to a layer structure.
Fulltext N'-(3-Bromo-5-chloro-2-hydroxy-benzyl-idene)-3,4,5-trihydroxy-benzohydrazide methanol solvate

Abdul Alhadi AA, Ali HM, Ng SW

Acta Crystallogr Sect E Struct Rep Online, 2009;65(Pt 4):o909.
PMID: 21582612 DOI: 10.1107/S1600536809010575

The benzohydrazide mol-ecule of the title compound, C(14)H(10)BrClN(2)O(5)·CH(3)OH, is non-planar, the two aromatic rings at either side of the -C(=O)-NH-N=CH- unit being twisted by 5.9 (1)°. The benzohydrazide mol-ecule is linked to the solvent mol-ecule by an O-H⋯O hydrogen bond. Mol-ecules are connected by further O-H⋯O hydrogen bonds and an N-H⋯O link into a two-dimensional array.
PASS-assisted design, synthesis and antioxidant evaluation of new butylated hydroxytoluene derivatives

Ariffin A, Rahman NA, Yehye WA, Alhadi AA, Kadir FA

Eur J Med Chem, 2014 Nov 24;87:564-77.
PMID: 25299680 DOI: 10.1016/j.ejmech.2014.10.001

New multipotent antioxidants (MPAOs), namely 1,3,4-thiadiazoles and 1,2,4-triazoles bearing the well-known free radical scavenger butylated hydroxytoluene (BHT), were designed and synthesized using an acid-(base-) catalyzed intramolecular dehydrative cyclization reaction of the corresponding 1-acylthiosemicarbazides. The structure-activity relationship (SAR) of the designed antioxidants was performed along with the prediction of activity spectra for substances (PASS) training set. Experimental studies based on antioxidant activity using DPPH and lipid peroxidation assays verified the predictions obtained by the PASS-assisted design strategy. Compounds 4a-b, 5a-b and 6a-b showed an inhibition of stable DPPH free radicals at a 10(-4) M more than the well-known standard antioxidant BHT. Compounds with p-methoxy substituents (4b, 5b and 6b) were more active than o-methoxy substituents (4a, 5a and 6a). With an IC50 of 2.85 ± 1.09 μM, compound 6b exhibited the most promising in vitro inhibition of lipid peroxidation, inhibiting Fe(2+)-induced lipid peroxidation of essential oils derived from the egg yolk-based lipid-rich medium by 86.4%. The parameters for the drug-likeness of these BHT derivatives were also evaluated according to Lipinski's 'rule-of-five'. All of the BHT derivatives were found to violate one of Lipinski's parameters (Log P ≥ 5) even though they have been found to be soluble in protic solvents. The predictive TPSA and %ABS data allow for the conclusion that these compounds could have a good capacity for penetrating cell membranes. Therefore, these novel MPAOs containing lipophilic and hydrophilic groups can be proposed as potential antioxidants for tackling oxidative stress and lipid peroxidation processes.
Fulltext Butylated hydroxytoluene analogs: synthesis and evaluation of their multipotent antioxidant activities

Yehye WA, Abdul Rahman N, Alhadi AA, Khaledi H, Weng NS, Ariffin A

Molecules, 2012 Jun 25;17(7):7645-65.
PMID: 22732881 DOI: 10.3390/molecules17077645

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.
Antioxidant, cytotoxic activities, and structure-activity relationship of gallic acid-based indole derivatives

Khaledi H, Alhadi AA, Yehye WA, Ali HM, Abdulla MA, Hassandarvish P

Arch Pharm (Weinheim), 2011 Nov;344(11):703-9.
PMID: 21953995 DOI: 10.1002/ardp.201000223

A new series of gallic hydrazones containing an indole moiety was synthesized through the reaction of gallic hydrazide and different indole carboxaldehydes. Their antioxidant activities were determined on DPPH radical scavenging and inhibition of lipid peroxidation. The in-vitro cytotoxic activities of the compounds were evaluated against HCT-116 (human colon cancer cell line) and MCF-7 (estrogen-dependent human breast cancer cell line) by the MTT method. An attempt to correlate the biological results with their structural characteristics has been done. A limited positive structure activity relationship was found between cytotoxic and antioxidant activities.
Fulltext 2-Hydr-oxy-5-nitro-benzaldehyde thio-semicarbazone

Alhadi AA, Ali HM, Puvaneswary S, Robinson WT, Ng SW

Acta Crystallogr Sect E Struct Rep Online, 2008;64(Pt 8):o1606.
PMID: 21203299 DOI: 10.1107/S1600536808022976

The mol-ecule of the title compound, C(8)H(8)N(4)O(3)S, is planar. Adjacent mol-ecules are linked through O-H⋯S, N-H⋯S and N-H⋯O hydrogen bonds into a three-dimensional network.
Fulltext N'-(5-Bromo-2-hydroxy-benzyl-idene)-3,4,5-trihydroxy-benzohydrazide dihydrate

Alhadi AA, Ali HM, Puvaneswary S, Robinson WT, Ng SW

Acta Crystallogr Sect E Struct Rep Online, 2008;64(Pt 8):o1584.
PMID: 21203282 DOI: 10.1107/S1600536808022708

The title compound, C(14)H(11)BrN(2)O(5)·2H(2)O, crystallizes as hydrogen-bonded sheets. The 2-hydr-oxy group on the benzyl-idene group forms an intra-molecular hydrogen bond to the N atom of the C=N double bond. The amino N atom is a hydrogen-bond donor to a water mol-ecule. The hydr-oxy group on the benzohydrazide group is a hydrogen-bond donor to one acceptor site, whereas each water mol-ecule is a hydrogen-bond donor to two acceptor sites.
Understanding the chemistry behind the antioxidant activities of butylated hydroxytoluene (BHT): a review

Yehye WA, Rahman NA, Ariffin A, Abd Hamid SB, Alhadi AA, Kadir FA, et al.

Eur J Med Chem, 2015 Aug 28;101:295-312.
PMID: 26150290 DOI: 10.1016/j.ejmech.2015.06.026

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.
Fulltext -Chemical profiling and biological activity of Peperomia blanda (Jacq.) Kunth

Al-Madhagi WM, Mohd Hashim N, Awad Ali NA, Alhadi AA, Abdul Halim SN, Othman R

PeerJ, 2018;6:e4839.
PMID: 29892499 DOI: 10.7717/peerj.4839

Background: Peperomia belongs to the family of Piperaceae. It has different uses in folk medicine and contains rare compounds that have led to increased interest in this genus. Peperomia blanda (Jacq.) Kunth is used as an injury disinfectant by Yemeni people. In addition, the majority of Yemen's population still depend on the traditional remedy for serious diseases such as cancer, inflammation and infection. Currently, there is a deficiency of scientific evidence with regards to the medicinal plants from Yemen. Therefore, this study was performed to assess the chemical profile and in vitro antioxidant and cytotoxic activities of P. blanda.
Methods: Chemical profiling of P. blanda was carried out using gas chromatography mass spectrometry (GCMS) followed by isolation of bioactive compounds by column chromatography. DPPH• and FRAP assays were used to evaluate antioxidant activity and the MTT assay was performed to estimate the cytotoxicity activity against three cancer cell lines, namely MCF-7, HL-60 and WEHI-3, and three normal cell lines, MCF10A, WRL-68 and HDFa.
Results: X-ray crystallographic data for peperomin A is reported for the first time here and N,N'-diphenethyloxamide was isolated for the first time from Peperomia blanda. Methanol and dichloromethane extracts showed high radical scavenging activity with an IC50 of 36.81 ± 0.09 µg/mL, followed by the dichloromethane extract at 61.78 ± 0.02 µg/mL, whereas the weak ferric reducing activity of P. blanda extracts ranging from 162.2 ± 0.80 to 381.5 ± 1.31 µg/mL were recorded. In addition, petroleum ether crude extract exhibited the highest cytotoxic activity against all the tested cancer cell lines with IC50 values of 9.54 ± 0.30, 4.30 ± 0.90 and 5.39 ± 0.34 µg/mL, respectively. Peperomin A and the isolated mixture of phytosterol (stigmasterol and β-sitosterol) exhibited cytotoxic activity against MCF-7 and WE-HI cell lines with an IC50 of (5.58 ± 0.47, 4.62 ± 0.03 µg/mL) and (8.94 ± 0.05, 9.84 ± 0.61 µg/mL), respectively, compared to a standard drug, taxol, that has IC50 values of 3.56 ± 0.34 and 1.90 ± 0.9 µg/mL, respectively.
Conclusion: The activities of P. blanda extracts and isolated compounds recorded in this study underlines the potential that makes this plant a valuable source for further study on anticancer and antioxidant activities.
Fulltext Synthesis, PASS-Predication and in Vitro Antimicrobial Activity of Benzyl 4-O-benzoyl-α-l-rhamnopyranoside Derivatives

Matin MM, Nath AR, Saad O, Bhuiyan MM, Kadir FA, Abd Hamid SB, et al.

Int J Mol Sci, 2016 Aug 27;17(9).
PMID: 27618893 DOI: 10.3390/ijms17091412

Benzyl α-l-rhamnopyranoside 4, obtained by both conventional and microwave assisted glycosidation techniques, was subjected to 2,3-O-isopropylidene protection to yield compound 5 which on benzoylation and subsequent deprotection of isopropylidene group gave the desired 4-O-benzoylrhamnopyranoside 7 in reasonable yield. Di-O-acetyl derivative of benzoate 7 was prepared to get newer rhamnopyranoside. The structure activity relationship (SAR) of the designed compounds was performed along with the prediction of activity spectra for substances (PASS) training set. Experimental studies based on antimicrobial activities verified the predictions obtained by the PASS software. Protected rhamnopyranosides 5 and 6 exhibited slight distortion from regular ¹C₄ conformation, probably due to the fusion of pyranose and isopropylidene ring. Synthesized rhamnopyranosides 4-8 were employed as test chemicals for in vitro antimicrobial evaluation against eight human pathogenic bacteria and two fungi. Antimicrobial and SAR study showed that the rhamnopyranosides were prone against fungal organisms as compared to that of the bacterial pathogens. Interestingly, PASS prediction of the rhamnopyranoside derivatives 4-8 were 0.49 < Pa < 0.60 (where Pa is probability 'to be active') as antibacterial and 0.65 < Pa < 0.73 as antifungal activities, which showed significant agreement with experimental data, suggesting rhamnopyranoside derivatives 4-8 were more active against pathogenic fungi as compared to human pathogenic bacteria thus, there is a more than 50% chance that the rhamnopyranoside derivative structures 4-8 have not been reported with antimicrobial activity, making it a possible valuable lead compound.
Bioassay-Guided Isolation and in Silico Study of Antibacterial Compounds From Petroleum Ether Extract of Peperomia blanda (Jacq.) Kunth

Al-Madhagi WM, Hashim NM, Awadh Ali NA, Taha H, Alhadi AA, Abdullah AA, et al.

J Chem Inf Model, 2019 05 28;59(5):1858-1872.
PMID: 31117526 DOI: 10.1021/acs.jcim.8b00969

Bioassay-guided isolation protocol was performed on petroleum ether extract of Peperomia blanda (Jacq.) Kunth using column chromatographic techniques. Five compounds were isolated and their structures were elucidated via one-dimensional (1D) and two-dimensional (2D) NMR, gas chromatography mass sectroscopy (GCMS), liquid chromatography mass spectroscopy (LCMS), and ultraviolet (UV) and infrared (IR) analyses. Dindygulerione E (a new compound), and two compounds isolated from P. blanda for the first time-namely, dindygulerione A and flavokawain A-are reported herein. Antimicrobial activity was screened against selected pathogenic microbes, and minimum inhibitory concentrations (MIC) were recorded within the range of 62-250 μg/mL. Assessment of the pharmacotherapeutic potential has also been done for the isolated compounds, using the Prediction of Activity spectra for Substances (PASS) software, and different activities of compounds were predicted. Molecular docking, molecular dynamics simulation and molecular mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) calculations have proposed the binding affinity of these compounds toward methylthioadenosine phosphorylase enzyme, which may explain their inhibitory actions.
Fulltext Rational Design and Synthesis of New, High Efficiency, Multipotent Schiff Base-1,2,4-triazole Antioxidants Bearing Butylated Hydroxytoluene Moieties

Yehye WA, Abdul Rahman N, Saad O, Ariffin A, Abd Hamid SB, Alhadi AA, et al.

Molecules, 2016 Jun 28;21(7).
PMID: 27367658 DOI: 10.3390/molecules21070847

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.
Fulltext Synthesis, characterization, X-ray crystallography, acetyl cholinesterase inhibition and antioxidant activities of some novel ketone derivatives of gallic hydrazide-derived Schiff bases

Gwaram NS, Ali HM, Abdulla MA, Buckle MJ, Sukumaran SD, Chung LY, et al.

Molecules, 2012 Feb 28;17(3):2408-27.
PMID: 22374313 DOI: 10.3390/molecules17032408

Alzheimer's disease (AD) is the most common form of dementia among older people and the pathogenesis of this disease is associated with oxidative stress. Acetylcholinesterase inhibitors with antioxidant activities are considered potential treatments for AD. Some novel ketone derivatives of gallic hydrazide-derived Schiff bases were synthesized and examined for their antioxidant activities and in vitro and in silico acetyl cholinesterase inhibition. The compounds were characterized using spectroscopy and X-ray crystallography. The ferric reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays revealed that all the compounds have strong antioxidant activities. N-(1-(5-bromo-2-hydroxyphenyl)-ethylidene)-3,4,5-trihydroxybenzohydrazide (2) was the most potent inhibitor of human acetyl cholinesterase, giving an inhibition rate of 77% at 100 μM. Molecular docking simulation of the ligand-enzyme complex suggested that the ligand may be positioned in the enzyme's active-site gorge, interacting with residues in the peripheral anionic subsite (PAS) and acyl binding pocket (ABP). The current work warrants further preclinical studies to assess the potential for these novel compounds for the treatment of AD.

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