Biomedical subjects

Sarel F Malan

Publications and source records attributed to Sarel F Malan.

15 recordsLinked to original sources

PubMed2006

Structure-activity relationships of pentacycloundecylamines at the N-methyl-d-aspartate receptor.

Prompted by our interest in neuroprotective agents with multiple mechanisms of action, we assessed the structure-activity relationship of a series of pentacycloundecylamine derivatives previously shown to have both L-type calcium channel blocking activity and N-methyl-d-aspartate receptor (NMDAR) antagonistic activity. We utilized a functional assay to measure NMDAR channel block using (45)Ca(2+) influx into synaptoneurosomes. The cage amine 8-benzylamino-8,11-oxapentacyclo[5.4.0.0(2,6). 0(3,10).0(5,9)]undecane (NPG1-01) proved to be the most potent experimental compound with an IC(50) of 2.98microM, while 8-amino-pentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane had the next most potent IC(50) of 4.06microM. Increasing the polycyclic cage size of NGP1-01 from a pentacycloundecane to a tridecane cage structure, but retaining the N-benzyl moiety decreased potency 10-fold, indicating a limitation on the volume of the cage that can be accommodated in the channel binding site. In the presence of NGP1-01, NMDA/glycine-induced maximal (45)Ca(2+) influx was attenuated by 34% with an insignificant effect on agonist potency. These results are consistent with uncompetitive antagonism for this group of compounds. Radioligand binding studies with [(3)H]MK-801 or [(3)H]TCP showed little or no displacement of these ligands by pentacycloundecylamines, suggesting that the latter compounds bind to a unique site in the NMDAR channel. The pentacycloundecylamines tested represent a novel group of NMDAR antagonists that have potential as therapeutic agents for neurodegenerative diseases including Parkinson's and Alzheimer's disease.

Amines↗

PubMed2006

Inhibition of monoamine oxidase B by analogues of the adenosine A2A receptor antagonist (E)-8-(3-chlorostyryl)caffeine (CSC).

The adenosine A2A receptor has emerged as a possible target for the treatment of Parkinson's disease (PD). Evidence suggests that antagonism of the A2A receptor not only improves the symptoms of the disease but may also protect against the underlying degenerative processes. We have recently reported that several known adenosine A2A receptor antagonists (A2A antagonists) also are moderate to very potent inhibitors of monoamine oxidase B (MAO-B). The most potent among these was (E)-8-(3-chlorostyryl)caffeine (CSC), a compound frequently used when examining the in vivo pharmacological effects of A2A antagonists. Since MAO-B inhibitors are also thought to possess antiparkinsonian properties, dual targeting drugs that block both MAO-B and A2A receptors may have enhanced therapeutic potential in the treatment of PD. In this study, we prepared selected analogues of CSC in an attempt to examine specific structural features that may be important for potent MAO-B inhibition. The results of a SAR study established that the potency of MAO-B inhibition by (E)-8-styrylcaffeinyl analogues depends upon the van der Waals volume (V(w)), lipophilicity (pi), and the Hammett constant (sigma(m)) of the substituents attached to C-3 of the phenyl ring of the styryl moiety. Potency also varies with substituents attached to C-4 with bulkiness (V(w)) and lipophilicity (pi) being the principal substituent descriptors.

Adenosine A2 Receptor Antagonists↗

PubMed2005

Effect of polycyclic cage amines on the transmembrane potential of neuronal cells.

A series of pentacycloundecylamine derivatives were synthesized and their influence on the transmembrane potential of human SH-SY5Y neuroblastoma cells was evaluated using laser scanning confocal microscopy in combination with the potentiometric dye tetramethylrhodamine methyl ester. Results indicate that these derivatives influence the profile of KCl-induced membrane depolarization and cause an overall reduction in cell membrane depolarization.

Amines↗

PubMed2005

Anti-inflammatory activity and QSAR studies of compounds isolated from Hyacinthaceae species and Tachiadenus longiflorus Griseb. (Gentianaceae).

Twenty-two homoisoflavanones and structurally related compounds isolated from plants were screened for anti-inflammatory activity. Seventeen compounds were isolated from southern African Hyacinthaceae species, one from the Madagascan gentian Tachiadenus longiflorus Griseb. and four were of synthetic origin. Inhibition of prostaglandin synthesis in cell microsomal fractions was first evaluated, followed by screening for specific inhibition of isolated cyclooxygenase enzymes (COX-1 and COX-2). Six homoisoflavanone and structurally related compounds showed significantly high levels of anti-inflammatory activity in the microsomal fraction assay. Only one compound exhibited a high level of anti-inflammatory activity in the COX-1 enzyme assay and no significant activity was detected in the COX-2 enzyme assay. Biological screening was followed by a computer-based quantitative structure-activity relationship (QSAR) study. The physicochemical descriptors: strain energy, heat of formation, volume, surface area, aqueous phase energy, dipole moment, enthalpy, entropy, molar refractivity, parachor, density, refractive index, surface tension, polarizability, logP, Van der Waals interaction energy, Coulombic interaction energy and nonbonded interaction energy were used to characterize the structures of the homoisoflavanones and structurally related compounds. This study produced three equations with significant prediction values for the anti-inflammatory activity of the compounds investigated. The derived models also provided valuable parameter guidelines for those properties influencing the anti-inflammatory activity of the studied compounds.

Animals↗

PubMed2005

Pharmacology and structure-activity relationships of bioactive polycyclic cage compounds: a focus on pentacycloundecane derivatives.

The chemistry of organic polycyclic cage compounds has intrigued medicinal chemists for over 50 years, yet little is published about their pharmacological profiles. Polycyclic cage compounds have important pharmaceutical applications, ranging from the symptomatic and proposed curative treatment of neurodegenerative diseases such as Parkinson's and Alzheimer's disease (e.g., amantadine and memantine), to use as anti-viral agents against influenza and the immunodeficiency virus (HIV). The polycyclic cage appears to be a useful scaffold to yield drugs with a wide scope of applications, and can be used also to modify and improve the pharmacokinetic and pharmacodynamic properties of drugs in current use. This review attempts to summarize the pharmacological profiles of polycyclic cage compounds with an emphasis on the lesser known pentacycloundecanes, homocubanes, and trishomocubanes.

Anti-Inflammatory Agents↗

PubMed2005

The relationship between surface adsorption and the hydrolysis of amitraz in anionic surfactant solutions.

The adsorption of amitraz to various adsorbents was studied in terms of the amount and rate of adsorption and the effect that adsorption had on the stability of amitraz in an aqueous environment. Adsorption results showed that in terms of their ability to adsorb amitraz from solution the adsorbents tested in this study can be ordered as follows: coarse carbon > cation exchange resin > or = anion exchange resin > fine carbon. Amitraz was not adsorbed on sand and potassium oxihumate. Adding sodium lauryl sulfate and potassium oxihumate to aqueous suspensions of suspended adsorbents containing adsorbed amitraz showed that both these anionic surfactants significantly increased the hydrolysis rate because the half-lives for amitraz was reduced from 27 days for a suspension to only 8 hours for amitraz adsorbed to a cation exchange resin and suspended in an aqueous buffer pH 5.8 containing 0.5% of the anionic surfactant sodium lauryl sulfate and 12 hours when 1% potassium oxihumate was added.

Adsorption↗

PubMed2004

Fluorescent ligands for the histamine H2 receptor: synthesis and preliminary characterization.

3-[3-(Piperidinomethyl)phenoxy]alkyl, N-cyano-N'-[omega-[3-(1-piperidinylmethyl)phenoxy]alkyl]guanidine and 2-(5-methyl-4-imidazolyl)methyl thioethyl derivatives containing fluorescent functionalities were synthesized and the histamine H2 receptor affinity was evaluated using the H2 antagonist [125I]-aminopotentidine. The compounds exhibited weak to potent H2 receptor affinity with pKi values ranging from <4 to 8.85. The highest H2 receptor affinity was observed for N-cyano-N'-[omega-[3-(1-piperidinylmethyl)phenoxy]alkyl]guanidines substituted with methylanthranilate (13), cyanoindolizine (6) and cyanoisoindole (11) moieties via an ethyl or propyl linker.

Fluorescent Dyes↗

PubMed2004

Synthesis and biological evaluation of pentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane derivatives as potential therapeutic agents in Parkinson's disease.

In previous studies, the polycyclic cage amine 8-benzylamino-8,11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane (NGP1-01) and a number of its derivatives showed positive effects in neuroprotection studies with MPTP, in vivo. In view of these findings, we examined these compounds for their effects on [(3)H]dopamine ([(3)H]DA) release and uptake inhibition in murine striatal synaptosomes, as well as for inhibition of baboon liver monoamine oxidase (MAO) B. In order to assess specificity, initial experiments focused on compounds that blocked dopamine uptake without causing appreciable release (<40% at 100 microM) of the transmitter. NGP1-01 blocked the uptake of [(3)H]DA with an IC(50) of 57 microM, while another compound, 8-phenylethyl-8,11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane, blocked uptake at an IC(50) value of 23 microM. These values were comparable to that of another polycyclic cage amine, amantadine (IC(50); 82 micro), that is used in parkinsonian therapy. Structure-activity relationships of this series of compounds support the importance of geometric and steric, rather than electronic effects, in determining biological activity. MAO-B inhibition for this group was weak, with less than 50% inhibition at 300 microM for any of the compounds in the series. The present study suggests that blockage of the dopamine transporter may underlie, at least in part, their neuroprotective effects against MPTP-induced parkinsonism. These compounds may be considered as potential lead compounds for Parkinson's Disease therapy.

Animals↗

PubMed2004

Preparation and physicochemical characterization of 5 niclosamide solvates and 1 hemisolvate.

The purpose of the study was to characterize the physicochemical, structural, and spectral properties of the 1:1 niclosamide and methanol, diethyl ether, dimethyl sulfoxide, N,N' dimethylformamide, and tetrahydrofuran solvates and the 2:1 niclosamide and tetraethylene glycol hemisolvate prepared by recrystallization from these organic solvents. Structural, spectral, and thermal analysis results confirmed the presence of the solvents and differences in the structural properties of these solvates. In addition, differences in the activation energy of desolvation, batch solution calorimetry, and the aqueous solubility at 25 degrees C, 24 hours, showed the stability of the solvates to be in the order: anhydrate > diethyl ether solvate > tetraethylene glycol hemisolvate > methanol solvate > dimethyl sulfoxide solvate > N,N' dimethylformamide solvate. The intrinsic and powder dissolution rates of the solvates were in the order: anhydrate > diethyl ether solvate > tetraethylene glycol hemisolvate > N,N' dimethylformamide solvate > methanol solvate > dimethyl sulfoxide solvate. Although these nonaqueous solvates had higher solubility and dissolution rates than the monohydrous forms, they were unstable in aqueous media and rapidly transformed to one of the monohydrous forms.

Chemical Phenomena↗

PubMed2004

Comparison of the physical and chemical stability of niclosamide crystal forms in aqueous versus nonaqueous suspensions.

In an effort to produce physically stable and pharmaceutically acceptable suspensions of niclosamide, this study reports the differences in physical and chemical stability of aqueous vs. nonaqueous suspensions of a niclosamide anhydrate, two monohydrates HA and HB, a 1:1 niclosamide N,N-dimethylformamide solvate, a 1:1 niclosamide dimethyl sulfoxide solvate, a 1:1 niclosamide methanol solvate, and a 2:1 niclosamide tetraethylene glycol hemisolvate. Evaluation of aqueous and nonaqueous suspensions showed that in aqueous suspensions anhydrous, and solvated niclosamide crystal forms were transformed to a monohydrate, HA, which was reasonably stable but which did eventually transform to the most stable monohydrate HB. The order in which these crystal forms transformed to monohydrate HB were: Anhydrate > N,N-dimethylformamide > dimethyl sulfoxide > methanol > tetraethylene glycol > monohydrate HA. In a nonaqueous propylene glycol vehicle, the transformation to the monohydrous forms was not observed and on desolvation the solvated crystals transformed to the anhydrous form. In all cases, immediately upon desolvation or dehydration, the crystal structures of the desolvated materials were similar to that of the solvated materials. However, the isomorphic structures, formed after desolvation, were unstable and rehydrated or resolvated when exposed to the solvent or converted to the anhydrous form in a dry environment. The crystal forms remained chemically stable in both aqueous and nonaqueous suspensions for the length of the study.

Antinematodal Agents↗

PubMed2003

Physicochemical prediction of a brain-blood distribution profile in polycyclic amines.

Recent investigation into the pharmacological character of the pentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecyl and related polycyclic amines has revealed interesting facts regarding their possible use as neuroprotective agents. At this stage however, a clear shortcoming in the quest for further development of this novel class of compounds is the lack of concrete data on their ability to cross the blood-brain barrier (BBB). Working towards the aim of predicting BBB permeability, a series of related N-substituted 8-amino-8,11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecanes were synthesised. Compounds were characterised by both experimental and calculative methods, followed by biological assessment and statistical manipulation of the results obtained. In doing so, a simple biological model was established for the comparative evaluation of brain-blood distribution properties within the class. A highly sensitive ESI-MS.MS analytical procedure was developed for the detection of these compounds in biological tissues, indicating significant drug concentrations in the brain after intraperitoneal administration to C57Bl/6 mice. Stepwise multiple linear regression analysis of all data yielded two meaningful models (R(2)=0.9996 and R(2)=0.7749) depicting lipophilicity (log P(oct)), solvent accessible molecular volume (SV), molar refractivity (MR) and system energy as the prime determinants of the brain-blood profile for these amines. The inherently high lipophilicity potential within the series is attributed to strong hydrophobic influences dominating hydrogen bonding effects. A possible conformational and energy dependent preference at the site of permeation is also suggested. The proposed estimations allow for the expedient and reliable prediction of brain partitioning behaviour for related polycyclic amines, facilitating the early rejection of unsuitable candidates and enabling research to focus on neuroprotective activity.

Amines↗

PubMed2003

Screening of novel pentacyclo-undecylamines for neuroprotective activity.

A novel series of pentacyclo-undecylamines with 8-benzylamino-8,11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane (NGP1-01) as the lead compound was synthesised and screened for neuroprotective activity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) parkinsonian mouse model. We hypothesise that these compounds may attenuate excitotoxic neuronal cell death mediated through the NMDA receptor (similar to memantine), and through calcium channel block. The pentacyclo-undecylamines (300 mg/kg) were administered to C57BL/6 mice 30 min before intraperitoneal (i.p.) MPTP administration (35 mg/kg). Striatal dopamine, 3,4-hydroxyphenylacetic acid (DOPAC), and homovanillic acid levels were analysed 10 days later by means of HPLC with electrochemical detection. Increased levels of DOPAC and homovanillic acid were observed when some of the test compounds were administered together with MPTP (compared to animals receiving only MPTP). One compound in the series, 8-phenylethylamino-8,11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane, attenuated MPTP-induced striatal dopamine depletion when compared to animals treated with MPTP only (p<0.05).

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2003

The structure and ion channel activity of 6-benzylamino-3-hydroxyhexa-cyclo[6.5.0.0(3,7).0(4,12).0(5,10).0(9,13]tridecane.

A novel compound, 6-benzylamino-3-hydroxyhexacyclo [6.5.0.0(3, 7).0(4, 12).0(5, 10).0(9, 13)]-tridecane, was synthesized as part of an ongoing study to explore the ion channel activity of polycyclic cage amines. The known polycyclic calcium channel antagonist, 8-benzylamino-8, 11-oxapentacyclo [5.4.0.0(2, 6).0(3, 10).0(5, 9)]undecane (NGP 1-01) served as the lead compound and as a positive control for channel activity. The title compound inhibited calcium currents at test concentrations of 10 microM at depolarized membrane potentials (in the potential range where the L-type calcium channel inactivates). At the test concentrations modulating effects were also observed for sodium and the delayed rectifier potassium currents. Due to its activity at both Ca(2+) and Na(+) channels, this compound may offer utility as a cardiovascular and/or neuroprotecting agent.

Animals↗

PubMed2002

The activity of p-methoxybenzylisothiocyanate against Neisseria gonorrhoeae, Haemophilus ducreyi, and other microorganisms.

p-Methoxybenzylisothiocyanate was isolated from Lepidium bonariense and found to be responsible for the plants antimicrobial and STD activity. MIC determinations were conducted for p-methoxybenzylisothiocyanate on Haemophilus ducreyi, Neisseria gonorrheae, Candida albicans, Bacillus subtilus, Micrococcus luteus, Staphylococcus aureus, Enterobacter sp., Escherichia coli, Klebsiella pneumoniae, and Psuedomanas aeruginosa. An in vitro cellular toxicity assay showed that at 100 microM (17,9 microg/mL) p-methoxybenzylisothiocyanate is not toxic to living cells.

Bacteria↗

PubMed2002

Antimalarial compounds from Parinari capensis.

The antimalarial activity of the raw petroleum ether and dichloromethane extracts of the stems of Parinari capensis (Chrysobalanceae) was determined. Phytochemical investigation of these extracts led to the isolation of three diterpene lactones that possess antimalarial activity with IC(50) values of 0.54, 0.67, and 1.57 microg/mL. Although their antimalarial activity is promising, the toxicity profiles of these diterpene lactones prevent further biological evaluation. They could however be used effectively as lead compounds in the synthesis of novel antimalarial agents.

Animals↗