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Neurodegenerative disorders are known to be multifactorial in nature and current research focus has moved from a ‘one-drug-one-target approach’ to that of drugs which are able to act at various relevant biological targets. These drugs are designed to address more than one etiological target, thereby increasing therapeutic effect and patient compliance and may lower the likelihood of encountering unwanted side-effects. Monoamine oxidase (MAO), nitric oxide synthase (NOS), and acetylcholinesterase (AChE) are enzymes that have long been associated as potential targets for neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease. The selective inhibition of the abovementioned enzymes and other relevant CNS targets may provide promising strategies in the development of multifunctional neuroprotective therapeutic agents for the treatment/prevention of neurodegenerative disorders

The aim of this study was to design drug-like molecules with multiple neuroprotective mechanisms which would ultimately inhibit N-methyl-D-aspartate (NMDA) receptors, block L-type voltage gated calcium channels (VGCC) and inhibit apoptotic processes as well as the monoamine oxidase-B (MAO-B) enzyme in the central nervous system. These types of compounds may act as neuroprotective and symptomatic drugs for disorders such as Alzheimer’s and Parkinson’s disease. In designing the compounds we focused on the structures of rasagiline and selegiline, two well known MAO-B inhibitors and proposed neuroprotective agents. Based on this consideration, the compounds synthesised all contain the propargylamine functional group of rasagiline and selegiline or a derivative thereof, conjugated to various polycyclic cage moieties. Being non-polar, these polycyclic moieties have been shown to aid in the transport of conjugated compounds across the bloodebrain barrier, as well as cell membranes and have secondary positive neuroprotective effects. All novel synthesised polycyclic derivatives proved to have significant anti-apoptotic activity (p < 0.05) which was comparable to the positive control, selegiline. Four compounds (12, 15 and 16) showed promising VGCC and NMDA receptor channel inhibitory activity ranging from 18% to 59% in micromolar concentrations and compared favourably to the reference compounds. In the MAO-B assay, 8-phenyl-ethynyl-8-hydroxypentacycloundecane (10), exhibited MAOB inhibition of 73.32% at 300 mM. This compound also reduced the percentage of apoptotic cells by as much as 40% when compared to the control experiments

The design, development and use of small molecule fluorescent ligands to directly or indirectly study receptors, enzymes and other targets in the central nervous system (CNS) have in the recent years become an intense area of investigation, especially for use in quantitative, sensitive and direct binding assays to study target proteins, both intra- and extra-cellularly and as prodromal diagnostic tools. The rapid development of ultra sensitive fluorescent spectroscopic approaches, such as fluorescence correlation spectroscopy, flow cytometry, confocal laser scanning microscopy, fluorescence polarization and multi-photon fluorescence microscopy, is opening new scenarios for the use of small molecule fluorescent ligands in the study of CNS pharmacology. In combination with effective and efficient labeling protocols, these techniques offer enormous possibilities at both micro- and nanometer level to develop parallel multifaceted tools in pharmacological and related sciences. This review covers small molecule fluorescent ligands that have been applied to study proteins and other targets in the CNS through visualization by means of fluorescent imaging technologies.

A novel series of polycyclic amines, containing nitrogen monoxide donating moieties, were synthesised and tested for calcium channel and N-methyl-D-aspartate receptor modulating activity. The synthesised compounds were classified into two groups, based on their nitrogen monoxide donating moieties: unsaturated nitro compounds (1, 2 and 3) and nitro esters, or nitrates (4, 5 and 6). The nitrates were obtained via the reaction of hydroxyl functionalities with thionylchloride nitrate. All of the compounds synthesised exhibited significant (p < 0.01) S-nitrosylation capacity. The calcium channel activity of the polycyclic amines was evaluated using a KCl mediated fluorescent calcium flux assay. All the compounds exhibited better calcium channel antagonism than the lead structure, NGP1-01, with compound 1 exhibiting calcium channel blockade comparable to the commercially available nimodipine at concentrations of 10 μM and 1 μM. Compounds 3 and 4 inhibited calcium flux to these levels at 10 μM concentrations. NMDA/glycine mediated N-methyl-D-aspartate receptor (NMDAR) calcium influx inhibition was evaluated at a 100 µM concentration using a fluorescent calcium flux assay. All the compounds exhibited NMDAR antagonism with compounds 1 (25.4 %), 2 (20.24 %), 3 (33.14 %) and 6 (24.55 %) showing the most significant NMDAR inhibitory activity (p < 0.01). No clear correlation was observed between the S-nitrosylation capabilities of the compounds and their calcium channel activity or NMDAR channel antagonism, indicating that other factors probably play a more decisive role in the mechanism of pentacycloundecylamine channel modulation. This could include the geometric and steric bulk considerations that have been described to contribute to the channel activities of the pentacycloundecylamines. All the compounds synthesised exhibited promising calcium channel and NMDAR channel inhibitory activity and show promise as potential lead compounds for drug development against neurodegenera

Neurodegenerative disorders are frequently associated with increased oxidative damage to the brain as a result of free radicals produced by cellular respiration. The onset and progression of neurodegeneration may therefore be curbed by exogenous hydrogen-donating antioxidant moieties such as the naturally occurring flavonoids. A series of 2-phenylquinolin-4(1H)-ones was synthesised and displayed moderate to high antioxidant activity when compared to structurally related flavones and quinolines. Activity of the hydroxy-2-phenylquinolin-4(1H)-ones (8–10) was established in reducing ferrous ions and diminishing hydrogen peroxide and hydroxyl radical production, in the FRAP (1.41–97.71% Trolox® equivalents), ORAC (9.18–15.27 μM Trolox® equivalents at 0.001 mM) and TBARS (0.05–0.72 nmol MDA/mg tissue) assays, respectively. The results indicated that the additional hydrogen donating groups on the synthesised 2-phenylquinolin-4(1H)-one series increased antioxidant activity.

A series of fluorescent heterocyclic adamantane amines were synthesised with the goal to develop novel fluorescent ligands for neurological assay development. These derivatives demonstrated multifunctional neuroprotective activity through inhibition of the N-methyl-D-aspartate receptor/ion channel, calcium channels and the enzyme nitric oxide synthase. It also exhibited a high degree of free radical scavenging potential. N-(1-adamantyl)-2-oxo-chromene-3-carboxamide (8), N-adamantan-1-yl-5-dimethyl-amino-1-naphthalenesulfonic acid (11) and N-(1-cyano-2H-isoindol-2-yl) adamantan-1-amine (12) were found to possess a high degree of multifunctionality with favourable physical-chemical properties for bioavailability and blood-brain barrier permeability. The ability of these heterocyclic adamantane amine derivatives as nitric oxide synthase inhibitors, calcium channel modulators, NMDAR inhibitors and effective antioxidants, indicate that they may find application as multifunctional drugs in neuroprotection.

A series of polycyclic fluorescent ligands were synthesised and evaluated in murine striatal synaptoneurosomes for N-methyl-D-aspartate receptor (NMDAR) mediated calcium flux inhibition and inhibition of calcium influx through voltage gated calcium channels (VGCC). Amantadine (a) and N-(1-adamantyl)-1,3-propanediamine (c) substituted with 1-cyanoisoindole (3), indazole (5), dinitrobenzene (7, 8), dansyl (9, 10) and coumarin (11) moieties showed moderate to high inhibition of the NMDAR. A high degree of VGCC inhibitionwas observed for the cyanoisoindole compounds (3, 4) the dansyl compounds (9, 10) and the coumarin compound (12). Fluorophores conjugated to hydroxy-4-aza-8-oxoheptacyclotetradecane (13, 14) did not exhibit any significant VGCC inhibition, but the indazole conjugate (14) showed promising NMDAR activity. Dose response curves were calculated for selected NMDAR inhibitors (8e11) and N-[3-(1-adamantylamino)propyl]-5-dimethylaminonaphthalene-1-sulfonamide (10) exhibited the highest activity of the novel compounds. Compound 10 was further used as a fluorescent NMDAR ligand in a fluorescent competition assay utilizing MK-801, NGP1-01 and amantadine as known NMDAR inhibitors to demonstrate the possible applications of the novel fluorescent compounds. These small molecule fluorescent ligands can be considered as possible pharmacological tools in assay development and/or other investigations in the study of neurodegeneration.

A large number of diseases such as cancer, cardiovascular disease, inflammatory disease, neurodegenerative disorders and ageing are consequences of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Deoxyribonucleic acid (DNA) damage, lipid peroxidation and protein damage are biomarkers for damage in the cell caused by ROS and RNS. Various plant extracts have been tested for anti-oxidant properties. Due to the chlorophyll in the extracts, false negative results from spectrophotometric tests are often observed. A pilot study was done to determine the stability of the secondary compounds with high performance liquid chromatography (HPLC) after the samples were bleached with ultraviolet (UV) radiation and treated with activated charcoal. The chlorophyll a was successfully degraded with UV radiation in all the samples leaving a bleached extract suitable for biological assays.

Dual action antidepressants have important therapeutic implications. Methylene blue (MB), a charged compound structurally related to tricyclic antidepressants, acts on both monoamine oxidase (MAO) and the nitric oxide (NO)-cGMP pathway, and has demonstrated antidepressant activity in rodents. We investigated the antidepressant properties of MB and selected structural analogues and whether their actions involve MAO, NO synthase (NOS) and regional brain monoamines. Acute imipramine (IMI, 15 mg/kg), saline, MB, acriflavine (ACR), methylene green (MG), methylene violet (MV), thionine (THI) and tacrine (TAC) (1-60 mg/kg i.p.) were tested for antidepressant activity in the forced swim test (FST), as well as MAO-A/B inhibitory activity. Active antidepressant compounds were subsequently studied at their most effective dose during sub-chronic treatment, followed by behavioural sampling in the FST and assay of cortico-limbic monoamines and hippocampal nitrate (for NOS activity). Only IMI, MB (15, 30, 60 mg/kg) and MG (7.5, 25, 40 mg/kg) reduced immobility in the acute FST. MB, MG and ACR were potent inhibitors of especially MAO-A. Following sub-chronic treatment, IMI (15 mg/kg) increased noradrenergic behaviour in the FST, while MB (15 mg/kg) and MG (15 mg/kg) enhanced serotonergic behaviour. MB and MG bolstered cortico-limbic serotonin (5HT) levels and to a lesser extent l-norepinephrine (l-NE), but did not significantly alter regional dopamine (DA) levels. MB, and to lesser degree MG, reduced hippocampal nitrate levels. MB and MG present with structure-specific antidepressant-like effects following acute and sub-chronic treatment, possibly involving NOS and MAO-A inhibition and cortico-limbic 5HT and l-NE release. A role for MAO-B and DA appears minimal

Based on recent reports that several (E)-8-styrylcaffeinyl analogues are potent reversible inhibitors of monoamine oxidase B (MAO-B), a series of 8-benzyloxycaffeinyl analogues were synthesized and evaluated as inhibitors of baboon liver MAO-B and recombinant human MAO-A and -B. The 8-benzyloxycaffeinyl analogues were found to inhibit reversibly both MAO isoforms with enzyme–inhibitor dissociation constants (Ki values) ranging from 0.14 to 1.30 μM for the inhibition of human MAO-A, and 0.023–0.59 μM for the inhibition of human MAO-B. The most potent MAO-A inhibitor was 8-(3-methylbenzyloxy)caffeine while 8-(3-bromobenzyloxy)caffeine was the most potent MAO-B inhibitor. The analogues inhibited human and baboon MAO-B with similar potencies. A quantitative structure–activity relationship (QSAR) study indicated that the MAO-B inhibition potencies of the 8-benzyloxycaffeinyl analogues are dependent on the Hansch lipophilicity (π) and Hammett electronic (σ) constants of the substituents at C-3 of the benzyloxy ring. Electron-withdrawing substituents with a high degree of lipophilicity enhance inhibition potency. These results are discussed with reference to possible binding orientations of the inhibitors within the active site cavities of MAO-A and -B

Monoamine oxidase (MAO) is an important drug target for the treatment of neurological disorders. A series of indole and benzofuran derivatives were synthesised and evaluated as inhibitors of the two MAO isoforms, MAO-A and MAO-B. In general, the derivatives were found to be selective MAO-B inhibitors with Ki values in the nanoMolar (nM) to microMolar (μM) concentration range. The most potent MAO-B inhibitor, 3,4-dichloro-N-(2-methyl-1H-indol-5-yl)benzamide, exhibited a Ki value of 0.03 μM and was 99 fold more selective for the B isoform. We conclude that these indole and benzofuran derivatives are promising reversible MAO-B inhibitors with a possible role in the treatment of neurodegenerative diseases such as Parkinson’s disease (PD)

Based on recent reports that several (E)-8-styrylcaffeinyl analogues are potent reversible inhibitors of monoamine oxidase B (MAO-B), a series of 8-benzyloxycaffeinyl analogues were synthesized and evaluated as inhibitors of baboon liver MAO-B and recombinant human MAO-A and -B. The 8-benzyloxycaffeinyl analogues were found to inhibit reversibly both MAO isoforms with enzyme–inhibitor dissociation constants (Ki values) ranging from 0.14 to 1.30 lM for the inhibition of human MAO-A, and 0.023– 0.59 lM for the inhibition of human MAO-B. The most potent MAO-A inhibitor was 8-(3-methylbenzyloxy) caffeine while 8-(3-bromobenzyloxy)caffeine was the most potent MAO-B inhibitor. The analogues inhibited human and baboon MAO-B with similar potencies. A quantitative structure–activity relationship (QSAR) study indicated that the MAO-B inhibition potencies of the 8-benzyloxycaffeinyl analogues are dependent on the Hansch lipophilicity (p) and Hammett electronic (r) constants of the substituents at C-3 of the benzyloxy ring. Electron-withdrawing substituents with a high degree of lipophilicity enhance inhibition potency. These results are discussed with reference to possible binding orientations of the inhibitors within the active site cavities of MAO-A and -B.

English: This study was undertaken to evaluate 11 wheat genotypes for aluminium tolerance using three laboratory based evaluation methods. Four parameters namely the root length before aluminium treatment, the root re-growth after aluminium treatment, the portion of the root affected by aluminium treatment, stained with hematoxylin and root tolerance index were measured on the two longest (primary and secondary) roots of each seedling to determine the effect of aluminium toxicity on the physiological development of the seedling roots. With the root re-growth method it was possible to distinguish between three categories of tolerance (moderate, intermediate and tolerant) that will be very helpful in future resistance breeding for aluminium tolerance. With this method it is possible to discriminate between individuals in a population for aluminium tolerance. Similar data was obtained for the primary and secondary roots, which indicated that the age of the roots are not a limiting factor for aluminium tolerance screening with the nutrient bioassay. Although the root re-growth method discriminated between the different aluminium tolerance categories, a better indication of aluminium tolerance categories was achieved with the root tolerance index method. With the above methodology in place it was possible to observe an increase in aluminium tolerance in some progeny after gene recombination and it was possible to discriminate between good aluminium tolerant progeny and progeny showing no genetic gain from the hybridisation. It was also shown that there were no reciprocal effects for aluminium tolerance in wheat. There were genetic differences for aluminium tolerance between the genotypes used in this study and this methodology can be successfully implemented in an aluminium tolerance-breeding programme for wheat. This study indicated that there is useful methodology to effectively follow the genetic gains during gene-recombination for aluminium tolerance and, secondly th, Afrikaans: Hierdie studie is onderneem om 11 koring genotipes te evalueer vir aluminium toleransie met die gebruik van drie laboratorium gebaseerde evaluasie metodes. Vier parameters naamlik die wortellengte voor aluminium behandeling, die hergroei na aluminium behandeling, die gedeelte van die wortel wat deur aluminium behandeling beïnvloed is en gekleur is met hematoksilien en wortel toleransie indeks wat gemeet is op die twee langste (primêre en sekondêre) wortels van elke saailing, is gebruik om die effek van aluminium toksisiteit op elke saailing se fisiologiese ontwikkeling van hulle wortels te bepaal. Dit was moontlik om te onderskei tussen drie kategorië van toleransie (laag, intermediêr en tolerant) met die wortel hergroei metode. Dit sal baie nuttig wees vir toekomstige weerstandsteling vir aluminium toleransie. Met hierdie metode was dit moontlik om tussen individue te onderskei vir aluminium toleransie binne ‘n populasie. Die data vir primêre en sekondêre wortels was baie dieselfde, wat aandui dat die ouderdom van die wortels nie ‘n beperkende faktor is wanneer daar met die voedings biotoets vir aluminium toleransie getoets word met nie. Alhoewel die wortel hergroei metode onderskei het tussen verskillende aluminium toleransie kategorië, is ‘n beter aanduiding van aluminium toleransie verkry met die wortel toleransie indeks metode. Met bogenoemde metodes was dit moontlik om die toename van aluminium toleransie in die nageslag te sien na kruisings en dit was moontlik om te onderskei tussen nageslag met goeie toleransie, en die wat geen genetiese verbetering na gee-herkombinering getoon het nie. Daar is ook gewys dat daar geen resiproke effekte vir aluminium toleransie in koring is nie. Daar was genetiese verskille vir aluminium toleransie tussen die genotipes wat gebruik is in hierdie studie en hierdie metodes kan dus suksesvol gebruik word in ‘n aluminium toleransie teelprogram vir koring. Die metodes is dus beskikbaar om genetiese verbetering in toleran, Agricultural Research Council (ARC), Agricultural Research Council-Small Grain Institute (ARC-SGI), National Research Foundation (NRF)

Identifying plant extracts as sources of antimalarial compounds needs to be addressed as numerous studies screen extracts without the means of eliminating extracts that are merely cytotoxic. Fifty-nine organic solvent extracts from South African plants were screened for antiplasmodial activity using the [3H]-hypoxanthine incorporation assay against the chloroquine-resistant Plasmodium falciparum. Variable antiplasmodial activity and toxicity was observed. Extracts form Combretum erythrophyllum and Crinum bulbispermum, had IC50 values ≤ 1 μg/ml with the ethyl acetate extracts of C. bulbispermum roots and bulbs having values comparable to chloroquine (0.04 µg/ml). Nine extracts had toxicity indexes ≥ 100. Lycorine, isolated from C. bulbispermum was as active as chloroquine (IC50 of 0.03 µg/ml) and had a favourable security index.

This paper describes the synthesis and in-vitro activity of pentacycloundecane-conjugated aminoguanidine and tryptamine analogues on nitric oxide synthase (NOS) using rat brain homogenate. Both aminoguanidine and tryptamine-derived NOS inhibitors show selectivity towards the inducible and neuronal isoforms of the NOS enzyme, but are weak inhibitors and complete inhibition of the enzyme occurs only at high millimolar concentrations. In view of the increased NOS inactivation observed with alkyl substitution of these structures, the present study aimed to evaluate the effect of the pentacycloundecane cage moiety as an alkyl substituent on the in vitro NOS inhibition of aminoguanidine and tryptamine compounds. Comparison of the IC50 values of aminoguanidine (IC50 = 2.306610–3 M) and 8-imino-N-guanidino-pentacyclo-undecane 2 (IC50 = 8.803610– 5 M) revealed a more than 26-fold increase in potency. The ability of tryptamine to inhibit NOS activity was also markedly improved by the various pentacycloundecane substituents. The compounds, 3-hydroxy-4-[3-(2-aminoethyl)indole]-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecane 4 and 8-[3-(2-aminoethyl) indole]-pentacyclo[5.4.02,6.03,10.05,9]undecane 7 showed the best activity of the tryptamine analogues with a more than 3-fold increase in nitric oxide synthase inhibition. The results confirmed that the pentacycloundecane structure substantially enhanced the NOS inhibitory potency as observed for the six new NOS inhibitors

The blood-brain barrier is formed by the brain capillary endothelium and plays the predominant role in controlling the passage of substances between the blood and the brain. Recent studies on polycyclic structures, i.e. pentacyclo[5.4.0.02,6.03,10.05,9]undecane and amantadine, indicated favourable distribution thereof to the brain and it was concluded that these polycyclic structures and their derivatives penetrate the blood-brain barrier readily. A series of novel polycyclic prodrugs incorporating the well known non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid and ibuprofen, were synthesised and screened for blood-brain barrier permeability and antioxidant activity. Increased levels of both NSAIDs were detected in the brain tissue of C57BL/6 mice after administration of the synthesised prodrugs, indicating favourable blood-brain barrier permeation. Results from a lipid peroxidation assay indicated that the ester and amide prodrugs significantly increased the ability of the drugs to attenuate lipid peroxidation. These novel prodrugs thus readily penetrate the blood-brain barrier and exhibit increased antioxidant activity when compared to the free NSAIDs.

Previous studies have shown that (E)-8-(3-chlorostyryl)caffeine (CSC) is a specific reversible inhibitor of human monoamine oxidase B (MAO-B) and does not bind to human MAO-A. Since the small molecule isatin is a natural reversible inhibitor of both MAO-B and MAO-A, (E)-5-styrylisatin and (E)-6-styrylisatin analogues were synthesized in an attempt to identify inhibitors with enhanced potencies and specificities for MAO-B. The (E)-styrylisatin analogues were found to exhibit higher binding affinities than isatin with the MAO preparations tested. The (E)-5-styrylisatin analogues bound more tightly than the (E)-6 analogue although the latter exhibits the highest MAO-B selectivity. Molecular docking studies with MAO-B indicate that the increased binding affinity exhibited by the (E)-styrylisatin analogues, in comparison to isatin, is best explained by the ability of the styrylisatins to bridge both the entrance cavity and the substrate cavity of the enzyme. Experimental support for this model is shown by the weaker binding of the analogues to the Ile199Ala mutant of human MAO-B. The lower selectivity of the (E)-styrylisatin analogues between MAO-A and MAO-B, in contrast to CSC, is best explained by the differing relative geometries of the aromatic rings for these two classes of inhibitors.

Monoamine oxidase B (MAO-B) and nitric oxide synthase (NOS) have both been implicated in the pathology of neurodegenerative diseases. In an attempt to design dual-target-directed drugs that inhibit both these enzymes, a series of pteridine-2,4-dione analogues were synthesised. The compounds were found to be relatively weak NOS inhibitors but showed promising MAO-B activity with 6-amino-5-[(E)-3-(3-chloro-phenyl)-prop-2-en-(E)-ylideneamino]-1,3-dimethyl-1H-pyrimidine-2,4-dione and 6-[(E)-2-(3-chloro-phenyl)-vinyl]-1,3-dimethyl-1H-pteridine-2,4-dione inhibiting MAO-B with IC(50) values of 0.602 and 0.314 microM, respectively. The pteridine-2,4-dione analogues thus show promise as scaffolds for the development of potent reversible MAO-B inhibitors and as observed in earlier studies, the most potent inhibitors were obtained with 3-chlorostyryl substitution.

The genotype effect of South African barley cultivars on malting quality under different nitrogen applications was determined by planting two- and six-row doubled haploid populations consisting of 7 and 67 lines respectively under irrigation at Vaalharts in 2006 and 2007 and at Rietriver in 2007. Three different nitrogen (N) treatments were applied to correlate the amount of leaf N to N in the kernel to implement a practical N fertilizer management system to obtain good malting quality. For treatment one, all of the fertilizer (110 kg/ha) was applied at planting. For treatments two and three, half of the fertilizer (55 kg/ha) was applied at planting while the other half (55 kg/ha) was applied at the sixleaf stage or when 50% of flag leaves were visible respectively. The best N application for the two-row population was treatment three compared to the six-row population which responded differently to all the N applications over years and localities. This study indicated that a practical N fertilizer strategy should include half the N application at planting (55kg/ha) for crop and tiller development and a split application of the other 55 kg/ha at six-leaf and flag leaf stage to enhance kernel plumpness, germination, absorption and yield and maintain optimum kernel N for good malting quality. Timing of N application had a significant effect on all the malting quality traits. However, RP-HPLC results of hordein fractions showed that there was no change in the composition of hordeins in response to timing of N application and to the environment. The two- and sixrow entries within a doubled haploid population differed in malting quality across environments. Genotypes contributed more to variation in a population than the environment for both kernel plumpness and yield. However, for kernel N, the environment contributed more to variation than the genotypes. There were significant correlations between malting quality traits and hordein fractions. In particular, the negativ

1-Methyl-3-phenyl-3-pyrrolines are structural analogues of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and like MPTP are selective substrates of monoamine oxidase B (MAO-B). As part of an ongoing investigation into the substrate properties of various 1-methyl-3-phenyl-3-pyrrolinyl derivatives, it is shown in the present study that their respective MAO-B catalyzed oxidation products act as reversible competitive inhibitors of the enzyme. The most potent inhibitor among the oxidation products considered was 1-methyl-3-(4-trifluoromethylphenyl)pyrrole with an enzyme-inhibitor dissociation constant (Ki value) of 1.30 μM. The least potent inhibitor was found to be 1-methyl-3-phenylpyrrole with a Ki value of 118 μM. The results of an SAR study established that the potency of MAO-B inhibition by the 1-methyl-3-phenylpyrrolyl derivatives examined here is dependent on the Taft steric parameter (Es) and Swain–Lupton electronic constant (F) of the substituents attached to C-4 of the phenyl ring. Electron-withdrawing substituents with a large degree of steric bulkiness appear to enhance inhibition potency. Potency was also found to vary with the substituents at C-3, again with Es and F being the principal substituent descriptors

In recent years polycyclic compounds have been shown to exhibit pharmacological profiles of importance in the symptomatic and proposed curative treatment of neurodegenerative diseases (e.g., Parkinson’s and Alzheimer’s disease). These structures also show modification and improvement of the pharmacokinetic and pharmacodynamic properties of drugs in current use. Nitric oxide (NO) is a molecular messenger involved in a number of physiological processes in mammals. It is synthesised by nitric oxide synthase (NOS) from l-arginine and its overproduction could lead to a number of neurological disorders. The aim of this study was to synthesise a series of novel indazole, indole and other fluorescent derivatives conjugated to polycyclic structures for evaluation in NOS assays. NOS is a target system where fluorescent techniques and fluorescently labelled NOS inhibitors can be used for detecting the biophysical properties of enzyme–ligand interactions and thus facilitate development of novel inhibitors of neurodegeneration. This could lead to a greater insight into the neuroprotective mechanism and a possible cure/treatment for neurodegenerative diseases. A series of compounds incorporating polycyclic structures such as 3-hydroxy-4-aza-8-oxoheptacyclo[9.4.1.0.2,100.3,140.4,90.9,13012,15]tetradecane and amantadine as well as suitable fluorescent moieties were selected for synthesis. In the biological evaluation the oxyhaemoglobin (oxyHb) assay was employed to determine the activity of the novel compounds at an enzymatic level of NOS. IC50 values of the novel fluorescent compounds were compared to that of aminoguanidine (AG) and 7-nitroindazole (7-NI), two known NOS inhibitors, and showed moderate to high affinity (IC50 values ranging from 7.73 μM to 0.291 μM) for the NOS enzyme

The adenosine A2A receptor has emerged as an attractive target for the treatment of Parkinson’s disease (PD). Evidence suggests that antagonists of the A2A receptor (A2A antagonists) may be neuroprotective and may help to alleviate the symptoms of PD. We have reported recently that several members of the (E)-8-styrylcaffeine class of A2A antagonists also are potent inhibitors of monoamine oxidase B (MAO-B). Since MAO-B inhibitors are known to possess anti-parkinsonian properties, dual-target-directed drugs that block both MAO-B and A2A receptors may have enhanced value in the management of PD. In an attempt to explore this concept further we have prepared three additional classes of C-8 substituted caffeinyl analogues. The 8-phenyl- and 8-benzylcaffeinyl analogues exhibited relatively weak MAO-B inhibition potencies while selected (E,E)-8-(4-phenylbutadien-1-yl)caffeinyl analogues were found to be exceptionally potent reversible MAO-B inhibitors with enzyme–inhibitor dissociation constants (Ki values) ranging from 17 to 149 nM. Furthermore, these (E,E)-8-(4-phenylbutadien-1-yl)caffeines acted as potent A2A antagonists with Ki values ranging from 59 to 153 nM. We conclude that the (E,E)-8-(4-phenylbutadien-1-yl)caffeines are a promising candidate class of dual-acting compounds.

Saturated polycyclic hydrocarbon structures such as the monocyclic octane, bicylic norbornane and tricyclic adamantane have attracted the attention of several research groups since the 1930s. In the 1950s the synthesis of the so called bird-cage pentacyclo[5.4.0.02,6.03,10.05,9]undecane-8,11-dione, also known as Cookson’s diketone was reported. This pentacyclic cage diketone is the product of the intramolecular photocyclized Diels Alder adduct of p-bensoquinone and cyclopentadiene. The conversion of this diketone to its monoketone analog formed the basis of a variety of monosubstituted derivatives. Furthermore, acid-based rearrangement reactions of hydroxyl-substituted compounds led to, amongst others, the unique D3-trishomocubane symmetrical compounds, which consists of only five-membered carbon rings. The D3 stereoisomerism of the trishomobubane affords unique chemical challenges with potential medicinal implications. The medicinal chemistry of these cage compounds gained momentum in the 1980s with the discovery of the calcium-channel-modulating effects and antiviral activity thereof. The 1990s and 2000s saw several reports on a variety of pharmacological areas, i.e., dopaminergic, catecholaminergic, and focusing on disorders, in particular that of the central nervous system, such as neurodegeneration (Parkinson’s disease). These polycyclic structures have proved to be very useful in drug discovery research, in particular during the past 25 years

Polycyclic hydrocarbon compounds exhibit a wide variety of biological activities, ranging from antiviral to Parkinson’s disease. Several structures such as the adamantanes have reached clinical status and are used therapeutically to treat, amongst others, neurodegenerative disorders such as Alzheimer’s. Polycyclics have also been utilised as carrier molecules to facilitate entry of drugs into the brain. The synthesis, molecular and crystal structure of a new polycyclic compound, 3-hydroxy-4-aza-8-oxoheptacyclo[9.4.1.02,10.03,14.04,9.09,13.012,15]tetradecane, are reported. NMR spectroscopy was applied for structure elucidation of the novel compound and a rearrangement mechanism is proposed for its formation. This compound crystallises in the orthorhombic system, space group Pbca (no. 61). The unit cell parameters are: a = 12.3763 (7), b = 11.6597 (6), c = 15.0539 (8) Å, V = 2172.3 (2) Å3 , and Z = 8 molecules in the unit cell. The reported structure was confirmed by X-ray analysis, which showed that the title molecules associate into centrosymmetric dimers via N–H···O hydrogen bonding