text:
Overview of the secondary data sources consulted.
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A great deal of research in heterocyclic chemistry concerns the development of strategies for efficient synthesis and the discovery of new methods of ring formation, since more than half of the biologically active compounds produced by nature contain a heterocyclic moiety as a fundamental unit in their structure. Also, heteroaromatic compounds are always of great importance for chemists and the identification and confirmation of highly potent and selective bioactive molecules is a decisive step both in academic and pharmaceutical research.
Heterocyclic compounds with a pyrrole cycle are significant both in materials and in medicinal chemistry [1]. Indoles and indolizines (heterocyclic aromatic compounds structurally and chemically isomeric with indoles) are important classes of N-fused heterocyclic compounds due to their interesting biological and optical properties. Although their chemistry is a well-established subject for researchers, they continue to attract much attention due to their diverse biological properties. Also, the correlation between indoles and indolizines has prompted speculation that indolizine analogs of biologically important indoles could conceivably have potent physiological activities [2].
Indoles and their derivatives are well-known as an important class of heterocyclic compounds, their core being a near-ubiquitous component of biologically active natural products, widespread in different species of plants, animals, and marine organisms. The indole is also well-known as one of the most important scaffolds for drug discovery, capable of serving as ligand for a diverse array of receptors and it has been a major focus of research [3]. Indole derivatives have the unique property of mimicking the structure of peptides and to bind reversibly to enzymes and exhibit significant physiological and pharmacological, industrial, and synthetic applications such as beneficial estrogen metabolism promoter in humans, anticarcinogenic properties, inhibitors of human prostate cancer cells, and free radical scavenging activities [1, 4]. The indole scaffold is widely used in antiviral drugs and reverse-transcriptase inhibitors, drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. Meanwhile, a number of bis (indolyl) alkanes have received considerable attention because of their occurrence in bioactive metabolites of terrestrial and marine origin [5].
Indolizine is the core structure of many of the naturally occurring alkaloids such as swainsonine (a potent inhibitor of Golgi alpha-mannosidase II, an immunomodulator and a potential chemotherapy drug), monomorine (might be used to lure ants to their doom), gephyrotoxin (muscarinic antagonist), and lamellarins (HIV-1 integrase inhibition and antibiotic activity) [6].
The indolizine synthetic derivatives also deserve special attention because of their pharmacological properties such as antibacterial, anti-inflammatory, antiviral and antileishmanial, analgesic and antitumor, antioxidant activities, aromatase inhibition, calcium entry blocking, histamine H3 receptor antagonist, and physicochemical properties such as strong fluorescence [6, 7].
Different strategies for generating diverse collections of small molecules with indole and indolizine moieties have been developed. They can be synthesized by means of classical and nonclassical pathways.
The development of simple, convenient, and an eco-friendly approach for the synthesis of these biologically important compounds is still in demand. For example, the very useful and green concept of a "click" reaction is a facile, selective, high-yield reaction under mild water-tolerant conditions with little or no by-products [8]. Cascade annulation reactions lead also to the formation of polycyclic fused six- and seven-membered heterocycles with indole and indolizine core [9].
Microwave irradiation, sonication, and solvent-free are green chemistry techniques that have been used for a variety of applications including organic synthesis. Microwaves and ultrasounds have been used as synthetic techniques for obtaining indole and indolizine derivatives in high-yield, higher reaction rate. The simplicity of the reactions using these techniques, the elimination of toxic solvents, and the synthesis carried out in a very short time period are particularly useful for the creation of diverse chemical compounds of "drug-like" molecules for biological screening [10].
Multicomponent reactions (MCRs) or tandem reactions have developed as a powerful tool for delivering the molecular diversity needed for the synthesis of interesting heterocyclic scaffolds, to efficiently construct a variety of intermediates possessing an indolyl or indolizyl subunit and are particularly attractive especially if they start from simple molecules [11].
The present study discusses the versatile nature of indole/ indolizine derivatives, new green methods for their synthesis, their possible mechanism of action, and also provides information about current/future prospects of the topics and different indole/indolizine derivatives in pharmaceutical/clinical trials.
Indole derivatives are, perhaps, the most studied nitrogen heterocyclic systems because of interesting biological properties that received particular interest due to the reserpine alkaloid, one of the first drugs used for the treatment of central nervous system (CNS) disorders. Different substituted indoles are particularly important in pharmaceutical chemistry being capable to bind many receptors with high affinity exhibiting various pharmacological activities. Therefore, it is important to explore new synthetic reactions and evaluate various properties of indole derivatives.
To obtain biologically relevant N-hydroxyindoles, a prudent step would be to synthesize O-protected hydroxyindoles, to avoid their dimerization into kabutanes. Such were the premises of one study, presenting the annulation of nitrosoarenes with various alkylating and acylating agents, able to afford the desired compounds with excellent regioselectivity [4].
The synthesis of 3,3-dimethyl-2-amide indoles could be achieved through the I2/DMSO promoted oxidative amidation reaction between 1,2,3,3-tetramethyl-3H-indolium iodide and secondary amines with moderate yields (Figure 1) [12].
Using a method involving four steps, 2-indole-3-yl-thiochroman-4-ones could be obtained (Figure 2), according to Song et al. In the final step, the Michael addition reaction of thiochromone and indole, an ionic liquid is used, to increase the yield, with the added advantage that it could be reused three times without a decrease of efficiency [13].
Polyvinylsulfonic acid, a biodegradable and recyclable polymeric acid rarely used in organic transformations, could be used as a Bronsted acid catalyst in the synthesis of bis (indolyl) methane [14]. Another pathway to obtain this compound would be to employ a reusable resin, Indion Ina 225H, as catalyst of the substitution reaction between indoles and aldehydes (Figure 3), reportedly attaining excellent yields in short reaction times [15].
Various carbonyl compounds, including ketones could also be building blocks for the much desired bis(indolyl)methanes, using catalytic amounts of iodine in the presence of sodium dodecylsulfate in aqueous solution above its critical micellar concentration and the protocol was also extended to afford 3-substituted indolyl ketones (Figures 4 and 5) [3].
The indolizine core has found numerous applications in the synthesis of biologically active compounds. Partially or completely reduced indolizine analogs are widely used in the synthesis of indolizidine alkaloids and related unnatural products. Among many other pharmacological uses, polycyclic analogs of indolizine, for example, have found a broad application as heterocyclic analogs of indene in the synthesis of ligands for transition metal complexes. Although many methods have been developed for their synthesis, they are generally time-consuming or require the use of stoichiometric amounts of organometallic reagents, Lewis acids, expensive catalysts or potentially toxic solvents, which limits their economical applications. Accordingly, development of alternative catalytic methods for construction of these important heterocyclic cores is necessary [9].
The mechanism of obtaining condensed five-membered ring systems via 1,3-dipolar cycloadditions implies the reaction of a dipole, in this case an N-ylide generated in situ from a cycloimmonium halide and a base or another deprotonating agent followed by its addition to a dipolarophile, olefinic, or acetylenic [7].
N-ylides could be generated employing 1,2-epoxybutane as both solvent and deprotonation agent, or by using triethylamine in DCM, with ethyl propiolate or DMAD as dipolarophiles, or again coupling the ylide with acrylonitrile and using TPCD for the aromatization step, all methods with similar medium to good yields (Figure 6) [7]. Moderate yields, up to 22%, are reported when reacting DMAD with N-ylides generated from pyridinium salts and K2CO3, using catalytic amounts of dicyclohexyl-18-crown-6 [16]. In another study, 20 substituted indolizines were obtained in just 30 min at room temperature, employing electron-deficient alkynes, in the presence of K2CO3 in DMF, with yields as high as 77% [17].
The solvent could have a great impact on the reaction mechanism, as one study demonstrates, using substituted ethenes (E-1,2-di(alkylsulfonyl)-1,2-dichloroethene) as dipolarophiles (Figure 7). In aprotic solvents, the reaction takes place as a 1,3-dipolar cycloaddition, with yields between 62 and 75% for the six indolizines obtained, but in protic solvents an addition–elimination reaction intervenes, leading to the competitive formation of furans, with indolizine yields as low as 9% [18].
One-pot reactions imply obtaining the product in a single step, by adding all the necessary reagents in the same reaction medium, without having to isolate and purify any precursors of the desired product. This type of procedure offers advantages such as swiftness, the preparation of complex compounds from readily available material, simplification of workup and atom economy.
Mishra et al. present a method to obtain 1-aminoindolizines from aldehydes, secondary amines, and terminal alkynes, in a one-pot reaction (Figure 8). After testing several solvents and metal catalysts, the best results are obtained with CuCl in PEG, synthesizing 15 substituted indolizines with yields exceeding 70%, after 3–4 h reaction time [19].
Substituted 3-aminoindolizines could be obtained via one-pot multistep reactions, from 2-pyridine carboxyaldehide and various nitriles, after 3 h reaction in toluene at 105°C, by adding 1.1 eq of Hantzsch ester as a hydride transfer agent and catalytic amounts of piperidinium acetate [20].
The synthesis of 2-acetyl-3-(phenylamino)indolizine-1-carboxamides could also be achieived in a single step (Figure 9), by combining pyridine-2-carbaldehyde, acetoacetanilide and isocyanides in toluene at reflux, with yields around 90% for the four compounds obtained [21].
A four-component tandem reaction is proposed by Zhenjun et al., by treating pyridine (or quinoline) with phenacyl bromides (or bromoacetophenones), ethyl glyoxalate, and Na2CO3 in refluxing acetonitrile. The resulting polysubstituted indolizines are obtained after 16 h of reaction time in moderate-to-good yields [22].
Seventeen polysubstituted indolizines could be obtained via a one-pot sequential addition-cyclodehydration-dehydrocyanation from of 2-(1H-pyrrol-1-yl) nitriles with α,β-unsaturated carbonyl compounds (Figure 10) [23].
The indolizine core could be accessible starting from pyrrole, with strategies involving intramolecular aldol cyclization or domino Knoevenagel condensation, shown in Figure 11 [24].
Another [3+3] annulation approach employs allyl bromides derived from Morita-Baylis-Hilman adducts (Figure 12), with the conclusion that electron withdrawing groups, as substituents at the aromatic ring, contribute to successful ring closure and result in accordingly substituted indolizines [25].
Novel 2-acyl-6-aryl substituted indolizines were obtained starting from 4-acyl-pyrrole-2-carbaldehyde and α, β-unsaturated esters, in the presence of K2CO3 in DMF, with yields between 42 and 68% after 8–12 h at 50°C [26].
Another possibility would be to perform a tandem oxidative C-H functionalization and 5-endo-dig cyclization, starting from 2-substituted pyridines and alkynes (Figure 13), which could be achieved with good yields using an Ag2CO3 reusable catalyst [27].
Substituted pyridines and acetophenones lead to the formation of 1,2,3-triarylindolizines with moderate-to-excellent yields, promoted by I2/DMSO at 100°C, the proposed mechanism for this reaction is presented in Figure 14 [28].
During the synthesis of N-heterocycles there are many problems of health and safety in addition to the environmental problems caused by their use and disposition as waste. Green methods are a route towards increasing the efficiency of indoles and indolizines synthesis, and stride to use less toxic solvents, to reduce the stages of the synthetic routes and minimize waste as far as practically possible for sustainable development.
A potential method to make synthetic chemistry more environment-friendly would be to reuse catalysts, such as ion-exchanging resins. Amberlite-IRA 402 (OH) could be employed as the ylide-forming base in the reaction between phenacyl pyridinium, quinolinium and isoquinolinium salts and alkynes (Figure 15) [29].
Unconventional activation techniques, such as microwave irradiation, not only lead to shorter reaction times but generally increase the purity of the desired compound. One study presents the synthesis of 8 indolizine derivatives in an aqueous medium that were obtained in good yields after 1 min of irradiation at 300W [30].
Biocatalysis could be employed to aid the formation of indolizine derivatives in an aqueous medium, as seen in Figure 16. Ultrasound activation was compared to conventional heating, affording 7,7′-bis-indolizines with similar yields in much shorter reaction times [31].
The Oxone-induced oxidation of indole-3-carbaldehydes and 5-halogenated analogs could lead to the formation of tryptanthrin derivatives (Figure 17), a highly functionalized biologically active natural product, at room temperature [32]. The phthalazine moiety could also be accessible with green methods, employing catalytic amounts of L-proline, with good yields and less than 2 h reaction time [33].
The reaction between indole and formaldeyde could produce high yields of hemiaminals, with the added value of mild conditions, such as room temperature and an aqueous medium, in the presence of TBAF [34].
The most eco-friendly approach when it comes to solvent choices would be not to employ any solvents. Analogs of 3-alkylindole, for example, could be prepared in solvent-free conditions, using MgO nanoparticles as catalyst [35]. Bis(indol-3-yl)methanes could be synthesized in solvent-free grinding conditions, employing a reusable catalyst, phosphate-impregnated titania, obtaining yields as high as 93% [36].
Unconventional activation techniques could also be used for indole functionalization. Within 10 min, including reaction and purification time, 3-pyranyl indole derivatives could be obtained with good yields, through one-pot microwave-assisted reactions, with InCl3 as catalyst (Figure 18) [37]. Indolyl chalcones could be prepared from indole-3-carboxaldehyde and heteroaryl active methyl compounds under conventional heating, but the yield was much improved and reaction time was drastically reduced (from more than 9 h to less than 15 min) when microwave irradiation was introduced [38]. Ultrasounds aid the selective formation of 11 3-selanylindole derivatives with good yields, proving superior to conventional heating and microwave irradiation for this synthesis [39].
Both indoles and indolizines could be functionalized via alkylation with enamides under mild conditions (Figures 19 and 20), using FeCl3, in short reaction times with good yields [2].
The Friedel-Crafts alkylation of indoles could also be performed in water, as presented in Figure 21, with yields as high as 97% in the presence of Keggin heteropoly acids, solid super-acid catalysts [40].
A novel approach presents the previously inaccessible regioselective formation of substituted pyrido[2,3-b]indolizine-10-carbonitriles, via a cascade transformation of α,β-unsaturated carbonyl compounds with a dimer of 1-(cyanomethyl) pyridinium chloride, in ethanol/water in the presence of sodium acetate [41].
As we have seen so far, interesting pathways have been proposed for the synthesis of indoles and indolizines. Many of these molecules have subsequently been involved in tests to assess their biological activity. Natural compounds with these moieties have also attracted interest, not just as extracts, but as targets for total/semisynthesis or as frameworks for compound libraries. Next, we shall review some of the extremely diverse pharmaceutical applications of these derivatives, ranging from fluorescence probes, to antiviral, to anticancer molecules currently in clinical trials.
Lead by Cialis, there are seven indole-containing commercial drugs in the Top-200 Best Selling Drugs by US Retail Sales in 2012. Examples of indole derivatives marketed as antiviral drugs, for example, are Arbidol (a broad-spectrum antiviral with anti-influenza and immunomodulating effects) and Delavirine (a non-nucleoside reverse transcriptase inhibitor) [42].
Bisindoles, such as hamacanthin A, isolated from marine sponges (Hamacantha sp., Spongosorites sp.), or the more famous indole-3-carbinol (I3C), a compound found in cruciferous vegetables (cabbage, kale, cauliflower, broccoli, Brussels sprouts) and its bisindole metabolite, 3,3\'-diindolylmethane (DIM), have displayed biological activities such as antimicrobial, antiparasitic, anti-inflammatory, and anticancer and are high up on the interest list of many researchers [43].
Some of the many studies published in this field have resulted in the elucidation of some of the mechanisms of their bioactivity. The influence of I3C, for example, on lung cancer cells, has been attributed to apoptosis via Fas activation and caspase-8 pathways and also cell-cycle arrest at the G0/G1 phase, and it was also shown that cancer preventive effects of I3C were mediated via modulation of the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway [44]. I3C was also shown to induce the expression of phase I and II enzymes by the binding of the aryl hydrocarbon receptor (AhR) (Figure 23) [45].
DIM has been found to increase bone mass by supressing osteoclastic bone resorption, in physiological and pathological conditions [46]. DIM could also help prevent heart failure, as one study indicates the compound improves myocardial energy metabolism imbalance via AMPKα signaling [47].
Strychnine and brucine are well known for their toxic effect that manifests in the form of hypertension and violent convulsions. Brucine is also a proposed anticancer drug candidate, as it inhibits VEGF-induced cell proliferation, reducing p-VEGFR2 kinase activity and inhibiting neovascularization in vivo [48].
Other indole alkaloids, isolated from marine sources, such as coscinamides, dragmacidin D, topsentins, or even fungal sources, such as asterriquinone, have exibited antiviral (anti-HIV), antimicrobial, antitumor activity, along with the inhibition of serine–threonine protein phosphatases or ascites hepatoma AH13, for example [49]. Such compounds, isolated from the Strychnos species, have also been found to inhibit quinine- and choloquinine-resistant P. falciparum [50]. One of the more studied indole alkaloids would be physostigmine, the template that led to the development of rivastigmine, globally licensed in 2006 to fight the symptoms of dementia associated with Parkinson\'s disease, also prescribed for the symptomatic treatment of Alzheimer's disease [51].
With methods of extraction developing since the 1960s, with many efforts concentrating on the efficiency and environmental impact of the process, terpenoid indole alkaloids and their pharmacological properties continue to attract attention as some of them are already marketed as anticancer, antihypertensive, or hypoglycemic agents, for example [52]. Some monoterpene indole alkaloids are in high demand, such as vinblastine (Catharanthus roseus) and camptothecin (Camptotheca acuminata, Nothapodytes foetida), currently used as chemotherapic drugs, and eyes have turned toward metabolic engineering. However, their biosynthetic pathways are still not fully elucidated and geneticians, chemists, and biotech specialists are scrambling to fill in the gaps, with resources such as cell- and organ-specific transcriptome databases on hand [53, 54].
A novel class of indole-2-carboxylate derivatives was designed starting from the structure of pyrroloquinoline quinone, with two compounds (Figure 26) emerging as more potent antiproliferants than the reference drugs, compounds that induced PARP cleavage and increased ROS generation dose-dependence [55].
Protein tyrosine phosphatases (PTP) are a novel, mostly untapped family of therapeutic targets, with implications in oncology (SHP2), autoimmunity (Lyp) or diabetes (PTP1B). X-ray crystal structural analysis has been performed on PTP-inhibitor complexes, revealing bicyclic benzofuran and indole-based salicylic acids as useful first steps toward the development of more potent inhibitors (Figure 27) [56].
Novel galantamine derivatives with indole moiety have exhibited an activity against acetylcholinesterase up to 95 times higher than the parent compound, with one promising lead binding in a region close to the peripheral anionic site of the enzyme, where the Ω-loop of amyloid beta peptide adheres [57].
Coronary heart disease, prevalent in industrialized regions, comes hand-in-hand with high levels of LDL-C ("bad cholesterol") and low levels of HDL-C ("good cholesterol"), treated mostly with statins, inhibitors of HMG-CoA reductase with dose-limiting hepato- and myotoxicity. However, the screening of a small indole chalcone fibrates library (Figure 28) has revealed three compounds with a more potent hypolipidemic effect than the standard drug, fenofibrate, coupled with high inhibition percentages of superoxide anions, hydroxyl radicals, and microsomal lipid-peroxidation [58].
Beneficial effects on lipid and also glucose metabolism were also reported concerning 1-(4-chlorobenzoyl)-5-hydroxy-2-methyl-3-indoleacetitic acid (GY3), which increased glucose consumption and decreased lipid accumulation through AMPK activation in hepG2 cells, with obvious implications in metabolic syndrome, type 2 diabetes, and nonalcoholic fatty liver disease [59].
Some indole derivatives also show promising antimicrobial activity. Five out of 24 bisindolylmethane Schiff base derivatives synthesized were found to specifically inhibit Salmonella typhi, S. paratyphi A and S. paratyphi B, even if the inhibition was moderate at best, when nitro or halogen substituents were introduced [43].
Natural products derived from the indolizine core, such as castanospermine, swainsonine, or tylophorine, polyhydroxylated indolizidine alkaloids, have attracted much attention, struggles toward total synthesis, or analog design issues. Their biological properties range from the antiviral to the anticancer realm, with promising effects on autoimmune diseases [60].
For example, castanospermine glycoside analogs inhibit breast cancer cells MCF-7 and MDA-MB-231, inducing cell cycle arrest and apoptosis without impact on normal cell proliferation [61]. Some 5α-substituted swainsonine analogs successfully inhibit Golgi alpha-mannosidase II, a key enzyme in the N-glycosylation pathway and a potential target for cancer chemotherapy, without much loss of activity by comparison with the parent compound [62]. Tylophorine was shown to inhibit VEGFR2 tyrosine kinase activity and its downstream signaling pathways, neovascularization, tumor angiogenesis and tumor growth, molecular docking simulations indicating that it could form hydrogen bonds and have aromatic interactions within the ATP-binding region of the VEGFR2 kinase unit [63].
In the indolizine nucleus, the six-membered ring suffers from low electron density, with a subsequent charge buildup in the five-membered ring, resulting in a large dipole moment and fluorescence properties. The influence of the substituents goes a long way into predicting a blue or red-shifted fluorescence; for example, the C-2 position could carry a lot of weight [26].
The 10π conjugated planar electronic structure, exhibiting strong fluorescence properties, can be useful for DNA interaction studies. Such is the case of some indolizinylpyridinium derivatives, found to interact similarly to ethidium bromide, binding in the minor groove, but having its fluorescence partially quenched [64].
Switchable biosensors could be designed starting from Seoul-Fluor (Figure 30), an indolizine scaffold with three positions for different radicals: R1 and R2 substituents affect electronic perturbation; R3 could be a functional handle for bioconjugation, thus creating a versatile platform with tuneable emission wavelength and controllable quantum yield [65].
Many indolizine derivatives have been proven to be worthy therapeutic agents, with a number of them undergoing clinical trials, notably five anticancer molecules that inhibit topoisomerase [66]. As is the case of photophysical properties, the substituents of the indolizine core can be tailored to suit the bioactivity requirements.
Following a SAR study, 49 indolizine derivatives were obtained and tested as potential HIV-1 infectivity factor inhibitors, one of which was found to exhibit an IC50 value of 11 µM [67].
A feature that makes indolizine derivatives attractive is the design possibilities. The facile replacement of substituents could lead to more in-depth perception toward their effect upon desired bioactivity, solubility, or other properties sought [66].
Two new classes of indolizines fused with phenantroline skeletons were designed and synthesized, obtaining compounds with a coplanar structure, potentially able to interact with DNA through an intercalation mechanism, compounds that also possess good solubility in microbiological medium. Furthermore, one of the compounds exhibit, under aerobic conditions, activity against M. tuberculosis H37Rv, with an IC50 = 67 µM. Two other compounds had a selective and significant antiproliferative activity (around 50%) against two breast cancer cell lines (MCF7 and T-47D) (Figure 31) [68].
During rational design efforts, concentrated on the identification of potential farnesyltransferase inhibitors (implications with respect to oncogenic Ras proteins), the replacement of the triazole unit with the indolizine nucleus resulted in IC50s in the low micromolar range. The substituents' influence on bioactivity and pharmacokinetic parameters was also investigated [69].
Rational design could be pushed even further, employing 3D-QSAR studies to yield pharmacophore models, as is the case for 15-lipoxygenase inhibitory activity. For this purpose, 47 indolizines with anti-15-LOX activity were used to obtain a statistically significant model [70].
The similarity of the two heterocycles has motivated researchers since 1967, when Harrell and Doerge postulated that indolizine analogs of bioactive indoles could possess similar or improved potency [66]. Such an endeavor was attempted with the synthesis of l-(2-aminoethyl)-3-benzyl-7-methoxy-2-methylindolizine, an analog of indole derivative benanserin, the replacement of indole with indolizine proving to have no effect on anti-acetylcholinesterase activity but diminished the antihistamine and anti-5-hydroxytryptamine activity [66].
Ramatroban, 3-((3R)-3-{[(4-fluorophenyl)sulfonyl]amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)propanoic acid, is a well-known prostaglandin D2 inhibitor and thromboxane receptor antagonist. Researchers from Merck and Amira have presented numerous ramatroban analogs with the indole moiety replaced with indolizine and aza-indole, both proving potential during SAR studies. Among them, a 4-aza-indole derivative (Figure 32) inhibited hCRTH2 with an IC of 6 nM and was active in a murine OVA-induced lung inflammation model [71-74].
LE 300 is a selective antagonist for dopamine D1/D5 and serotonin 5-HT (2A) receptors, bearing an azecine ring fused to an indole ring on one side and a benzene moiety on the other side. New analogs of this compound were prepared, namely pyrrolo[2,3-g]indolizine, pyrrolo[3,2-a]quinolizine rings and their corresponding dimethylpyrrolo[2,3-d]azonine, and dimethylpyrrolo[2,3-d]azecine [75]. The study concludes that the indolizine and quinolizine derivatives show no activity concerning the receptors analyzed, while their azonine and azecine counterparts exhibited only weak antagonistic effects for serotonin and histamine receptors, remaining nonresponsive toward the four dopamine receptors tested.
Secretory phospholipases A2 (sPLA2s) is successfully inhibited by substituted indole and indolizine derivatives, as previously reported by Lilly and Shinogi researchers, with compounds like indoxam and Me-indoxam exhibiting favorable pharmacokinetic profiles [76-79]. Oslund et al. have prepared a set of benzo-fused analogs, among which they identified a compound that was the first reported potent inhibitor of groups IID and IIF sPLA2s and the most generally potent sPLA2 inhibitor reported to date (Figure 33) [80].
James et al. have prepared a series of indole and indolizine-glyoxylamides (Figure 34) and subsequently tested the compounds' cytotoxicity against cancer cell lines, identifying high antiproliferative activities, even in the case of multidrug-resistant phenotypes. After searching among numerous cores, with the goal to replace indole, the researchers synthesized a novel class of cancer agents with an indolizine core, with a lead compound that proved effective against multidrug-resistant cell lines such as MES-SA/DX5 and HL60/TX1000, resistant to treatment with Taxol [81].
Considering the growing interest for biologically active compounds, we believe that in the future the search for novel indole and indolizine derivatives will result in the emergence of new synthesis pathways and new and unexplored biologically active derivatives with pyrrole moieties.
Taking into account the importance of anticancer drugs, like vinblastine, irinotecan, topotecan, or camptothecin, the development of biologically active derivatives of new natural lead compounds containing indole and indolizine nucleus might be helpful in the design and development of novel and more potent anticancer drugs, antiviral agents, intercalating agents.
With the remarkable number of approved indole-containing drugs as well as the importance of the indolizine moiety, it can be easily concluded that indole and indolizine derivatives offer perspectives on how pyrrole scaffolds might be exploited in the future as bioactive molecules against a broad range of diseases.
This work was supported by a grant of the Romanian National Authority for Scientific Research, CNCS – UEFISCDI, project number PN-II-ID-PCE-2011-3-0226
Gauteng city region is defined as the economic hub of South Africa constituting Johannesburg metropolitan city, Ekurhuleni metropolitan city as well as Tshwane (formerly Pretoria) city [1, 2, 3]. This means that economic and social opportunities are spatially concentrated in the Gauteng city region, which contributes approximately 40% of the gross domestic product (GDP) for the South African economy although the geographic space occupied by the region is 2% of the total land area of South Africa [4]. Within the auspices of this current spatial structuring and subject to the processes and outcomes of successive restructuring actions and measures occurring in the Gauteng city region, various forms of spatial and transportation challenges and opportunities have emerged. As a result, the Gauteng city region is experiencing rapid urbanisation, which is a common feature for cities in the global South [4, 5, 6]. In South Africa, when one compares all the nine provinces, Gauteng attracts the largest number of migrants, with an estimated recorded net increase of 543,000 between the years 2011 and 2016 [7, 8, 9, 10]. Given the apartheid geography and history of South Africa, Gauteng province inherited a spatially fragmented, scattered and sprawled urban set-up [11, 12]. This existing spatial structure has implications regarding long commuting times, long journey times and great distances that buses, motorists and trains travel between areas of residences with respect to areas of socio-economic opportunities [4, 7, 13, 14, 15]. This spatial formation has led to spatial inefficiency and inequity that manifests itself in terms of multiple forms of deprivation that impact on family systems, spatial disconnects, continued public transport subsidy (which is argued by others as the invisible apartheid transport tax that current generations and government has to live with) as well as a complex non-optimised governance delivery set-up and inadequate institutional and governance structure [2, 16, 17, 18, 19].
This chapter examines the impact of rapid rural–urban migration on the Gauteng space structure, economy and transportation landscape. This impact is critiqued with respect to the ensuring pressure on infrastructure created, the unravelling capacity constraints faced and mismatches in urban governance structures with respect to service delivery utilising a transportation and spatial planning approach and perspective. The objectives of this chapter include:
Exploring the concepts and notions of spatial fragmentation and restructuring modalities with respect to the Gauteng province of South Africa
Examining the key spatial and transportation challenges facing the Gauteng province of South Africa
Describing the impact of rapid urbanisation on the spatial arrangements and systems in Gauteng province making use of the transportation platform as a unit of analysis and intervention lever
Providing a rejoinder regarding how the spatial and transportation challenges in the region can be addressed with a view to closing the gaps regarding spatial and transport inefficiencies in the Gauteng city region of South Africa
In answering the four mentioned questions, the overarching question 'is a transportation solution the answer' was used to unpack and construct the departure point for the paper.
A desktop survey methodology was adopted in analysing spatial and transportation documents found at both the national, provincial and municipal level in the Gauteng city region. Table 1 presents an overview of the secondary data sources that were accessed and analysed for spatial and transportation trends and themes used in compiling this chapter.
|Population census 1996-10-09
|Population census 2001-10-09
|Population census 2011-10-09
|Datasets accessed
|Documents accessed
|City of Johannesburg
|Metropolitan municipality
|City of Tshwane (Pretoria)
|Metropolitan municipality
|Ekurhuleni (East Rand)
|Metropolitan municipality
|Local Municipality
|Local municipality
|Merafong city
|Local municipality
|Local municipality
|Mogale city
|Local municipality
|Local municipality
|Local municipality
|South Africa
From Table 1, the researcher further made use of a gap analysis to identify and codify themes for detailed discussion. The analytical framework was informed by the application of the spatial and transportation system theory within the context of a polycentrism urban spatial growth paradigm approach. The application of the above-explained methodology was instrumental in generating vital insights and establishing patterns linked to spatial and transportation landscape in the study area with respect to whether efficiencies or lack of efficiencies exist thereof.
Understanding spatial restructuring and transportation solutions for Gauteng city region requires an appreciation of the notions and concepts that constitute spatiality as well as sustainable transportation solutions. This section, therefore, reviews the key concepts and notions of spatial fragmentation, spatial restructuring, urban systems theory as well as the urban polycentricism growth and management approach. This is critical in order to provide a common understanding of how these key notions, concepts and approaches are used in this chapter.
Spatial fragmentation is defined as the physical separation, division, scattering, alienation, divorce and exclusion of urban land parcels/areas/settlements/locations/uses/activities by the use of great distance and through buffering techniques such as open spaces, roads, railway lines, etc. from complementary and critical socio-economic opportunity areas [2, 4]. Urban spatial fragmentation therefore manifests itself in terms of sprawled settlements, urban settlements in which commuters travel long distances from residential areas to industrial/commercial working areas and is associated with low-density developments that promote the use of automobiles.
Spatial restructuring is the exercise aimed at changing and transforming the spatial structure of an existing urban area from a growth and development trajectory that encourages inefficiency and fragmented development to one that encourages land densification, compaction and integration of urban land parcels/areas/settlements/locations/uses/activities through in-fill developments, promoting high-density developments ably supported by a transit-oriented development philosophy as well as integration of activities [2, 4]. Spatial restructuring therefore manifests itself in terms of spatial development frameworks/physical plans/master plans and urban design plans aimed at redressing spatial inefficiencies and inequalities in an area, measures that promote public mass modes of transport over private motorist-based transportation approaches as well as urban development initiatives that support vertical (upward growth) rather than lateral (sprawling) urban development outcomes.
The classical theory of urban systems recognises that urban elements that constitute the structure are in a state of equilibrium that promotes system efficiency and effectiveness [22]. If the assemblage components of an urban system are disturbed, the system will malfunction or become inefficient or operate at suboptimal performance creating repercussions that affect all system components. In this regard, the urban structure is viewed as a complex system with the following elements: size, function and scale; accessibility and movement; economic integration and pluralism of activities; ecological and environmental ecosystem services; infrastructure and services; and policy, institutions, governance and management arrangements. From the identified six (6) main elements, it is important to acknowledge that these components are interdependent, interrelated and interconnected. In any event, the functioning of these system components manifests themselves in terms of a 'territorial dynamics approach' with implications linked to centrality, specialty and peripherality of urban territories in any spatial setting.
Urban polycentrism growth and management approach draw its roots from the commuting models of polycentric and multicentric city structures [12, 23]. The polycentric commuting spatial model is predicated on the presumption that the city has an equal distribution and spread of sub-centres of employment of a similar scale that have the capacity and capability to generate trips from all over the city in all directions [7]. In this scenario, the characteristics of commuting with respect to spatial clustering and scattering are represented by a wide dispersion of scattered random origins and destinations, appearing almost everywhere. However, on the other hand the multicentric growth and management approach in acknowledging the existence of multiple sub-centres of commuting and spatial power introduces the overarching principle of primacy/dominant commuting and spatial attraction sub-centre. It is this dominant sub-centre that tends to explain the urban commuting and spatial structuring skewedness and abnormality regarding spatial inefficiencies, spatial fragmentation and transportation inadequacies in an urban setting [7, 11, 14]. The urban commuting flows would be composites of both random and radial patterns. In this regard, the poly- and multicentric urban growth and development paradigms lend themselves to spatial structuring approaches that require the need to generate solutions applicable to different multilevel systems of city scales, spatial and transportation governance, funding and partnership system. This is suggested as a way of developing and generating customised responses to rapid urbanisation in response to spatial and transportation needs.
Spatial planning in Gauteng province is managed through the Gauteng Spatial Development Framework among other development planning instruments as reflected on Map 1. The spatial plan represents a future desired spatial vision for Gauteng province. The spatial structure represented is an amalgamation of the common overarching development principles applicable to the individual local spatial development frameworks of all local authorities in the province.
From Map 1, we can deduce that the GSDF identifies several strategic initiatives destined for implementation between 2011 and 2030, which relate to urban structuring and priority action areas. These initiatives are regarded as the primary spatial focal points to act as catalysts in terms of significant urban transformation in Gauteng province over the next decade. The GSDF as reflected on Map 1 is based on key spatial transformation development principles that have strong resonate in addressing the urban transportation bottlenecks in Gauteng province. The interventions are linked at the containment of urban sprawl by way of applying the urban edge principle, implementing a growth management strategy that seeks to advance compaction, residential densification and in-fill development within the existing urban fabric. At the same time, the approach is to advance social and economic integration of disadvantaged communities into the urban system, particularly those on the urban periphery. Central to all these initiatives is the promotion of the land use-public transport integration through nodal and corridor development. Evident from the above principles is the strong emphasis on public transport becoming the basis of the movement system in the province, with urban corridors, activity spines and public transport routes creating the 'skeleton' for future processes of densification and intensification, including transit-oriented development around road and rail-based public transport facilities. However, challenges relate to the pace of implementing the transformative and catalytic projects that are linked to inadequate investment and funding framework. At the same time, the low population densities in the Gauteng province fight against the implementation of sustainable public mass transit systems. The fragmented local transport governance systems need to graduate into a Gauteng transport authority at a faster rate than what the Gauteng Transport Commission is operating at. While good intentions and initiatives are in place, these are falling short of addressing holistically the spatial and transportation inadequacies that characterise Gauteng province.
In this section, the main findings of the study are discussed. These are covered in terms of the following subheadings: rapid urbanisation, high motorisation rates, spatial fragmentation and inefficiencies. The synthesis of the three above-mentioned areas is then presented in the form of a subsection that discusses the spatial and transportation complexities and challenges linked to reconciling rapid urbanisation challenges to a transportation solution. In any case, the section is then summarised through advancing recommendations and implications emanating from the study aimed at suggesting practical spatial and transportation solutions for the Gauteng city region in South Africa.
The overall growth rate of 30.7% between 2001 and 2011 (and a further 7.5% between 2011 and 2015) reflects high levels of in-migration into the Gauteng province [20]. This high growth rate is not only directed at the urban areas of the metros but also into the economic hubs of the local municipalities. Growth across the municipalities in Gauteng province has consistently varied from 9.7% in Emfuleni local municipality (LM) to over 35% in the city of Johannesburg (COJ) and city of Tshwane (COT), to 48% in Midvaal LM. The only municipalities to have experienced very low growth and negative growth rates between 2001 and 2011 census period were Westonaria LM (1.8%) and Merafong LM (−6.2%). Between 2002 and 2013, the household growth rate for the Gauteng province in total was 39%, while the next closest growth rate in South Africa was the Western Cape at 12.3% [20, 21]. Even Emfuleni LM in Gauteng, which had the lowest growth in household of all municipalities in the province (17.8%), exceeded the household growth rate of the Western Cape. Map 2 illustrates spatially the change in total population per sub-place in Gauteng city region 1996–2011.
From Map 2, we can deduce that generally Gauteng city region experienced high population changes between 2001 and 2011 census periods. This high rate of growth in the number of households formation relates to the impact of in-migration, which is most pronounced in the Gauteng province, making the work of the Gauteng municipalities more than challenging. Mismatches, deficits, tensions and capacity constraints in providing for employment/job creation, housing, facilities, transport infrastructures and services emerge as critical challenges as the region is underprepared for the rapid urbanisation wave occurring under its area of jurisdiction.
The national vehicle fleet in 2015 consisted of 10,317,262 registered vehicles, with 39% of all vehicles registered in Gauteng province. Passenger cars comprise 73% of vehicles registered in Gauteng province with heavy-duty vehicles (HDV) and buses collectively making up just 3.8% of the provincial vehicle fleet. Table 2 presents a tabular illustration of the registered vehicles in the Gauteng province in the year 2015.
|Passenger cars
|Gauteng province
|National total
From Table 2, one can deduce that passenger cars are the largest vehicle category of registrations, while light delivery vehicles (LDVs) also form a significant component of the vehicle population. The total amount of diesel and petrol sold in South Africa was 13,492 and 11,470 mL, respectively. The amount of fuel sold in Gauteng in 2015 was 3160 mL of diesel and 4119 mL of petrol. The greater volume of petrol to diesel is reflective of the larger number of passenger cars in Gauteng province. The high automobile dependency on small and inefficient vehicles has negative implications in terms of urban road space utilisation, carbon footprint as well as congestion including road-based accident-related data. Map 3 presents a spatial map illustrating the current public transport bus subsidy spatial portrait of subsidy allocation and distribution in South Africa. This is discovered to be strongest in the Gauteng city region around Pretoria, Johannesburg, Randfontein and Ekurhuleni.
From Map 3, we can deduce that the fragmented nature of spatial settlements in South Africa has huge implications for the current public transport subsidy policy by the government. The subsidies are highest in Gauteng city region as well as in Cape Town city, for example. Following on then, Table 3 presents a comparison of the estimated annual emissions of air pollutants and CO2 from registered motor vehicles in Gauteng than the national emission outputs. The CO emission of 440,22 t/a is the highest of the air pollutants and is equivalent to 35% of the national emission [28]. Emissions of non-methane volatile organic compounds (NMVOC) are relatively high and account for 35% of the national emission with the NOx emission accounting for nearly 30% [28]. Emissions of lead are very low due to the phase-out of lead in fuels. Similarly, SO2 emissions are relatively low with the low sulphur content in fuels. The total CO2 emission for the national vehicle fleet is estimated to be 54,258,926 with 16,213,749 t/a from vehicles registered in Gauteng province, accounting for nearly 30% of the total CO2 emission [28]. The city of Johannesburg, city of Tshwane and Ekurhuleni metropolitan municipality have the highest pollutant emission rates for all pollutants.
|Gauteng province
|National total
However, Table 4 presents the total emissions of air pollutants and CO2 by vehicle category in Gauteng province. The significant contribution from passenger cars to the CO emission is noteworthy, as well as their contribution and that of HDVs and buses to the NOx emission.
|Passenger cars
|HDVs and buses
From Table 4, we can deduce the automobile dependence cost on emissions in Gauteng province. Attempts at land and transportation solutions that move towards low-carbon economy are therefore a welcome development.
In the South African context, there are three critical concerns in relation to urban form and density. First, densities overall are very low in international terms, resulting in high costs of infrastructure provision, long and costly travel for individuals, inefficient logistic networks and low market thresholds [13, 14, 29, 30, 31, 32]. Second, the density gradient is frequently inverted: the highest densities are found in pockets of low-income settlements along the periphery, rather than closest to the urban centre [33]. Third, spatial fragmentation of the labour market disperses available work [34]. South Africa's metropolitan areas have an average density of 2960 people/km2, than 8292 people/km2 for low- and middle-income countries and 3100 people/km2 for high-income countries [32, 35]. Internationally, the only cities with lower average densities than South African cities, and longer travel distances to work, are the sprawling cities of North America, which rely heavily on individual passenger cars rather than public transport [22, 36, 37]. A comparative analysis of Johannesburg metropolitan area with cities in developed countries shows that there is the existence of low density in Johannesburg which becomes a critical development problem. On average most Johannesburg residents live in townships far from the city centre [14]. This development pattern contrasts with the population distribution of other large cities, since density is usually greatest towards the city centre. Transport is a major challenge in this type of urban environment [13, 29, 31]. Most people in Johannesburg live far from the city centre and their place of work. The high density in townships also presents service delivery challenges, and crowding reduces quality of life. A city cannot therefore be quickly restructured. However, the need for inner-city revitalisation, mixed-use development and densification in central urban areas is one way of resolving the issue. The need to focus development in townships in city planning and development is also vital. The Gautrain and surrounding development hubs are therefore a good step in this direction.
Map 4 captures density variations in the Gauteng province in a graphic manner. While such variations are not uncommon internationally, what is unusual in South Africa's case is the low densities in middle-class residential areas, than high densities on the urban periphery. Particular concerns include the extreme levels of dispersal within Gauteng, South Africa's economic heartland, which makes it difficult to operate as an integrated city region, and the persistence of the profoundly constrained pattern of 'displaced urbanisation', most clearly evident in Tshwane (Winterveld) and Mangaung (Botshabelo). However, since the early 1990s, a growing concentration of people living in inner-city Johannesburg has begun to counteract the distortion of a negative density gradient. In many cases, this is happening through informal process such as increased densities in informal settlements close to work and growing numbers of backyard shacks. Table 5 presents relative transport modal splits for nine different countries.
|Urban area
|Transport modal split
|Public transport (%)
|Walking (%)
|Cycling (%)
|Private motorists (%)
|New York
|Sao Paulo
From Table 5, one can deduce that Johannesburg is a relatively energy-inefficient city in global terms. Johannesburg has furthermore high levels of unemployment and poverty (around 25%) and is home to one of the highest Gini coefficients in the world (0.75 than 0.38 for Asian cities) [12, 23]. Transport accounts for 31% of SA's energy consumption (56% in cities) and 16% of CO2 emissions [38]. The big transport modal split trend in the lower-income groups of South Africa has been the shift away from using publicly owned public transport (bus and rail) to privately owned public transport (taxis). As an example in Gauteng, changes and trends in public transport were recorded with respect to the use of minibus taxis increased from 3% in 1975 to 41% in 2009 with bus declining from 22 to 4% and train from 20 to 8%. At the same time, despite the travel flexibility associated with taxis, travel times for this group have remained static or declined in places. However, a worrying development is the fact that the middle-income group has remained resolutely car-oriented and travel times have increased dramatically since 1980 (nearly 60%) [39, 40].
From Map 4, we can deduce that there is a challenge of spatial distribution of population in Johannesburg. The underlying factor is that Gauteng province is not densified than other cities in the World. The spatial fragmentation manifests itself in spatial mismatches between residential areas and areas of economic opportunity. This has also strong resonates with constrained transportation and commuting challenges [41]. Given these spatial inefficiencies and misfits, transport costs and modal choice are constrained generally for passengers but in particular for employees and learners who use public transport. Map 5 presents transport indicators by metro in South Africa which has resonates with the spatial and transport inefficiencies.
The high cost of transportation is partly due to spatial form and partly to do with modal splits and inefficiencies affecting particular types of transport (refer to Map 5). Internationally, spatial planning methods, such as transit-oriented development (TOD), have been developed and are touted as the antidote to address the spatial and transportation disjuncture as illustrated in Gauteng. The cities in Gauteng province are typically 'sprawling cities' that were not originally planned, designed and built to meet the needs of a large majority of the commuting population. A way of addressing this anomaly is through devising and crafting an urban development agenda that places at the centre the integration of public transport with the built environment as paramount. Steps towards building compact, inclusive, resilient, integrated and connected cities are part of the solution package aimed at enhancing commuting experiences in Gauteng. In South Africa these principles have been acknowledged and the need to foster a strong and conducive environment suggested. Grant frameworks can be used to encourage densification and facilitate transition to a low-carbon economy in Gauteng province in particular and South Africa by extension. A major plank of the spatial transformation necessary in South African cities is densification—people moving from the periphery to the centre—and the formation of 'mobility corridors' [33, 42, 43], for those who remain outside the centre.
Rapid urbanisation further complicates the realisation of a sustainable transportation solution in Gauteng province. This is because the government has to respond to many issues including the housing backlog matters, growing informalities in the cities which also manifest themselves in expanding and expansive informal settlements. At the same time, an unemployment challenge is also created and continues to remain stubbornly high (estimated at 35%) [20]. In this set-up priority matters become housing, employment, provision of socio-economic facilities, fighting crime and increasing security, while transport features in the low rungs of priority matters. As an example, in the 1970s, it was identified and costed that an underground tube transport was solution for the transportation matters in Gauteng province. The project was however not implemented because it was seen as too costly requiring US 7 billion dollars at that time [13]. Parallel to the implementation of the Gauteng rapid rail link in the build-up to the 2010 World Cup, the idea of a light tram system to complement the Gautrain as well as existing conventional bus services and taxi transport systems was also mooted. However, the project was terminated at an advanced stage of preparing the logistics for its implementation owing to the fact that necessary government project approval and protocol compliance matters had been overlooked. While the Gautrain rapid rail link project has been implemented, the project suffers from having an inadequate and incomplete geographic coverage and spread to provide all-round transport system to all areas. In any case, the BRT systems for the three metro are at various stages of implementation with the BRT Rea Vaya (Johannesburg) running, while Tshwane Areyeng is also in operation. The BRT Harambee (Ekurhuleni) is yet to commence operation. While all these transformation and advanced new generation of transport systems are welcome, there is still need to improve the integration between the modes through switching and implementing the single public transport ticket system. In addition, to make public transport more sustainable from a funding perspective and growing sales, there is need to densify the public transport corridors which are currently lowly populated. The Gauteng improvement freeway programme that was implemented by the government with tolling as a principle to manage road space in Gauteng province has met with spirited resistance from the road users with toll paying defaulting rates stand at approximately 78% of the road users. Different stakeholders have continued to argue that the project though welcome was not properly structured. Its introduction to the commuters at least regarding public participation and funding and sustainable models for repaying the loans has been singled as having been inadequately structured and conveyed to stakeholders. At the same time, a sustainable steering and integration model that is acceptable to the minibus taxi industry is still yet to be developed and agreed on. Overall, rigorous efforts towards spatially transforming Gauteng city form from fragmented structure into a compact transit-oriented driven spatial structure are fundamental if the transportation and spatial inefficiencies in Gauteng are to be redressed. In this set-up in which the public system is yet to establish itself as the choice of commuters, the growth in car ownership continues unabated. The consequence is the vicious loop of an automobile-dependent society in the Gauteng province. While land densification programmes and initiatives in place are acknowledged, the downside to the arrangement is that these are inadequate in terms of the scale, size and desired impact to witness a significant change in travel patterns, driving behaviour as well as new housing and building density set-ups. At the same time, the use of separate transport systems and institutions by the local municipalities creates cracks and lack of transportation integrated solutions in the Gauteng city region. This is because each municipality plans and implements spatial and transportation projects as if it is isolated and not linked to each other in the bigger Gauteng province transport set-up and spatial dynamics network of settlements, industry and commercial enterprise.
From this review, it can be recommended that resolving the urban spatial and transportation solutions in Gauteng province requires a mixture of both spatial and transportation and non-spatial and transportation solutions. Optimising public transport is one way of addressing the transport commuting constraints in Gauteng province [44, 45]. The need for transforming Gauteng province into a smart city region through the smart bus rapid transport (BRT) systems should be upscaled to cover all aspects of a smart city and metropolitan region such that we have a city landscape supported by smart planning systems, smart building and construction systems, smart infrastructure maintenance and rehabilitation systems, smart recording and system management systems, smart information and communication system, et cetera [46, 47]. All these initiatives should enable increased accessibility of the Gauteng city region so that the productivity and competitiveness of the region are increased [48]. The need to consolidate governance and transport authority systems that can migrate, integrate and plan for all the transport needs of Gauteng province holistically and comprehensively in terms of a transport authority for the region rather than single areas requires further improvement and is an initiative in the right direction. Such transport authorities have been seen to assist in managing urban transport and spatial planning better in areas such as the Greater London region in the United Kingdom as an example [49, 50, 51, 52, 53, 54]. The region is therefore encouraged to find the right balance in terms of implementing advanced spatial planning systems that reverse spatial fragmentation problems, making use of smart transport solutions to solve the transport problems of lack of integrated pricing system as well as fully develop and implement a transport authority that provides the overall intelligence to address todays transportation problems while having a master plan to address the future transport problems in the Gauteng region.
This chapter has managed to illustrate the multiple and complex spatial and transportation challenges that the Gauteng city region faces and is faced with. These challenges are partly explained by the fact that the Gauteng city region forms an extended economic hub and network of socio-economic opportunities and activities. This unique status of Gauteng city region accounts for high in-migration which creates differential pressure on all facets of socio-economic infrastructure and facilities. In response to the high urbanisation and motorisation rates experienced in Gauteng city region, the municipalities have developed a range of spatial and transportation interventions to resolve spatial fracturing, fragmentation, dislocation and urban traffic congestion problems. The interventions have met with mixed fortunes from an implementation perspective, although generally the sum effect of these interventions is the development of strategic forward-looking urban structure and transportation solutions. While the expansion of freeways through road construction and highway expansion (physical instrument) is appreciated, the downside of this intervention is that it supports a predominantly automobile-dependent growth at the expense of development of other equally important transport dimensions such as improving the metrorail, expanding and popularising urgently the Gauteng rapid rail link as well as the development of transit-oriented development (TOD) to facilitate a compact and pedestrian urban and friendly urban structure. The introduction of e-tolling of roads (financial instrument) has met with spirited resistance, and the matter remains largely unresolved. The debate points have revolved around inadequate consultation and participation during the build-up of the project; at the same time, the economic funding model has been questioned as inappropriate. Suggestions have ranged from increasing a fuel levy nationally to having a special fuel tax for Gauteng city regions, while others have argued that the government should fund the budget from the income tax paid by individuals and companies, respectively. From this chapter's review, the need for continued research and development aimed at delivering more efficient and carbon-neutral spatial and transportation solutions beckons. It is also high time that the autonomous and electric vehicle/buses technology and implications regarding reconfiguration and spatial planning and organisation of land-use debate should be allowed to take centre stage. A sustainable spatial and transportation approach for the Gauteng city region is one that is anchored on providing innovative solutions to addressing current problems as well as balancing future intelligent innovations to create an adaptive, progressive and robust spatial structuring set-up that can be adequately supported by appropriate transportation solutions. In any case, the solution to the spatial structure mismatches, disconnects and transportation inadequacies does not lie solely in the domain of spatial and transportation planning and management per see. The need to outreach and create space for a multi-, trans- and cross-disciplinary integrative and cooperative partnerships is crucial in achieving the anticipated spatial and transportation turn linked to advanced forms of the next generation of spatial and transportation solutions. Indeed, restructuring the Gauteng city region from a spatial and transportation perspective is a daunting task, which however requires attention and can be tackled with the application of a clear spatial and transportation implementation road map plan, supported by an adequate provision of resources (financial, economic, human, political support and dedicated leadership) within the orbit of an appropriate institutional and governance delivery system and framework.
I acknowledge the Council for Scientific and Industrial Research (CSIR), Pretoria, and the University of Venda-Directorate Research and Innovation for invaluable inputs that assisted in shaping this paper. The authors acknowledge Mr. Farai Dondofema for the GIS mapping and production.
The authors make a no 'conflict of interest' declaration.
The Internet has changed the dynamics of scholarly communication and publishing which is why we find it necessary to clearly indicate our stance on what we consider to be a published scientific work.",metaTitle:"Prior Publication Policy",metaDescription:"Prior Publication Policy",metaKeywords:null,canonicalURL:"/page/prior-publication-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"
A great number of working papers, early drafts and similar works in progress are openly shared online between members of the scientific community. It has become common to announce one's own research on a personal website or a blog to gather comments and suggestions from other researchers. Such works and online postings are indeed published in a sense that they are made publicly available, but this does not mean that if submitted for publication by IntechOpen they are not original works. Therefore, we differentiate between reviewed and non-reviewed works when determining whether a work is original and has been published in a scholarly sense or not.\\n\\n
The significance of peer review must be stressed when it comes to defining what a published scientific work is. It is widely considered to be the cornerstone of a modern publishing process and a publisher's key value adding contribution to a scholarly manuscript.\\n\\n
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IntechOpen's Retraction & Correction Policy and various publication ethics guidelines available online consider both redundant publication and (self)plagiarism to fall within the definition of research misconduct, thus constituting grounds for rejection or issuing a retraction if the work has already been published.\\n\\n
In order to facilitate the tracking of a manuscript's publishing history and development from its earliest draft to the manuscript submitted, we encourage authors to disclose any instances of a manuscript's prior publication, whether it be a conference presentation, a newspaper article, a working paper publicly available in a repository, a blog post, etc.\\n\\n
A note to the academic editor containing detailed information about a submitted manuscript's previous public availability is a preferred means of reporting prior publication. This helps us determine if there are any earlier versions of a manuscript that should be disclosed to our readers or if any of those earlier versions should be cited and listed among a manuscript's references.\\n\\n
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Given that conference papers and presentations generally pass through some sort of peer or editorial review, we consider them to be published in a scholarly sense, especially if they are published as a part of conference proceedings.\\n\\n
All submitted manuscripts originating from a previously published conference paper should contain at least 50% of new original content to be accepted for review and considered for publication.\\n\\n
Authors are required to report any ties their manuscript might have with their earlier conference papers and presentations in a note to the academic editor, as well as in the manuscript. Additionally, authors should obtain any necessary permissions from the publisher of their conference paper if copyright transfer occurred during the publishing process. Failure to do so may prevent us from publishing an otherwise publication-worthy work.\\n\\n
2. NEWSPAPER & MAGAZINE ARTICLES\\n\\n
Newspaper and magazine articles usually do not pass through any extensive peer or editorial review and we do not consider them to be published in a scholarly sense. Besides, articles appearing in newspapers and magazines rarely possess the depth and structure characteristic of scholarly articles.\\n\\n
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Although such papers are regularly made publicly available via personal websites and institutional repositories, their general purpose is to gather comments and feedback from authors' colleagues in order to further improve a manuscript intended for future publication.\\n\\n
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4. SOCIAL MEDIA, BLOG & MESSAGE BOARD POSTINGS\\n\\n
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A great number of working papers, early drafts and similar works in progress are openly shared online between members of the scientific community. It has become common to announce one's own research on a personal website or a blog to gather comments and suggestions from other researchers. Such works and online postings are indeed published in a sense that they are made publicly available, but this does not mean that if submitted for publication by IntechOpen they are not original works. Therefore, we differentiate between reviewed and non-reviewed works when determining whether a work is original and has been published in a scholarly sense or not.\n\n
The significance of peer review must be stressed when it comes to defining what a published scientific work is. It is widely considered to be the cornerstone of a modern publishing process and a publisher's key value adding contribution to a scholarly manuscript.\n\n
Other than the issue of originality, there is also the looming issue of research misconduct.\n\n
IntechOpen's Retraction & Correction Policy and various publication ethics guidelines available online consider both redundant publication and (self)plagiarism to fall within the definition of research misconduct, thus constituting grounds for rejection or issuing a retraction if the work has already been published.\n\n
In order to facilitate the tracking of a manuscript's publishing history and development from its earliest draft to the manuscript submitted, we encourage authors to disclose any instances of a manuscript's prior publication, whether it be a conference presentation, a newspaper article, a working paper publicly available in a repository, a blog post, etc.\n\n
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Some basic information about the editorial treatment of different varieties of prior publication is laid out in the following sections.\n\n
1. CONFERENCE PAPERS & PRESENTATIONS\n\n
Given that conference papers and presentations generally pass through some sort of peer or editorial review, we consider them to be published in a scholarly sense, especially if they are published as a part of conference proceedings.\n\n
All submitted manuscripts originating from a previously published conference paper should contain at least 50% of new original content to be accepted for review and considered for publication.\n\n
Authors are required to report any ties their manuscript might have with their earlier conference papers and presentations in a note to the academic editor, as well as in the manuscript. Additionally, authors should obtain any necessary permissions from the publisher of their conference paper if copyright transfer occurred during the publishing process. Failure to do so may prevent us from publishing an otherwise publication-worthy work.\n\n
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Newspaper and magazine articles usually do not pass through any extensive peer or editorial review and we do not consider them to be published in a scholarly sense. Besides, articles appearing in newspapers and magazines rarely possess the depth and structure characteristic of scholarly articles.\n\n
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Although such papers are regularly made publicly available via personal websites and institutional repositories, their general purpose is to gather comments and feedback from authors' colleagues in order to further improve a manuscript intended for future publication.\n\n
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Nevertheless, authors are encouraged to disclose the existence of any internet postings in which they outlined and described their research or posted passages of their manuscripts. Such occurrences are welcome to be reported in a note to the academic editor, but we will not be strictly enforcing it as a rule as we understand that it may be difficult to keep track of all one's internet postings in which his or her current research may be mentioned.\n\n
In case there is any overlap between the submitted manuscript and related internet postings authored by the submitter or any indicated co-authors, we will generally not consider it to be an instance of self-plagiarism.\n\n
For more information on this policy please contact email@example.com.\n\n
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