Modification of the 4-Quinolone Scaffold

Modification of the 4-Quinolone Scaffold Discovery: Quinolones are antibacterial agents that are of major importance in the antibacterial field as the can act as the model antibiotic. This is due to their broad range of activity, the high potency and good bioavailability with both intravenous and oral administration possible. This is coupled with high serum levels and a distribution within tissues that specifies concentration levels and results in, theoretically, few occurrences of unwanted side effects.1 The timeline for the development of this class of antibacterial agents begins with the isolation of the bactericidal naphthyridine, nalidixic acid, in the 1960s by George Lesher as the first synthetic quinolone antibiotic. Nalidixic acid is illustrated in Figure 1 below and is a by-product that was isolated from a chloroquine synthesis.2 Figure 1: Nalidixic Acid The clinical use for naldixic acid was to treat urinary tract infections (UTIs) caused by gram negative organisms. The successive generations of quinolones had activity against both gram negative and gram positive bacteria as well as anaerobic bacteria. This development lead to fluoroquinolones which are latest in quinolone antimicrobials. The clinical uses for the quinolones today include respiratory tract infections, bacterial meningitis and gastrointestinal infections as well as the historical use of treating UTIs. The development of fluoroquinolones resulted in a more extended spectrum of activity and improved pharmacokinetics then the first generation of quinolones.3,4 Structure: The general quinolone class of molecules is comprised of 4-quinolone and 1,8-napthyridine ring structures. The naphthyridine ring structures differ slightly from the 4-quinolone core due to the presence of two nitrogen atoms in the rings of the molecule (Figure 2). The substituents R5, R6, R7 and R1 were added to improve the activity of the quinolone core before the development of highly potent fluoroquinolones.1 Figure 2: General Structure of 4-Quinolones The first fluoroquinolone to be developed was Flumequine; illustrated in Figure 3. It had a fluoro-group at the 6 position and was the first compound to show that modifications of the quinolone core could results in improved activity against the gram-positive bacteria that nalidixic acid had no effect on.1 Figure 3: The first fluoroquinolone- Flumequine Mechanism of Action: Inhibition of bacterial DNA gyrase (topoisomerase II) and topoisomerase IV is achieved by quinolones. These enzymes play a vital role in the uncoiling of DNA. DNA gyrase acts as the target in gram negative microbes and topoisomerase IV as the target in gram positive microbes for quinolone activity. The widely-accepted mechanism of action is that quinolones bind to complexes, formed between DNA and one of the enzymes, to generate a Quinolone-DNA-Enzyme complex that inhibits DNA replication. The binding of quinolones and topoisomerase is enabled by a water-metal ion bridge. The inhibition is bacteriostatic as replication is reversible.   Eventually apoptosis occurs due to the fragmentation of the DNA ends of the complex. This results in bactericidal inhibition. The most common form of resistance to the quinolones is due to specific mutations in the topoisomerase II and IV that interfere with the water-metal ion bridge interaction.2,3 Development: Quinolones are grouped into generations depending the activity of the molecules. The first generation showed activity against gram negative bacteria that caused UTIs. The second generation showed enhanced activity against gram negative bacteria and improved activity against gram positive. This enabled the list of conditions that quinolones could treat to expand. This generation displayed improved pharmacokinetics; due to the use of a C7-piperdinyl substituent. The third generation provided improvement in efficacy in inhibiting gram positive and anaerobic pathogens. 3,5 The fourth generation of drugs observed dramatically increased activity against DNA gyrase and gram positive microbes, improved pharmacokinetics and pharmacodynamics. The major changes were the addition the fluoro-group at the C-6 position and a ring substituent at C-7. Norfloxacin (1), second generation, was the first broad spectrum quinolone with ciprofloxacin (2) the first quinolone to have activity observed beyond the treatment of UTIs.2 Currently, Garenoxacin (3), fourth generation, is of interest due to its distinct carbon-carbon bond at position C7 and its broad spectrum of activity.3 Figure 4:Generations of quinolone drugs. Three modified quinolone cores have acted as templates for drugs that are on the commercial market. The cores were 4-oxo-1,4-dihydroquinolone (4), 7-oxo-2,3-dihydro-7H-pyrido-[1,2,3-d,e]-1,4-benzoxazine (5) and 4-oxo-1,4-dihydro-[1,8]-naphthyridine (6). These selected cores are illustrated in Figure 5.3 Figure 5: Cores used as templates for commercial drugs Retrosynthesis: Scheme 1: Retrosynthesis of 4-Quinolone core6 A carbon-carbon disconnection between the ketone and the aromatic ring, the reverse would be a Friedel-Crafts reaction.   The double bond is opened and the hydroxyl group that is added is converted to a carbonyl group. The final disconnection, N-C, results in the starting materials; a keto ester and the substituted aniline. Synthesis: Several synthetic approaches have been taken to generate the 4-quinolone core. The Gerster-Hayakwa and Chu-Mitscher reactions are used specifically for the synthesis of the drug Levofloxacin. The Chu-Li route was established primarily for 9-cyclopropylpyrimidinones. The Gould-Jacobs reaction, Grohe-Heitzer cycloacylation and Conrad-Limpach-Knorr are appropriate methods of synthesising the generic 4-quinolone core.3 The Conrad-Limpach-Knorr synthesis will generate quinolones but this reaction will give different products depending of the whether it is kinetically or thermodynamically controlled. Aniline and 3-keto ester are mixed and at room temp the keto group joins the nitrogen of the aniline giving an enamino ester (kinetic product) and cyclisation at 250 °C results in a 4-quinolone. Thermodynamically controlling this reaction, by carrying it out at 140 °C, results in an amido-ketone dominating regardless of the less reactive ester on the keto ester being the centre of the first nucleophile attack. Ring closure results in a 2-quinolone.7 Scheme 2: Conrad-Limpach-Knorr Synthesis (kinetically controlled) As the substrate for the cyclisation needs to be the high-energy tautomer and cyclisation causes loss of aromaticity in the ring, solvents with high boiling points are generally used in this synthesis.8 The reactions are encouraged by electron-donating substituents in the aromatic ring including methoxy or amino groups. These give increased yields in the condensation and ring closure steps. A CF3 group can act as an acceptor at C-4.9 The short reaction sequence limits possibility of loss of yield. Rational Drug Design: Illustrated in Scheme 3 is the process of rational drug design. Computational screening is used to identify the target and generate the lead compound. This is modified considering the biological aspects, the 3D structure, the QSAR and reactivity of the compound. This generates a new lead which is optimised and put forward for preclinical trial. Scheme 3: Rational Drug Design Process10 Nilsen et al. used endochin as a lead for optimisation in a rational drug design study. The target selected was the multiple stages of the life cycle of malaria. Endochin is potent against malaria but is not active in vivo due to rapid and extensive metabolisation. Optimisation was required to form endochin-like quinolones (ELQ) that retained the activity of endochin but were biologically active. The aims for optimisation was to improve metabolic stability and aqueous solubility as well as eradicate cross-resistance.11 Figure 6: Structural Representation of Endochin The EQLs were synthesised by converting the quinolones to quinolines, followed by nucleophilic displacement. The quinoline undergoes Suzuki-Miyaura coupling with a boronic ester and finally the protecting group is removed (Scheme 4 A). An OCF3 group was also added to the side chain for further optimisation (Scheme 4 B). Scheme 4: Synthesis of ELQ An orally active class of quinolones were synthesised; 4(1H)-quinolone-3-diarylethers. The initial lead, ELQ-233 (Figure 7: ELQ-233Figure 7), displayed low nano-molar IC50 values. The optimisation step was to introduce an aryl group at C-3. A lipophilic diphenylether side chain was used as it had been previously reported as integral in other antimalarial drugs. This was to work with the methyl group at C-2 to cause out of plane movement of the sterically large aromatic ring, altering the à Ã¢â€š ¬Ãƒ ¢Ã‹â€ Ã¢â‚¬â„¢Ãƒ Ã¢â€š ¬ stacking from the numerous H-bonds. This variation would not be perused as ELQ-233 was equipotent to endochin. Figure 7: ELQ-233 Due to the success of adding a fluoro group to the quinolone, to further build on the optimisation of endochin, a fluorine was added at C-6 on a second optimised molecule (7) along with a methoxy group at C-7 (as is in the endochin structure); illustrated in Figure 8.11 The methoxy group is a useful substituent due to its lipophilic and hydrophilic components in close proximity. Figure 8: Illustration of Compound 7 However, both ELQ-233 and 7 were metabolically unstable and therefore did not fulfil the optimisation requirements. Table 1: Values obtained for the optimised molecules Compound cLogP EC50 (nm) Endochin 3.35 3.8 ELQ-233 3.70 8.4 7 3.73 40 8 5.66 2.2 Further derivatives were generated and the pattern that emerged indicated that the substitution pattern on the aromatic ring influenced the reactivity with malaria. This result led to the rational design of further ELQ derivatives. Straight-forward reactions were continued to be used. The boronic ester with a varying diarylether side chain undergoes palladium mediated coupling with the quinolone then a demethylation occurs using hydrobromic acid to give the desired product. Repositioning the OCF3 group to the side chain increased the efficacy and the metabolic stability. The compounds that was found to be metabolically stable and potent had a chloro-group at C-6 and OCH3 ­at C-7. Figure 9: Structural representation of compound 8 Although compound 8 was the most potent compound, the high logP value is a disadvantage as it does not follow Lipinskis Rule of Five which is the basis for most developed drugs. To improve solubility and allow for lower dosages of 8, bioisoteres of the side chain were employed. The OCF3 was replaced by CF, Cl and F by Nielson et al. and displayed subnanomolar activity. Other options would be to double the terminal OCF3 group, double the substituents on the diaryl side chain, convert the diphenyl ether side chain to a dipyridine ether side chain or replace a phenyl ring in the side chain with a cyclopropane group. Phenyl rings can be replaced by a heteroaromatic ring or a saturated ring to improve efficacy, lipophilicity and specificity of binding. The introduction of a pyridine ring should reduce the metabolism of the phenyl ring and toxicity of metabolites.12 In heterocycles, metabolism can be more complicated with hetero-atoms being oxidized and/or ring opening reactions possible- slowing metabolism. Cyclopropane was explored as derivative of the phenyl ring resulting in compounds with reduced molecular weights and lower lipophilicities. It also limits the conformations available and increase yields of ELQs.11 Scheme 5 below are the same coupling reactions that are stated by Nielson et al. but with the suggested changes to further improve the lea d. Caution must be taken when adding substituents to the side chain so that Lipinskis rule of five is obeyed; there must be no more than 5 hydrogen bond donors or 10 hydrogen bond acceptors and the molecule should be below 500 Da. Scheme 5: Suggested further optimised lead molecules Rational drug design is an advantageous modification method as it is a streamline process when compared with SAR or QSAR as there is no trial and error, all leads and derivatives are prepared having been predicted by computational means previously. The computational aspect allows for all compounds and potential targets to be envisaged in 3D before they are synthesized. This computed information is then stored on large databases which can assist future drug development work. Rational drug design can be an expensive technique as a specialized team is required with knowledge in biology, chemistry and computer science. Costs rise due to payment of wages for the team and the specialized equipment and computer software that is vital. Although the computational aspect of this method is beneficial it can also be a disadvantage as not all predicted compounds can be synthesized and if the compounds are synthesized they may not act as predicted when in vivo.   Specifically, in this ratio nal drug design study, the reactions utilised readily available reagents that were also inexpensive. They were straight-forward reactions that gave high yields and could be scaled up. These are vital as the cost of antimalarial drugs must be kept down so that all people can afford to access it.11 Structure-Activity Relationship (SAR): SAR studies examine how the structure of the molecule effects the activity. SAR considers structural characteristics and relates them the activity therefore it is necessary to have a well characterized database to compared the results against. The basic principle of SAR, that structure determines properties and reactivities in a biological system, is of importance when determining toxicological properties. This is of huge significance for quinolone development as they must be nontoxic in vivo while remaining bacteriosidal.13 Figure 10: Areas SAR Studies consider13 These studies examine which modifications are possible to the core ( Figure 11) and which substituents cannot be modified without negatively interfering with the activity and potency of the drug.   There can be qualitative and quantitative aspects to these studies. The quantitative considerations are part of a quantitative structure activity relationship (QSAR) which will be discussed later. Figure 11: Quinolone core positions for the SAR study Table 2: Important Positons on the Quinolone core-SAR Study results14 Position Influence On: Preferred substituent: Effect of substituent: 1 The pharmacokinetics and has control on overall potency. Cyclopropyl increase activity against gram negative microbes 5 Activity against gram-positive bacteria. NH2 and CH3 moiety improve activity against gram-positive bacteria 7 Spectrum of activity and pharmacokinetics. 5/6 membered N heterocycle (aminopyrrolidines and piperazines) Alkyl group Aminopyrrolidines: increase activity against gram-positive bacteria Piperazines: increase activity against gram-negative bacteria. Alkyl: enhance gram- positive potency and lengthen the serum half-life 8 Pharmacokinetics and specific activity on anaerobes. CF, CCl and COMe improve activity against anaerobic bacteria. alter specific interaction of the agent in vivo. SAR studies reveal that a hydrogen at R2 is preferred. Any larger moiety would likely cause steric hindrance with the adjacent carboxyl group at C-3 and the oxygen at C-4. These substituents are vital for activity as these positions are where binding to DNA bases occur before the sites are made available for other hydrogen bonding to proceed by DNA gyrase. A small molecule is best for potency at R6. This is usually a fluorine group in later generations of quinolones as it produces molecules of between 5 to 100 times greater potency that when a hydrogen is positioned at R6.14 Ciprofloxacin (Figure 12) is one of the original patented quinolone anti-bacterial agents. It is first generation as it has moderate activity towards gram negative bacteria, poor pharmacokinetics and poor bioavailability. Figure 12: Structural representation of Ciprofloxacin However, using the results of the SAR, Ciprofloxacin can be further optimized. Scheme 6 utilizes straight-forward reactions to attach an -NH2 moiety to the core at positon 5 where the SAR study indicates it has the greatest influence. Firstly, nitration of the aromatic ring occurs, followed by a reduction of the nitro group to an aniline with palladium on carbon. Scheme 6: Further optimisation based on SAR Study Results The new lead is still in agreement with the SAR results as the carboxyl and oxygen are present at C-3 and C-4 respectively. The preferred substituent as stated in Table 2 are also used throughout the reaction scheme; the piperazine is at position 7, the fluoro group at positon 6 and the cyclopropyl group at positon 1. These substituents can positively influence the spectrum of activity the potency and the overall pharmacokinetics of the molecule. The addition of extra hydrogen bond acceptors/donors must be limited so as not to disobey Lipinskis rule of five by having more than 5 hydrogen bond donors or 10 hydrogen bond acceptors. These reactions, like the rational drug design reactions, utilize readily available, generally inexpensive reagents which is important to keep the cost of the anti-malarial drug down. Palladium is an exception as it is a rare metal but cheaper alternatives could be used for this step such as Raney Nickel although this generates intermediates before the aniline is formed unlike the direct formation when the palladium catalyst is used.15 SAR studies can represent molecules as 2D, atoms and bonds, or 3D, steric effects and electrostatics. 3D is best for when the receipt-mediated mechanism is known. Successful SAR studies also need appropriate methods of analysis which depend on whether quantitative or qualitative analysis is being perused and if the mechanism is known. The ideal SAR model should have adequate molecules for fair statistical analysis, a wide range of activities and an even distribution of molecules in each compound class. This model is rarely found when toxicology is considered.13 Quantitative Structure-Activity Relationships (QSAR): The basic principle of QSAR is that similar molecules have adequate similar mechanistic elements so that a common rate-determining step is shared among them and that they have comparable energy requirements for activity. This principle is taken further and the assumption is that differences in reaction rates results in differences in activity or potency.13 Lipophilic, electronic and steric effects are considered in QSAR studies. QSAR provides an equation that quantifies the SAR and allows for predictions about which property has an important role in the distribution/ mechanism of the drug. Predictions cut down on the volume of analogues to be synthesised. Equations are only applicable to compounds of the same structural class. Outliers indicate when a feature is important and can produce new leads. The QSAR may not give accurate predictions as the parameters have covariance on each other; the predicted model may vary in vivo.6 Lipophilicity/Hydrophobicity: This can be considered as the lipophilicity of the molecule or the lipophilicity of the substituents attached. Partition Coefficient, P, is the parameter associated with the lipophilicity of the molecule and is measured by Equation 1. Equation 1: Representation of the lipophilicity parameter. Solvents chosen to represent the Central nervous system The activity of a molecule can be related to the P value as a molecule must be able to cross membranes and be transported through the body to its target site which is dependent on its lipophilicity. Varying substituents on the core can alter the P value in whichever direction is more beneficial for the activity of the molecule. From SAR studies increased quinolone activity occurs when a lipophilic substituent, such as a halogen, is attached at C-6. Simple reactions, including nitration and chlorination (Scheme 7), will add these substituents to the core, again using cheap and readily available reagents. In general, increasing lead hydrophobicity increases activity (Figure 13). This does not go to infinity as there is a point at which the lead is to hydrophobic to be transported in vivo.6 LogP should not be more than 5 per Lipinskis rule of 5; high enough to bind, low enough to be released. Scheme 7: Addition of lipophilic substituents to the quinolone core to alter the P value Figure 13: Linear relationship between biological activity 1/C and lipophilicity6 Electronics: This parameter can influence ionisation and polarity which alters how a drug passes through a membrane or how strongly it binds to a receptor. Hammett substitution constant (à Ã†â€™) is the measure of the electron withdrawing or donating ability for substituents on an aromatic ring. à Ã†â€™ affects the equilibrium and the value is dependent on induction/resonance effects and whether the substituent is para or meta directing. Ortho is not considered due to sterics.6 Table 3:Substituents that can alter the à Ã†â€™ parameter Electron Donating Group (para): Electron Withdrawing Group (meta): -NH2 -NO2 -OH -CONH2 Halogen -CN Generally, electron-withdrawing substituent, positive à Ã†â€™ values, increase activity (Table 3). Simple reactions like those illustrated in Scheme 7 are used to attach the à Ã†â€™-influencing substituents to the quinolone. Sterics: Drug molecules must approach and successfully bind to a receptor and the sterics of the molecule can alter this approach. Bulk can result in nonbinding as the drug is sterically hindered from approaching the target site. It can also limit the available conformations so that only the most efficient arrangement binds to the receptor. Table 4: Parameters for measurements of steric effects6 Measure of Steric Effect: Key Feature: Other Factors: Tafts Steric Factor (Es) Quantifies steric feature of substituents Limited to use on certain substituents Molar Refractivity (MR) Measures volume occupied by atom(s) Corrects for ease of polarisation. Verloop Steric Parameter Computer programme calculates steric values For use with any substituent Using the quinolone core, modifications can be made so that the sterics prevent rapid metabolisation of a drug molecule in vivo which will extend its half-life and lead to better activity. Binding the quinolone to a large side chain restricts it from binding to smaller sites which Nilsen et al. conclude lead to better selectivity.11 Scheme 8 illustrates the addition of bulky side chains that can give better selectivity as they will only approach the sites they fit into. Furthermore, the double bond linkage and aromatic rings restrict the conformation that the molecule can adopt, increasing selectivity. Bulky side chains can prevent rapid metabolism occurring. When adding bulk, caution must be taken to ensure the molecule stays below the recommended 500 Da. Scheme 8: Reactions to alter the sterics of a quinolone core16 3D-QSAR: 3D-QSAR considers the relative spatial arrangement of model compounds and aims to correlate the features across molecules that affect activity and are required for ligand binding. 3D-QSAR studies the geometry, pharmacophore and molecular field. Key assumptions of 3D-QSAR13: The model compound and not its metabolite cause the biological response. The studied conformation is bioactive. Solvent effects are not considered The system is in equilibrium All compounds bind in the same manner to the one target. 3D-QSAR puts compounds with common configurations in a 3D grid, calculates the interaction and tabulates the results. An equation is then created based on the relationship between the calculations and the reported values. This verifies QSAR results. Conformers are superimposed to display the common ligand-binding orientation to the receptor. Probe atoms calculate steric and electrostatic fields.13 3D-QSAR studies on 1,3,5-triazine, quinolone derivatives, determined less bulky groups on the heteroatom ring, more bulk on the aro

Coffee and Starbucks Essay

Walk several blocks in almost any city in America and you’ll pass at least one Starbucks, if not more. And the same is true for most cities outside of the United States. The Starbucks empire has grown to 6,000 U.S. outlets and about 2,500 international locations. For some consumers, Starbucks is an obsession, and they just can’t begin their day without their cup of Starbucks coffee! In addition, while years ago people used to hang out at the corner candy store, today many people spend considerable time at their local Starbucks. They drink coffee, tea, and/or other specialty beverages, they bring their laptop and wirelessly connect to the Internet, they meet friends to chat, or they meet business associates to make deals. Is there anyone in America, at least old enough to be in kindergarten, who doesn’t know what Starbucks is? Questions Since everybody knows Starbucks, answer the following questions in the Indian context. For example, against question 1 below view the person as an India; and in response to question 4, identify an Indian celebrity. Some search on the internet about Starbucks and what its brand imagery stands for would help you with your answers. 1. If Starbucks was a person, describe the person in terms of demographics, personality, and lifestyle characteristics 2. If Starbucks was an animal, which animal would it be, and why? 3. If Starbucks was a color, which color would it be, and why? 4. If Starbucks was a celebrity (e.g., a sports figure, a movie or TV star), which celebrity would it be, and why? And why was your choice male or female?

Strengths and Weaknesses of the Qualitative Methodology

Cotte’s paper primarily deals with the Economic, Symbolic and Hedonic motives of gambling (2-3). Her method is centered on Ethnographic Participant Observation (1). The study was conducted on a Northeastern casino (10) for 90 hours that was accumulated through 30 visits between October 1995 and March 1996 (9). This critique will concentrate on the analysis of Cotte’s Literature Review, Research Design and Methods and Subjects chosen for the study. Literature Review Cotte’s literature review tackles the economic, symbolic and hedonistic motives of recreational gambling.With an emphasis centered on â€Å"Experiential Consumption† (6) which explains the role of motives in human behaviors and decisions, the paper was able to prove its point that the human drive to gamble stems out from the desire to learn and evaluate the game (12), to have a feeling of a â€Å"rush† (14), to demonstrate self definition such as being a â€Å"variety-seeker, rebel, and casino pro† (15), to fulfill the desire to be a risk-taker (18) and to view â€Å"cognitive self classification† that is primarily achieved through â€Å"interpersonal relationships† (19).Similarly, the study reveals that urge for â€Å"emotional self classifications† are also evident (19); similarly, human competition (20) and communion (21) are also part of the characteristics that were studied. The paper’s main criticism for the author’s literature review is: Cotte, by opting to focus on the hedonistic aspect of gambling has established the claim that recreational gambling primarily is a result of emotion in its most â€Å"barbaric sense† and provides no rational explanation whatsoever on the concept of recreational gambling.Cotte presented eight cells (12-21) which tells the reason in a form of conversation between her (i. e. the researcher) or other people through overheard conversations or observations explaining why people gambl e. It could be significantly noted that Cotte have made various explanations linking the results of the observation and or interview to her related literature; and it appears that those explanations are only liked to the situations wherein there is an emphasis on the hedonistic drive (12-18).The author explained that the feeling of excitement, rush, the unknown etc are the primary reasons why people keep on coming back to the casino and even bringing their families with them to gamble as well (18). However, the paper would like to assert that although the first few cells are significantly linked on the theories that the author used, the last three cells were explained by the author in such an abrupt manner that she suddenly inserts a theory that in no way was she was able to elaborate on her literature review (19, 21).The Utilitarian Theory which definition is not established or discussed at all was inserted and was used to explain â€Å"emotional self classification† (19) an d communing (21) . In virtue of its philosophical roots, the Utilitarian theory was introduced by JS Mill and is commonly known of having this maxim: the greatest amount of happiness for the greatest number of people. However, the paper would want to establish that the author coined a different concept to the theory by equating utilitarianism to â€Å"rationality† which is definitely not the case.The paper acknowledges however that linguistics of course allows convention to give a different meaning to a particular word. However, if this is the case, the author should have at least provided an operational definition on her review of related literature. Research Design and Methods The author’s method is qualitative research focusing on Ethnographic Participant Observation (1). Her data gathering method was done primarily through unstructured interviews (Bailey, 1994) and observation (Holloway, 2002). The paper has two main criticisms: (1) Unstructured interviews are rela tively prone to bias (Bailey, 1994, 195).The unstructured interview wherein the interviewer has the advantages of probing her subjects more has a high degree of possibility to be interpreted in a different manner than what the subjects really intend it to be (195). Also, in comparing the unstructured interview to the structured interview, Bailey argued that â€Å"the mere fact that a highly structured interview has a neatly typed questionnaire is easy to code, and seems to be reliable does not ensure that the information gathered will be superior to that gathered with an unstructured interview† (195).(2) The second criticism of the paper is that observations that are primarily documented through field notes and should be in four types: condensed account, the expanded account, the fieldwork journal, and analysis and interpretation notes (Holloway, 2002, 135). However, it could be noted that the author has made clear on her paper that she only has â€Å"field notes† (whi ch is a generalized note) and â€Å"introspections† (10) for her data gathering. Holloway (2002) by quoting Spradley (1979) on her book explained that it is necessary that all of these field notes should be done by any researcher who will use the Ethnographic method.However, the paper also recognizes the advantages of the unstructured research. It is also noted by Bailey (1994) that most cases reveal that unstructured interviews have the capability of eliciting more favorable responses from its subjects. The fact that the interview is more informal in its setting and is generally friendly, most researchers are able to get the innermost feelings of their subjects that the subjects on the other hand might not consciously realize that they possess.Similarly, the descriptive ethnography method (Holloway, 2002) is capable of presenting an account of a particular behavior on a specific area or industry. Similar on the case of the recreational gamblers in the northeast, the author w as able to present what type of recreational gamblers those people are going in that casino. Cotte’s output as she stated on the latter part of her paper could be grounds for better and improved researches. Subjects of the Study The subjects of the study are randomly chosen.As evident on the research conducted, the author claims that most of the data gathered are from abrupt conversations, overheard conversations and observations. Hence, the paper claims that there is no way that the author could further verify if the same emotions or motives still apply after that particular day or the days after that particular study. Similarly, the context of the study (Holloway, 2002) that is in Northeast America does not allow the study’s conclusion to be extended to other locations or cultural contexts. Conclusion:The paper would say that the author’s attempts to verify that recreational gambler’s motivations in gambling are primarily driven by their hedonistic moti ves are successful. However, there should be enough detail that should be given in terms of the literature’s completeness, further efforts to make the methodology more valid and a more diverse choosing of the respondents. Literature Cited Holloway, I. (2002). Qualitative Research Methods in Public Relations and Marketing Communications. London: Routledge. Bailey K. (1994). Methods of Social Research. New York: The Free Press.

society Essay - 571 Words

Argument: Why You Should Not Smoke Cigarettes nbsp;nbsp;nbsp;nbsp;nbsp;You should not smoke cigarettes because of three reasons: Smoking causes cancer, Smoking is an expensive habit and Smoking also can cause heart disease. Smoking is linked to cancer of the lung, mouth, larynx and esophagus. Smoking is an expensive habit with cigarette packs cost anywhere from three to four dollars a pack, it adds up to a great expense. Also smoking cigarettes can cause a higher risk to develop heart disease. nbsp;nbsp;nbsp;nbsp;nbsp;The first reason why you should not smoke cigarettes is because it causes cancer. According to National Cancer Institute article entitled, Cigarette Smoking and Cancer: Questions and Answers, quot;Cigarette†¦show more content†¦In one month one pack a day can add up to ninety dollars two packs day one hundred and eight dollars. In six months at one pack a day it can cost five hundred and fifty dollars. In six months two packs a day can cost one thousand one hundred dollars. This amount really surprised me, but when I read the article, Twenty good reason to stop smoking from the Cancer Society , it stated that â€Å"At a rate of twenty cigarettes per day a smoker will pay around $3102 per year to support the habit. Over 20 years that is $62,040 which is two cars or a major house extension or your children’s education.† If someone has a small child and they are smoking at the present moment they should look at this quote and take it to he art. The third reason why you should not smoke cigarettes is because it increases your chances for a heart disease. According to American Heart Association website, Cigarette Smoking and Cardiovascular Diseases, â€Å"Cigarette smoking increases the risk of coronary heart disease by itself. Smoking increases blood pressure, decreases exercise tolerance and increases the tendency for blood to clot.† I think heart disease is a great risk for death, smoking increases the chances of someone developing a serious disease, and this is something people should think of before they light up. These are the reasons someone should stop smoking. You can tell someone who smokes all these facts but they must look at the whole picture and tell themselves it is time to quit. I alsoShow MoreRelatedLiterature: Mirror of Society1167 Words   |  5 PagesLiterature: Mirror of Society That literature is a reflection of the society is a fact that has been widely acknowledged. Literature indeed reflects the society, its good values and its ills. In its corrective function, literature mirrors the ills of the society with a view to making the society realize its mistakes and make amends. It also projects the virtues or good values in the society for people to emulate. Literature, as an imitation of human action, often presents a picture of what peopleRead MoreLiving in a Fallen Societies852 Words   |  3 PagesBecause faults in the society lead to its failure.All societies fail, but why? Corrupt leaders, lack of resources, and failure in security can all lead to the downfall of a society. Now not all societies fail for these reasons, but Nazi Germany, ancient India, Rome, and the Glade, a fiction society in The Maze Runner book by James Dashner, have. The are usually many faults in our government and every government whatever type of government it is. Leaders are very important in a society because everyoneRead MoreRomance Love And Society1475 Words   |  6 Pages Romance, Love and Society Love is arguably one of the most overused words in the English vocabulary. People use love as a synonym for sexual desire, for expressing friendly care, or for appreciating inanimate objects. In a romantic date, for instance, one can say â€Å"I love you† to a beloved and, at the same time, say â€Å"I love this meal† in reference to the good food that was served. However, when it comes to love between two people, love or romance is a very powerful abstract force in human natureRead MoreMemories And Its Impact On Society1387 Words   |  6 Pagesworld. The mechanisms at the basis of our memory have always fascinated scholars, and the study of memory has soon shifted from the individual dimension to the collective one. How collective memories define an entire society and the role these have when, due to traumatic events, the society is threatened has been studied thoroughly. It is widely recognized that historical memory plays an essential role in the development of id entity politics but unfortunately also in the rise of ethnic and civil conflictsRead MoreTechnology And Its Impact On Society921 Words   |  4 Pagesits customers lots of convenience as well as hindrance (Kelly 299). Some people believe automation will eventually bring the human society into abyss, while others believe that human should work with these high-tech machineries and bring convenient to the public. However, indubitably from both sides of the fence, the fast growing of automation has totally shape the society today. People today are more likely to enjoy movies such as the Terminator more than other kinds of movies, because they feel itRead MoreLord Of The Flies : Society1406 Words   |  6 Pagesâ€Å"Society exists only as a mental concept; in the real world there are only individuals.† The posed question is if society is controlled by people, or are people controlled by society. Some may argue that society is controlled by people, but if you step into the light is that really the case. If you were to look at society, really look at it, who is being controlled. Its not society itself, sure people affect the directions society turns, but that is a small group of people who represent societiesRead MoreEssay on Indian Society809 Words   |  4 Pageslarge part of Indian society, who are subjected to loss of rights and mistreatment due to their place in the caste system. In the novel QA by Vikas Swarup, a street boy, Ram Mohammad Thomas narrates the events of mistreatment and abuse in no t only his life, but several others characters with the same fate. Throughout the novel, the experiences of Ram, Salim and Nita are told, contributing to the privileging of social, gender and religious marginalisation in Indian society as foregrounded by SwarupRead MoreBuilding Healthy Society2130 Words   |  9 PagesThe peoples of the dominant human societies lost their sense of attachment to the living earth, and societies became divided between the rulers and the ruled, exploiters and exploited. The brutal competition for power created a relentless play-or-die, rule-or-be-ruled dynamic of violence and oppression and served to elevate the most ruthless to the highest positions of power. Since the fateful turn, the major portion of the resources available to human societies has been diverted from meeting theRead More Reflection of Cannibalistic Societies through Diary of a Madman And the Correlation to Todays Society1685 Words   |  7 Pages The meager image depicted by Lu Xun s Diary of a Madman projects an illustration of society that stresses submission to authority, and the ultimate compliance to tradition. Lu Xun battles the idea that society is constantly being manipulated and controlled by the masses of people who know no better than to follow tradition. His story Diary of a Madman gives the representation of a culture that has not only failed, but failed by the cannibalistic nature of humans corrupting them-selves overRead MoreComparison of Industrial and Foraging Societies703 Words   |  3 PagesI normally consider myself to be a person who appreciates simplicity, so my initial reaction to this question was that I would prefer a foraging society to an industrial society. By the time I had finished thinking it through, however, I was less certain of my preference. Four advantages of a foraging society that I find particularly compelling (in addition to â€Å"simplicity,† to whatever extent that assumption is true) relate to human healt h, population control, egalitarianism, and sustainability