Skip to content

Licofelone Synthesis Essay

1. Introduction

NSAIDs are some of the most frequently used medications in the world [1]. Their widespread use is usually associated with several serious side effects and complications [2,3,4]. Erosion and bleeding of the gastric mucosa are the most prevalent risks. Many of these complications can be life-threatening and several mortalities have been reported [4,5]. The gastrointestinal toxicity of NSAIDs is mediated either by the inhibition of the cytoprotective PGs biosynthesis [6] or by the induction of GIT necrotic effects [7]. These necrotic effects were detected for selective and nonselective COX inhibitors [8], even at low prophylactic doses [9].

To date, there is no safe nonsteroidal anti-inflammatory agent that could be used in patients with peptic ulcers, renal failure or asthma. However, on reviewing the literature, several strategies were found to afford GIT safer anti-inflammatory agents. Of these strategies, conversion of the acidic COX inhibitors into non-acidic prodrugs [10], improving selectivity for the COX-2 enzyme [11] and development of nitric oxide releasing NSAIDs [12] were the most commonly utilized. Recently, introducing dual COX/5-LOX inhibitors were the focus of researchers in order to develop safer anti-inflammatory agents [13]. Several pyrrolizine derivatives (Figure 1) were identified to have anti-inflammatory, analgesic, and antipyretic activities. Of these derivatives, ketorolac (1) is a nonselective COX-1/2 inhibitor with a selectivity ratio of 2.9 for COX-1 [14]. Owing to its potent analgesic activity, ketorolac is often used in the treatment of severe neuropathic pain [15]. Moreover, licofelone (2) acts as a dual COX/5-LOX inhibitor with IC50 values in the submicromolar range [16]. Interestingly, licofelone revealed anti-inflammatory and analgesic efficiency in asthmatic patients. Compared to other COX/5-LOX inhibitors which showed also good GIT tolerance, licofelone is the only COX/5-LOX inhibitor that showed an acceptable safety level in clinical use [17]. The replacement of the 4-chlorophenyl group at C5 in licofelone with a 5-chlorothiophen-2-yl moiety in compound 3 resulted in almost the same COX-1/5-LOX inhibitory activity [18].

Figure 1. The IC50 values of pyrrolizine-based anti-inflammatory agents 13 linked with a carboxylic acid moiety.

Figure 1. The IC50 values of pyrrolizine-based anti-inflammatory agents 13 linked with a carboxylic acid moiety.

In order to avoid the gastric side effects, several reported pyrrolizines with nonselective COX inhibitory activity lacking the distinctive free carboxylic group were designed [19,20,21]. For instance, the diphenylpyrrolizine 4 [19] and the 1-methoxypyrrolizine 5 [20] showed anti-inflammatory activity mediated by COX/5-LOX inhibition. Additionally, masking the carboxylic group in licofelone (2) using a tolylsulfonimide moiety as in compound 6 retained the 5-LOX inhibition (IC50 = 0.26 µM) and increased the mPGES-1 inhibitory activity [21], as shown in Figure 2.

Figure 2. The IC50 values of pyrrolizine-based anti-inflammatory agents 46 lacking the free carboxylic acid group.

Figure 2. The IC50 values of pyrrolizine-based anti-inflammatory agents 46 lacking the free carboxylic acid group.

Earlier, we have reported several pyrrolizine derivatives with moderate to high anti-inflammatory activities [22]. In this report, compound 7 exhibited approximately 50% reduction in rat paw edema in comparison with ketorolac (Figure 3). Prompted by the aforementioned findings, we aimed in this work to develop novel potent anti-inflammatory and analgesic agents with low GIT side effects. We have designed several different analogs based on our previously reported anti-inflammatory agent 7 using a lead optimization approach in drug design. In doing so, the free carboxylic group in compound 7 was replaced with other non-acidic fragments (R′) to avoid the direct gastric insult complications of the carboxylic group.

The impact of the electronic effect of these substituents (R′) on COX-1/-2 binding patterns was evaluated by a molecular docking study. Moreover, the variation in the length of the spacer between the pyrrolizine ring and the terminal (R) moiety was conducted. Seven compounds 1218 from the virtual designed library were selected for synthesis (Scheme 1, Scheme 2 and Scheme 3) and biological evaluation based on an initial filtration process using the docking tool against COX enzymes (Figure 3). Finally, a hybrid compound 19 composed of the pyrrolizine precursor 12 and ibuprofen was designed to evaluate the possible synergism resulted from the combination of these two compounds into one scaffold.

Scheme 1. Synthesis of compound 12. Reagents andreaction conditions: (a) (CH3)2SO4, benzene, CH2(CN)2; (b) ClCH2COCl, AcOH, CH3COONa; (c) acetone, K2CO3, reflux, 24 h.

Scheme 1. Synthesis of compound 12. Reagents andreaction conditions: (a) (CH3)2SO4, benzene, CH2(CN)2; (b) ClCH2COCl, AcOH, CH3COONa; (c) acetone, K2CO3, reflux, 24 h.

Scheme 2. Synthesis of compounds 1316. Reagents andreaction conditions: (a) ClCH2COCl, benzene, 48 h; (b) 1-methylpiperazine, NaHCO3, absolute ethanol, reflux, 6 h; (c) KHCO3, DMF, rt, 48 h; (d) benzoyl chloride, benzene, rt, 48 h.

Scheme 2. Synthesis of compounds 1316. Reagents andreaction conditions: (a) ClCH2COCl, benzene, 48 h; (b) 1-methylpiperazine, NaHCO3, absolute ethanol, reflux, 6 h; (c) KHCO3, DMF, rt, 48 h; (d) benzoyl chloride, benzene, rt, 48 h.

Scheme 3. Synthesis of compounds 1719. Reagents and reaction conditions: (a) p-toluenesulfonyl chloride, acetone, K2CO3; rt, 12 h; (b) oxalyl chloride, dry acetone, rt, 24 h; (c) 1. ibuprofen, SOCl2; 2. compound 12, dry benzene, rt, 24 h.

Scheme 3. Synthesis of compounds 1719. Reagents and reaction conditions: (a) p-toluenesulfonyl chloride, acetone, K2CO3; rt, 12 h; (b) oxalyl chloride, dry acetone, rt, 24 h; (c) 1. ibuprofen, SOCl2; 2. compound 12, dry benzene, rt, 24 h.

Figure 3. Design strategies for compounds 1218.

Figure 3. Design strategies for compounds 1218.

The word “synthesis” is defined as a combination of elements to form a connected whole. Thus, a synthesis essay definition is an essay that combines different ideas into a whole to prove a point (otherwise called the thesis). Often, it comes with a text that you should analyze.


Table Of Contents


Writing Process

A key factor of writing a synthesis essay is an analysis of a given text or a prompt. In order to successfully analyze it, you must comprehend the text’s purpose, rhetoric, and the argument that the author’s claim, in other words, you are answering the question: “So what?”. Then, you must build your own claim, and write an essay around that.

Most Common Topics

A synthesis essay prompt must be negotiable. Like in the EssayPro's example above, Andrew Jackson’s negative views on Native American people were widely supported, today, however, they would be appalling. Depending on your assignment, you may have to choose a primary text. Choose a text that might have opposing viewpoints.

Good topics would be ones that are debatable, for example:

  • Daylight savings
  • Minimum wage
  • Abortion
  • Immigration policy
  • Global warming
  • Gun control
  • Social media

How Do I Write A Thesis?

Once you pick a topic of your paper, read your sources and establish your position. Make sure you thoroughly analyze the sources and get a good understanding of them, structure your claim or argument and write your thesis.

Example: Andrew Jackson’s fear of the Native American “savages” reflects the prejudices and ideas of the colonist people in the Union and the Congress.*

How Do I Write An Outline?

Creating an outline will help maintain the structure of your paper. If your essay is split into three parts, split your outline into three chunks. Paste supporting evidence, sub-arguments, and specific points in the appropriate sections. Make sure that every point somehow proves the claim in your thesis. Extra information or tangents will only hinder your essay. However, if information goes against your central claim, then you should acknowledge it as it will make your essay stronger. Make sure you have read all of your sources. When writing about the sources, do not summarize them; synthesis denotes analysis, not plot-summary.

Example:

  • Introduction
  • Thesis
    • Main point 1
    • Main point 2
    • Main point 3
  • Body
  • Main point 1
    • Evidence (quote from a source)
    • Analysis of Evidence
  • Main point 2
    • Evidence (quote from a source)
    • Analysis of Evidence
  • Main point 3
    • Evidence (quote from a source)
    • Analysis of Evidence
  • Conclusion
  • Restate main points and answer unanswered questions

Read more about how to write a great INTRODUCTION

How Do I Format My Essay?

The format depends on what style is required by your teacher or professor. The most common formats are: MLA, APA, and Chicago style. APA is used by fields of Education, Psychology, and Science. MLA is used for citing Humanities, and Chicago style is used for Business, History, and Fine Arts. Purdue Owl is a format guide that focuses mainly on MLA and APA, and Easybib is a citation multitool for any of your external sources.

Some key points are:

  • Times New Roman 12 pt font double spaced
  • 1” margins
  • Top right includes last name and page number on every page
  • Titles are centered
  • The header should include your name, your professor’s name, course number and the date (dd/mm/yy)
  • The last page includes a Works Cited

APA Format

Some key points are:

  • Times New Roman 12 pt font double spaced 1” margins
  • Include a page header on the top of every page
  • Insert page number on the right
  • An essay should be divided into four parts: Title Page, Abstract, Main Body, and References.

How do I write an AP English Synthesis Essay?

AP English Language and Composition is an extremely rigorous course that requires you to write essays that demonstrate deep understanding of the subject matter. In fact, if on the AP exam, your essay has perfect grammar and structure, you might still be awarded just 1 out of 9 points for not “defending, challenging, or qualifying your claim.” Sounds difficult, but it is doable. Before entering any AP class, it is best to read over the course overview and become familiar with the exam.

While writing, focus on the three branches of the AP English and Composition course: argument, synthesis, and rhetorical analysis.

Argument is the easiest component; create your claim and find specific supporting evidence. Convince your reader that you are right.

Synthesis requires you to read into multiple perspectives and identify an agreement and a disagreement between sources. This step is crucial to finding your own claim.

Rhetorical analysis deals with the author and his intentions. What was their purpose for writing this? Who is their intended audience? How does the author appeal to the audience and how does he structure his claim?

Essay Tips

There are two acronyms that are helpful with the three AP Lang writing branches.

Tip #1: SOAPS

Example text: Andrew Jackson’s speech to the Congress about sending Native Americans to the West.

Speaker: Identify the speaker of the piece, then analyze for bias and apply any prior knowledge that you have on the speaker.

Example: President Andrew Jackson had a bias against Native Americans. A piece written by Andrew Jackson about Native Americans will probably be written with a bias against him.

Occasion: Determine the time and the place of the written text, then identify the reason the text was written. Even if you aren’t sure of the reason, assume one and make your claim around it.

Example: Andrew Jackson was in office from 1829 to 1837. At this time, the Congress sent Native Americans to the West in order to clear the land for the colonists. Jackson was the one who made the proposal.

Audience: Who was the text directed to?

Example: Andrew Jackson’s speech was directed to a council.

Purpose: What is the text trying to say? Here, you analyze the tone of the text.

Example: Andrew Jackson appeals to pathos by calling Indians “savages”. His purpose is to portray Native Americans in a negative light, so the Congress passes the Indian Removal Act.

Subject: What is the main idea? What is the claim?

Example: Andrew Jackson wants the Congress to pass the Indian Removal Act because he believes Native Americans are uncultured and savage people.

Tip #2: Logos, Ethos, and Pathos

As you’ve probably learned before, Logos appeals to reason, Pathos appeals to emotion, and Ethos appeals to moral philosophy or credibility. However, for the AP Lang exam requires a wider understanding of the three.

If the text uses facts, statistics, quotations, and definitions, the speaker is appealing to Logos. Constituting various backup information is an extremely effective for people who want to persuade.

If the text uses vivid imagery and strong language it denotes Pathos, which is used to connect the audience to a piece emotionally; it is hardest to change the mind of a person who is linked to a subject via a strong emotion.

If the text attempts to demonstrate the speakers reliability or credibility, it is a direct appeal to Ethos. Using the example above, Andrew Jackson could have appealed to Ethos by stating the fact that he is the President of the United States, and thus, knows what is best for the union.

Often, Logos, Ethos, and Pathos lead to the use of logical fallacies.

Tip #3: DIDLS

This is a good shorthand for all textual analysis. While reading a text, try to pinpoint Diction, Imagery, Details, Language, and Sentence Structure in a piece. If anything stands out, add it to your analysis.

Rubric

  • High range essay (8-9 points)
  • Effectively develops a position on the assigned topic.
  • Demonstrates full understanding of the sources or text.
  • Correctly synthesizes sources and develops a position. The writer drives the argument, not the sources.
  • The writer’s argument is convincing.
  • The writer makes no general assertions and cites specific evidence for each point. His/her evidence is developed and answers the “so what?” question.
  • The essay is clear, well-organized, and coherent. It is a stand alone piece rather than an exam response.
  • Contains very few grammatical and spelling errors or flaws, if any.

Note: 8-9 essays are an extreme rarity. A strong ‘7’ paper can jump to an 8-9 if the writing style is mature and perceptive.

Middle-Range Essay (57)

  • Adequately develops a position on the assigned topic.
  • Demonstrates sufficient understanding of the ideas developed in sources
  • Sufficiently summarizes the sources and assumes some control of the argument. ‘5’ essays are less focused than ‘6’ and ‘7’.
  • The writer's argument is sufficient but less developed.
  • Writer successfully synthesizes the sources and cites them.
  • Writer answers the “So what?” question but may use generalizations or assertions of universal truth. Writer cites own experience and specific evidence.
  • Essay is clear and well organized. ‘5’ essays less so.
  • Contains few minor errors of grammar or syntax.

Note: A ‘7’ is awarded to papers of college-level writing.
A ‘5’ on one of the AP English Language and Composition essays designates a 3 on the AP exam. It most likely relies on generalizations has limited control of the claim and argument. ‘5’ essays often lose focus and digress.

Low-Range Essays (1-4)

  • Inadequately develops a position on the assigned topic.
  • The author misunderstands and simplifies the ideas developed in the sources.
  • Over-summarizes the sources, lets the sources drive the argument.
  • Writer has weak control of organization and syntax. Essay contains numerous grammatical/spelling errors.
  • Writer does not cite the sources correctly, skips a citation, or cites fewer than the required minimum of the sources.
  • Notes: ‘4’ or ‘3’ essays do assert an argument but do not sufficiently develop it.
  • A ‘2’ essay does not develop an argument.
  • A 1-2 essay has severe writing errors and do not assert a claim.

Synthesis Essay Example

Essay Writing Advice From Our Professional Team

James Owen, online essay writer from EssayPro

The article reviews the basics of how to write a synthesis essay as well as how to dissect and analyze text when writing an AP English essay. One thing I would like to reemphasize is the importance of your thesis statement. When you write an essay for class or exam, make sure to state your argument clearly. If the reader of your essay doesn’t understand your point of view then what you’ve written is futile.

My advice is: when writing an essay in a short period (such as in an exam room) make sure to articulate your argument in every paragraph and connect every single one of your ideas to the thesis. My tip is to write your thesis down on a piece of paper and reread it at every point to ensure that the information applies and reinforces what you’ve stated in your thesis. This tip also goes for when you are writing a longer piece of writing, as it is very easy to lose focus and stray away from your main point.

Struggling With Writing an Essay?

Still having trouble crafting a synthesis essay? Need editing or writing help? You should seek advice from professional writers. Here at EssayPro, writers have written countless papers and are experts in their field. You can request to write your paper or editing or proofreading assistance. Rest assured that your paper is in good hands!