NTA Level 5 • Semester 1 • PST05106

Structure – Activity Relationship of Quinolones

Pharmaceutical Organic Chemistry • Source Session/Topic 28

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Session 28: Structure – Activity Relationship of Quinolones.

Total Session Time: 120 minutes

Prerequisites

None

Learning Tasks

By the end of this session students are expected to be able to:

• Define Quinolones

• Explain Chemical structure of Quinolones

• Explain the structure – activity relationship of Quinolones

Resources Needed:

• Flip charts, marker pens, and masking tape.

• Black/white board and chalk/whiteboard markers.

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing.

STEP 2: Definition of Quinolones (10 minutes).

|Activity: Brainstorming (5 minutes) |

| |

|Ask students to brainstorm on the following question: |

| |

|What are Quinolones? |

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|ALLOW few students to respond |

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|WRITE their responses on the flip chart/ board |

| |

|CLARIFY and SUMMARISE by using the table below |

• The Quinolones (fluoroquinolones) are broad-spectrum antibiotics with

particular activity against gram-negative organisms,

especially Pseudomonas aeruginosa.

• The fluoroquinolones are bactericidal antibiotics that act by

specifically targeting DNA gyrase.

o Fluoroquinolones can be classified as;

o First-generation drugs (e.g., nalidixic acid)

o Second-generation quinolones (e.g., ciprofloxacin)

o Third-generation drugs (e.g., levofloxacin)

o Fourth-generation quinolone drugs (e.g., trovafloxacin)

STEP 3: Chemical Structure of Quinolones (40 minutes).

The following are chemical structure of quinolones; [pic]

STEP 4: Structure – Activity relationship of Quinolones (45 minutes).

|Activity: Small Group Discussion (20 minutes) |

| |

|DIVIDE students into small manageable groups. |

| |

|ASK students to discuss on the following question |

|What is the importance of SAR of fluoroquinolones? |

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|ALLOW students to discuss for 15 minutes. |

| |

|ALLOW few groups to present and the rest to add points not mentioned. |

| |

|CLARIFY and SUMMARIZE by using the contents below |

[pic]

Structure of quinolone

• Structure of the quinolone molecule, using the accepted numbering scheme

for positions on the molecule.

• An R indicates possible sites for structural modification.

• Molecules at positions marked by a dashed box can also be changed;

however, the most commonly used structure is shown.

Position 1.

• This position is part of the enzyme-DNA binding complex and has a

hydrophobic interaction with the major grove of DNA.

• A cyclopropyl substituent is now considered the most potent modification

here, followed by addition of a 2,4-difluorophenyl.

• Most other substituents, including one with only the wrong stearic

position ((R)-ofloxacin) can presumably lower the number of molecules

capable of binding to the enzyme-DNA pocket, and therefore reduce

potency.

• Interestingly, ofloxacin has a tricyclic ring structure with a CH3

attached to the asymmetric C-3 position on the oxazine ring, thus

connecting positions 1 and 8 with a fused ring.

• Although this has been a useful alternative to the cyclopropyl

substituent, the S- isomer exhibits twice the order of magnitude of

activity as the R- isomer, which seems to be determined by the number of

molecules that can be assembled, or stacked, in the enzyme-DNA complex

binding pocket.

• Even the potency of the purified S- isomer fused ring is less than that

of the cyclopropyl substituent, suggesting the difficulty of improving

upon this latter modification.

Position 2.

• This location is very close to the site for DNA gyrase (or topoisomerase

IV) binding so it is believed that any added bulk inhibits access and

results in a lower level of microbiological activity.

• Only sulfur, incorporated into a small ring, has been able to replace

hydrogen at the R-2 position.

• To accomplish this, researchers reconfigured positions 3 and 4.

Positions 3 and 4.

• These two positions on the quinolone nucleus are considered critical for

binding to cleaved or perturbed DNA, and no useful substitutions have yet

been reported.

• Therefore, the 3-carboxylate and 4-carbonyl groups are considered

essential for antimicrobial activity.

Oxoquinolizines.

• This is a new addition to the quinolone class, in which nitrogen replaces

the carbon between ring carbons C-4 and C-5.

• Making this alteration renumbers the other positions so that 5- becomes 6-

, 6- becomes 7-, 7- becomes 8-, and 8- becomes position 9.

• This substitution enhances the in vitro and in vivo (mouse protection)

activity against gram-positive cocci, including methicillin-resistant S.

aureus (MRSA) that are resistant to ciprofloxacin.

Position 5.

• Substituents at this position of the basic quinolone nucleus appear to

have the capacity to alter overall stearic configuration (planar

structure) of the molecule, which is how changes here are thought to

affect activity.

• Modestly sized additions, such as an amino, hydroxyl, or methyl group can

markedly increase in vitro activity against gram-positive bacteria, as

well as enhance potency against Toxoplasma gondii.

• Also, it was found that the methyl group enhances action against gram-

positive but not against gram-negative bacteria.

Position 6.

The addition of a fluorine molecule here markedly improved antimicrobial

activity compared to the original quinolone agents and gave rise to the now

widely used and clinically successful fluoroquinolone compounds.

Position 7.

• This position is considered to be one that directly interacts with DNA

gyrase, or topoisomerase IV. The optimal substituents at this position

have been found to be groups that contain, at a minimum, a 5- or 6-

membered nitrogen heterocycle.

• The most common of these are aminopyrrolidines and piperazines.

• Placement of an aminopyrrolidine improves gram-positive activity, whereas

a piperazine generally enhances potency against gram-negative bacteria.

• Alkylation (-CH3) of the 5-membered or 6-membered heterocycle

(pyrrolidines and piperazines, respectively) also enhances activity

against gram-positive bacteria.

Position 8.

• This position is considered to affect overall molecular stearic

configuration, similar to position 5.

• Therefore, changes made here affect target affinity, probably by altering

drug access to the enzyme or DNA binding sites.

• A free halogen (F or Cl) here may improve activity against anaerobes.

• Halogen substituents, as well as a methyl or methoxy also increase the in

vitro activity against gram-positive cocci, even in those bacteria

resistant to older fluoroquinolones.

• Interestingly, the R-8–substituted quinolones also exhibit enhanced

bacteriostatic and lethal activities against GyrA mutants of both E. coli

and Mycobacterium species. Furthermore, in S. aureus a substitution here

created the most lethal agent for both wild type cells as well as those

strains with a preexisting topoisomerase IV mutation.

• Substituents such as ring nitrogen or a free C-8 methyl or methoxy in the

core quinolone molecule substantially reduce the likelihood of emergence

of resistant microbial strains that have no preexisting QRDR mutations.

• Recently, the optimal substituent placed here, combined with a bulky

addition at the C-7 position, and has also been shown to markedly reduce

the development of fluoroquinolone resistance in S. aureus.

STEP 5: Key Points (10 minutes).

• The Quinolones (fluoroquinolones) are broad-spectrum antibiotics with

particular activity against gram-negative organisms,

especially Pseudomonas aeruginosa.

• The fluoroquinolones are bactericidal antibiotics that act by

specifically targeting DNA gyrase.

• A number of substitutions at position 1 to 8 can be done in the

fluoroquinolones that may result in modification of their therapeutic

effect.

STEP 6: Evaluation (10 minutes).

• What are Quinolones?

• Draw a general chemical structure of Quinolones

• What is the importance of structure – activity relationship of

Quinolones?

References

Ternay, A.L (1976). Contemporary Organic Chemistry. Philadelphia, United

States: W.B. Saunders Co.

Morrison R.T and Boyd R N (1997). Organic Chemistry (6th Ed.). New Delhi,

India: Prentice Hall of India

Graham Solomon et al (2014). Organic Chemistry (11th Ed.). New Jeysey,

United States: John Willey and Sons.

Rama Rao Nadendla (2005). Principles of Pharmaceutical Organic Chemistry.

New Delhi, India: MacMillan Publishers

Bruice Y (2013). Organic Chemistry (7th ed.). New York, United States:

Prentice Hall Pearson.

Delgado J. N. Et al (1998). Wilson and Gisvold's Textbook of Organic

Medicinal and Pharmaceutical Chemistry (10th Ed.). Calfornia, United

States: Lippincott Williams

Bhassin S.K, Gupta R. (2013). Pharmaceutical organic chemistry (E-book

Kindle edition). New Delhi, India: Elsevier Publishing Services

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