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ASSIGNMENT

ON

Medicinal Chemistry (definition, scopes, limitations and aromatic and heteroaromatic compounds)

Course name: Medicinal Chemistry I Course code: PHRM -302

SUBMITTED TO:

MEHREEN RAHMAN Lecturer Department of Pharmacy

SUBMITTED BY:

SAMIYA KHONDAKER RINTA ID: 2010-3-70-048

Submission date: 28 th January, 2014

MEDICINAL CHEMISTRY

Medicinal chemistry is the chemistry discipline concerned with the design, development, synthesis, biochemical effects, regulatory and ethical aspects of pharmaceutical drugs for clinical use in the treatment of disease. It is a highly interdisciplinary science combining organic chemistry with biochemistry, computational chemistry, biology, molecular biology, physiology, pharmacology statistics, and physical chemistry to identify, develop and synthesize chemical agents that have a therapeutic use and also to evaluate the properties of existing drugs.

Medicinal chemistry provides pharmacy students with a thorough understanding of drug mechanisms of action, structure-activity relationships (SAR), acid-base and physicochemical properties, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles. A comprehensive understanding of the chemical basis of drug action equips pharmacy students

with the ability to answer rationally the “why” and “how” questions related to drug action.

Scopes of Medicinal Chemistry

  • 1. Rational design and synthesis of lead compounds and modification of novel biologically active molecules.

  • 2. New drug discovery technologies, including HTS and combinatorial chemistry.

  • 3. Computational and „virtual‟ approaches in synthesis and modeling.

  • 4. Therapeutic strategies and emerging targets.

  • 5. Evaluation and development of chemical structural feature (structure-activity relationship), physico-chemical property, stability.

  • 6. Development of new drug target and delivery, such as prodrug/co-drug strategies.

  • 7. Studies involving the use of NMR, X-ray crystallography, CD and other biophysical techniques.

  • 8. Structural basis for in vitro/vivo mechanisms of action and molecular recognition (e.g., drug- receptor interactions).

  • 9. Evaluation and development of pharmacokinetic (ADME) parameters; side-effects and adverse effects; and toxicological investigations of new drug compounds.

10. Purification and proper characterization of the new chemicals.

Limitations of Medicinal Chemistry

Medicinal chemistry has become the most time-consuming step in the drug discovery process, and new discovery technologies are likely to increase the burden on lead optimization and refinement. Although medicinal chemists are able to optimize hits/leads very quickly and successfully with regard to potency, improving the kinetic, metabolic and toxicological properties of a compound remains as a difficult obstacle and a limitation.

The search for new drugs to treat a wide range of human ailments such as heart disease and cancer remain a great challenge to the pharmaceutical and biotechnology industries and it is still

where medicinal chemistry has limited information and progress.

There are limited success rates for new biological targets. Recent data indicate that productivity has not kept pace with increasing resource allocation to the drug discovery process. Large numbers of drugs fail in pre-clinical stages due to poor pharmacokinetics and oral bioavailability. Moreover large amount of expenses occur in these research processes. This is responsible for the very high cost of bringing a drug to market.

With the pressure to increase the number of drugs receiving market approval, the science of medicinal chemistry needs to change in order to address the high attrition rates in pre-clinical and early clinical earlier on in development.

AROMATIC AND HETEROAROMATIC COMPOUNDS

Aromatic compounds: These compounds are hydrocarbons having a closed ring of alternate single and double bonds with delocalized electrons. The chemically simplest aromatic hydrocarbon is benzene.

where medicinal chemistry has limited information and progress. There are limited success rates for new biological

Figure 1: Benzene Heterocyclic compounds: These compounds are also aromatic compounds. In these compounds, at least one carbon atom is replaced by one of the heteroatoms oxygen, nitrogen, or sulfur. Examples of non-benzene compounds with aromatic properties are furan, a five-membered ring that includes an oxygen atom, and pyridine, a six-membered ring containing one nitrogen atom.

where medicinal chemistry has limited information and progress. There are limited success rates for new biological

Figure 2: Pyridine

Figure 3: Furan

Differences between aromatic hydrocarbons and heterocyclic compounds

 

Aromatic hydrocarbons

   

Heterocyclic compounds

 

Compounds

contain

carbon

and

hydrogen

Compounds have at least one carbon atom

atoms only.

 

replaced by one of the heteroatoms oxygen, nitrogen, or sulfur.

Have

higher

C:H

ratio

than

heterocyclic

Have

lower

C:H

ratio

than

aromatic

compounds.

 

hydrocarbons.

 

Electron donating capacity of benzene is more than pyrimidine (a 6-membered heterocyclic compound) but less than furan (a 5-membered heterocyclic compound).

Electron donating capacity of furan is more than benzene due to the electron-donating effects of the oxygen heteroatom and pyrimidine has less electron donating capacity than benzene.

Resonance energy of

benzene

is

130-

Resonance energy of 5-membered heterocyclic

140kJ/mol, which is

higher than

that

of

5-

compounds like furan is 67 kJ/mol and that of

membered heterocyclic compounds, like furan and pyrrole.

pyrrole is 88 kJ/mol, both of which are less than resonance energy of benzene.

Benzene is less reactive than furan, a 5- membered heterocyclic compounds because of absence of lone pair electrons.

5-membered heterocyclic compounds, like furan, are more reactive than benzene because of lone pair electrons.

Benzene undergoes electrophilic aromatic

6-membered

heterocyclic

compounds,

like

substitution reactions more readily than 6-

pyridine,

enter

into

electrophilic

aromatic

membered heterocyclic compounds, like

substitution

reactions

only

under

vigorous

pyrimidine.

conditions.

Benzene undergoes electrophilic aromatic substitution reactions less readily than 5- membered heterocyclic compounds, like pyrrole.

5-membered heterocyclic compounds, like pyrrole, enter more readily into electrophilic aromatic substitution reactions than benzene.

Benzene does not undergo diazotization and Reimer-Tiemann reactions.

5-membered heterocyclic compounds, like pyrrole, undergo diazotization and Reimer- Tiemann reactions.

No

lone

pair

electrons

are

involved

in

In 5-membered heterocyclic compounds, lone

satisfying the criteria for aromaticity.

 

pair electrons from N, O or S is involved in occupying a p orbital in order to satisfy the criteria for aromaticity.

Benzene

shows

more

aromaticity

than

Since one or more of the atoms in the aromatic

heterocyclic compounds.

 

ring is of an element other than carbon so the ring's aromaticity is less than that of benzene.

Since

in

aromatic

hydrocarbons,

lone

pair

Since in 5-membered heterocyclic compounds,

electrons

are

not

in

the

aromatic

ring,

lone pair electrons

are

in the aromatic ring,

protonation does not does not affect

protonation destroys aromaticity of the

aromaticity of the compound.

 

compound.

REFERENCES

Bahl, A. and Bahl, B.S. (2006) A Textbook of Organic Chemistry, 18 th edition, Rajendra Ravindra Printers: New Delhi.

Jones, R. A. (2009) The Chemistry of Heterocyclic Compounds. John Wiley & Sons: New York Katritzky, A. R. (2003) „Short Course on Heterocyclic ChemistryUniversity of Florida Krchnak, V. and Dalton C. (2002) „GRABBING GOLDEN: Medicinal chemists may soon reap the benefits of solid-phase split-and-pool combichem techniques.Modern Drug Discovery. Khurana J.M. (2006) „ORGANIC CHEMISTRY: Chemistry of Heterocyclic CompoundsUniversity of Delhi

Lombardino, J. G. and Lowe, J. A. (2004) „THE ROLE OF THE MEDICINAL CHEMIST IN DRUG DISCOVERY THEN AND NOWNature Reviews: Drug Discovery