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.

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.

Figure 2: Pyridine Figure 3: Furan
Differences between aromatic hydrocarbons and heterocyclic compounds
Aromatic hydrocarbons Heterocyclic compounds
Compounds contain carbon and hydrogen
atoms only.
Compounds have at least one carbon atom
replaced by one of the heteroatoms oxygen,
nitrogen, or sulfur.
Have higher C:H ratio than heterocyclic
compounds.
Have lower C:H ratio than aromatic
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-
140kJ/mol, which is higher than that of 5-
membered heterocyclic compounds, like furan
and pyrrole.
Resonance energy of 5-membered heterocyclic
compounds like furan is 67 kJ/mol and that of
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
substitution reactions more readily than 6-
membered heterocyclic compounds, like
pyrimidine.
6-membered heterocyclic compounds, like
pyridine, enter into electrophilic aromatic
substitution reactions only under vigorous
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
satisfying the criteria for aromaticity.
In 5-membered heterocyclic compounds, lone
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
heterocyclic compounds.
Since one or more of the atoms in the aromatic
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
electrons are not in the aromatic ring,
protonation does not does not affect
aromaticity of the compound.
Since in 5-membered heterocyclic compounds,
lone pair electrons are in the aromatic ring,
protonation destroys aromaticity of the
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 Chemistry University 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 Compounds
University of Delhi
Lombardino, J. G. and Lowe, J. A. (2004) THE ROLE OF THE MEDICINAL CHEMIST IN
DRUG DISCOVERY THEN AND NOW Nature Reviews: Drug Discovery