Med Chem.

Exam 1

Drug Classification
 Pharmacodynamic Agents: drugs that act on the various physiological functions of
the body
o Ex. General anesthetics, sedatives, analgesic, etc.
 Chemotherapeutic Agents: drugs which are used to fight pathogenic or invasive
agents
o Ex. Antibiotics, antimalarial, antiviral, anticancer, etc.
 Infectious Diseases: transmitted from person to person by outside agents, bacteria,
fungi, viruses & parasites
 Non-infectious Diseases: disorders of the human body caused by genetic
malfunction, environmental factors, old age, stress, etc.
 Non-diseases: alleviation of pain, prevention of pregnancy, etc.
 Pharmacokinetic: how the organism affects the drug (ex. t1/2)
 Pharmacodynamic: how the drug affects the organism

Properties of Drugs
 Drug action results from the interaction of drug molecules w/ either normal or
abnormal physiological processes
 Drugs normally interact w/ targets (proteins, enzymes, cell lipids, pieces of DNA or
RNA)
 The ability of a chemical compound to elicit a pharmacological/ therapeutic effect
is related to the influence of its various physical and chemical (physiochemical)
properties

1910 Paul Ehrlich

 Tested >600 structural analogs of atoxyl
 Synthesis of arsphenamine (#606)
o Active against Treponema pallidum (syphilis)
 Chemotherapy: using toxic drugs, in the right dose
 Therapeutic Index: toxic dose for 50% of population divided by effective dose
o TI = Td50/Ed50
o Narrow TI means there’s a small difference b/t effective (what will cure) and
toxic (what will kill)
 Structure-Activity Relationships (SAR): idea that you can isolate pieces of the drug
structure and see how each part of the molecule is responsible for doing different
things
  Pharmacophore: the specific piece (atom or functional group) of a drug molecule
that is essential for binding to its target
o Ex. Arsenic in the drug he was using

Where Do New Drugs Come From?

 Natural Compounds
 Synthetic Compounds: either pure synthetic or synthetic versions of naturally
occurring compounds
 Semi-synthetic Compounds: some compounds either cannot be purely synthesized
or can’t be isolated from natural sources
o The natural intermediate of such drugs can be used for the synthesis of a
desired product

Drugs from Plants

 Plants have always been a rich source of lead compounds (molecules w/ potential
to be drugs)
 Provides structural complexity that would not be discovered by traditional synthesis
 Plants have advantage of evolution (they’ve adapted overtime to survive)
Drugs from Marine Sources
 Great potential for anti-inflammatory and against infectious diseases

Drugs from Microorganisms

 Wide range of anti-microbial agents
 Interest began w/ penicillin
 NCA (National Cancer Institute) led worldwide screening of compounds that had
potential as antibiotics
Drugs from Animal Sources
 Not as common now b/c we have recombinant DNA (rDNA) to have bacteria
produce the drugs for us

Synthetic Drugs
 Often established structures are modified to make new drugs
o Privileged structure = core; pharmacophore

Activity #1

Chemical Properties of Functional Groups:

Electronic Effects: measured by functional groups ability to donate e-‘s to adjacent atoms/
functional groups, or withdraw e-‘s away from its neighbors
 Resonance
o Delocalization of e-‘s in a molecule
o Often helps stabilize the molecule
o Can occur when atoms have adjacent double bonds & lone pairs of e-‘s

o
 Inductive Effects:
o Related to electronegativity
o Larger electronegativity= greater ability of atom/functional group to attract
e-‘s
o Creates a partial charge separation b/t atoms (dipole)
 Electron Donating Groups:
o EDG’s can donate some electron density into a conjugated  system via
resonance or inductive effects makes system more nucleophilic
o Nucleophilic groups
 Attracted to + charges
 “Activating groups”- often cause rxns b/c they go after nuclei of other
molecules b/c they have electrons to give
 o e- donating groups

o
 Attacks reactive electrophilic compounds present in the body (ex. a
drug)
 Electron Withdrawing Groups
o Positively charged or more electronegative than their neighbors
o Do NOT participate in resonance w/ neighbors
o Ex. halogens
o Electrophilic Groups
 electron loving
 “leaving groups”
*Aromatic ring: more in the center b/c it can pull or sometimes share e-‘s

Solubility Effects: how drugs interface w/ water or lipids

 Factors contributing to water solubility:
o Ionized functional groups (acids/bases)
o Polar functional groups- able to form H bonds (hydroxyl groups, amides,
ketones, etc.)

o
 Red= acidic, blue= basic
 Factors contributing to lipid solubility:
o *more C’s = more lipid soluble
o Aromatic rings
o Alkyl groups, rings, chains
o Halogens
o Ketones, esters, ethers (some overlap here)
o
*if it meets >1 rule there’s a 90% chance it has poor oral bioavailability
1. MW>500  if it’s too big it won’t cross membranes
2. Log P> 5 if it’s too fatty won’t be soluble in blood/GI
3 & 4. Too much H bonding= too polarwon’t cross membranes/be absorbed
*His model says:
H bond donors= NH & OH
H bond acceptors= O & N

Steric Effects
 May enhance binding of drugs to their receptors by restricting formation of
conformers
o If you have a lot of ability to flex around you don’t stay locked into your
target as well as if steric hindrance is preventing rotation
 May increase selectivity of drugs to various receptor sub-types
 May alter of prevent metabolism

Activity 2!