In the name of ALLAH, the most beneficient & mercifull.

GENETIC ENGINEERING (rDNA);

DNA which is a long chain of nucleotide. It is composed of million & millions of nucleotide & the info
which is present in DNA in inherited info & is transferred to next generation.
Gene is the small portion or part of DNA. If DNA composed of million of nucleotides means gever has
thousands of nucleotide & that is responsible for hereditary character. DNA is specific for each &
every specie quantitatively (no. of nucleotide)& QUALITATIVELY (series of nucleotide) .
Info present in DNA able to synthesize protein or synthesis of protein is regulated & monitor by the
Which is present in DNA . any change, modification mutation in genetic material result in synthesis
of abnormal protein that is also one of the reason or cause of cancer.
Chemotherapy, radio therapy all these then use to inhibit synthesis of abnormal protein in case of
cancer.
Synthesis of protein include 3 steps:
TRANSCRIPTION:
In which info is transferred from DNA to RNA.
TRANSLATION:
In DNA the information which is present is converted or use in synthesis of protein OR the
information which is present in DNA is decoded so as to make new proreins.
REPLICATION:
In which the DNA itself divide to give 2 daughter cell & each daughter cell should have got the exact
information.
When we use recombinant DNA technology in this we obtain the specific genetic information or a
specific gene which is responsible for synthesis of specific protein.
In 1st step we obtain to get required information or gene that gene is then inserted or place in
another DNA or gene functionally. After insertion of gene in other gene than that gene will
incorporate with DNA & with DNA it is going to be transcribed, translated or replicated & we get
protein e.g we have e.coli bacteria & bacteria is not able to synthesize no. of proteins like insulin &
we inert it in DNA of e.coli. so e.coli will be able to synthesize no. of protein like insulin so when we
take specific information for synthesis of insulin & we insert it in DNA of e- coli.. so e-coli will be able
to synthesize insulin although normal e-coli not able to synthesize insulin.
In same way we are synthesizing no. of hormones. E.g somatostatin also going to synthesize by
bacteria & other protein like interferon, insulin & no. of hormones synthesize by using DNA
technology.
Q. how can we get or obtain the specific gene??
There are no. of methods but specifically we have 2 or 3 methods.
Page 1 of 20

Classical method that we called genomic cloning method. In this method we get DNA or
mixture of genetic information. (DNA is polymer & give is its part) & that mixture or that DNA
is than fragmented or broken down by using enzymes or by endo-nucleases which is enzyme
for fragmentation of DNA or mixture of genetic information.
Now we have mixture & how we identify or obtain specific information so it is obtain by using
the probes.
Probes are the known sequences of nucleotide & those probes & nucleotide are either
radiolabelled or they are fluorescent. It means when they are radio-labeled or fluorescent
than it carry to detct or identify those nucleotide so after fragmentation probes use.

Q. why we use those probes???

b/c they are use to identify the sequence of unknown nucleotide present in mixture.

Q. how can we identify those???

in synthesis of protein we have specific characteristics or steps; e.g as a universal law or rule
we sat that genetic information always flow uni-directionally or in 1 direction i.e from DNA to
RNA & from RNA to protein. It is called universal law of molecular genetics i.e genetic
information always flow uni-directionally although there are certain exeption e.g in case of
retro-virus which is RNA virus.
The law is violated or diverted from central dogna of molecular genetic but it is natural
phenomenon. Here information move from RNA mRNA & in this enzyme include
transcriptase.
During synthesis we see that they are complementary route or base pairing route include
like.

XXXXXXX NUCLEOTIDES;
In this we have got base pairing like adenine with thiamine & guanine with cytosine. By this we get
known sequence which pair with unknown nucleotide. But we can identify the un
Lecture attended by : sitwaz naz hasan
RECOMBINANT DNA TECHNOLOGY OR GENETIC ENGENEERING:
DNA is as long chain of nucleotide and the information and transferred to next generation.
Gene is as small portion of DNA and as part of DNA that is responsible for each and every
species quantitatively and qualitatively.
DNA has 4 nucleotides which are respective units. By information in DNA, we are able to
synthesize protein. Any modification mutation or change in genetic material will result
information synthesis of abnormal protein,/.
That is one of cause of cancer chemotherapy , radiotherapy etc used information cancer we
inhibit the synthesis of abnormal proteins
SYNTHESIS OF PROTEIN :
Transcription information which information is transferred from DNA to RNA.
Translation: information which is present and used in synthesis of protein. The information
present in DNA is decoded organization translated in form of protein that is; synthesis of new
protein.
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 Replication: in which DNA itself divides to give to daughter cell and each daughter cell should
have got the exact information., when we are using recombinant DNA technology, we obtain
the specific genetic information or specific gene for synthesis of specific protein.
In 1st step we get required gene. That gene is inserted in an other DNA organization gene
functionally. The information should be transferred to the DNA. That insertion should be
functional. When that gene is transferred into another DNA, that DNA is going to be
transcribed, translated and reputated and we get the rntire protein. E,g we have e.coli or
bacteria . the bacteria is not able to synthesize a number of protein e.g insulin but when we
are taking specific information and insert it in DNA of E.coli, the e.coli will be able to
synthesize the insulin although normal e.colidoes not synthesize this.
We are synthesizing a number of hormones and other protein e.g. somatostatins, interferons.
They are also synthesize by using DNA technology.
Q: How can we get or obtain the specific gene???
There are number of methods but specifically two or 3 methods.
Classical methods:
i.e known en as genomic cleaning. In that method we are going to get the DNA or genetic
information . DNA is a polymer and a part of it have different information. We haved mixture
and that DNA is fragmented/broken down.
1st step --- mixture of specific information or DNA, we get the fragments. By help of enzyme
endonucleases. For specific part , specific enzyme , but general name is endonucleases.
Now we have mixture of fragments to obtain the specific information by using the probes
Probes are the known sequence of nucleotides and those probes or nucleotides are either
radio labeled or they are fluorescent. When they are radio labeled i.e fluorescent, they are
easily to identified these nucleotide .
Probes are used to identify the sequence of unknown nucleotide .
In the synthesis of protein we have same specific steps and characteristics e,g as a universal rule,
we say that the genetic information always flow unidirectional.
I.e from DNA-----RNA-------protein that is a universal law of molecular genetics and that is
termed as central dogma of molecular genetics i.e genetic information always flow
unidirectional.
There are certain exeptions e.g in the case of retrovirus i.e a RNA virus, the law is violated or
deviatedom central law.
The enzyme for retrovirus is reverse transcriptase, we have exeption for retrovirus.
During synthesis we have certain complementary base rule. We have four nucleotide and in
these nucleotide we have base pairing.
o Adenine with thymine
o Guanine with cytosine
That are complementary rule, we identify unknown nucleotide i.e by known. E.g if we have
known adenine , it will bind with thymine in the mixture .
The sequence obtain can be checked from the genomic libraries. Which have sequence of
nucleotide , by that method we get identified gene or information and that is ready for
insertion in another polymer or gene.
Identification of genetic material is also known as finger prints. Some other methods are
also there but that are not commonly used.

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 Reverse transcriptase is able to get information from mRNA instead of DNA , although
violation of central dogma. That is not commonly used method.
In other method we also used automatic analyzers.
Genomics cloning is most commonly used methods.
Amino acid analyzer is an equipment which give sequence of amino acid. So we get the
genetic codes which are already known. That is termed as automatic method.
20-8-2013
Genomic DNA:

There are 6 steps represent in the diagram.

1-genes desired - which inserted in plasmid (a circular portion of DNA hereditary characters) which
become open by endonucleases . the desired gene inserted in plasmid then sealing by ligases
enzyme occur . now this plasmid+gene in a host bacteria, myoloma cells, & when inserted the host
& tag to these all are covalent attachment & then culture & then isolation & specification after
replication..

Somatostatin-
a hormone which 1st synthesize by rDNA technique.
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It is a polypeptide have 14 amino acids.

The genome of somatostatin is construction of genome of somatostatin.
It is well studied gene.
It is constructed genome for somatostatin.
We go to take gene but when constructed we need to add & place other gene which dont
have direct relation with somatostatin for initiation of process for methyonin gene use to
construct & initiating the process

A terminalion code is also used which terminate the process.

Marker genes-TCR (tetra cycline resistance gene_), APR (ampicithin cyclin resistance gene)
It can be degraded by enzyme present in bacteria so we introduce another gene to protect
e.g beta glactocydase enzyme which can degrade so we inserted gene which form
combination with pepetide prevent degradation.
Inusulin have two chains one is long which should be cleavage.
These two chains are cleavage and culture- and than prepare two chain separately than
isolate & than join both chains..
Post translational process-two chains are join after synthesizing separately. This is invitro
process.
Specific codes:
Initiator=5 (starter) AUG(analine uracil guanine)3(end)
Terminator =UAA, UGA< UAG (any one can use)
In recombinant DNA technology , we consider different parts.
Gene responsible for synthesis of insulin have 22 exons and 21 introns.
Page 5 of 20

The receptor are linked up by disulphate linkage.

Exons are responsible for encoding.
In case of insulin we have post translation.
Product of single polypeptide will be open or broken down by enzyme in humans but not
possible in bacteria thats why we have two chains which are going two combine .
Insulin take part in number of process i.e metabolism of carbohydrates.
It regulates different process,.
Type ii diabetes is most common, in case of type one the only therapy is insulin.
We can use different compound for hypoglycemic effects. We have different classes, e,g
sulfonyl urea, thiazolidine.
Mode of action: sulfonyl urea and other.
Insulin itself is synthesized by human or is an endogeneous substance responsible for
monitoring or regulating a number of metabolic process.
Insulin will increase the membrane transfer of glucose, amino acid and potassium.
In the case of modificational study, may be we are going to make molecule of abnormal
insulin , it is deffecient or sometimes it is totally absent.
Surface of cell has got insulin receptor and those receptor also have

and

chain and they are linked up by disulphide linkage when the resistance is

developed. When the insulin is present but it is not going to regulated level of glucose. This
may be due to infection or inflammatory condition.=
In this case, the increase in dose of insulin may help to maintain the glucose level.

ORAL HYPOGLYCEMIC AGENT:

e.g, sulphonyl urea, thiazolidine or thiazolidine dione derivative sulphonyl urea will stimulate
the release of insulin.
The first generation includes tolbutamide, chlorpamide and hexamide.
In 2nd generation we have glipizide and binanide termed as antihyper-glycemic agent. Insulin
release is not effected.
They will increase the action in the peripheral tissues ,reduce hepatic glucose output.
They inhibit gluconeogenesis.
They reduce absorption of glucose. E.g metformin, phenformin,,.
Meglipinide:
they are substituted benzoic acid derivative.
They have got the action like sulphonyl urea.
They increase the pancreatic release of insulin.
Thiazolidine dione derivative.
Increases the insulin sensitivity or reduces the resistance.
They effect circulatory lipids.
Before starting therapy, lipid profile is checked after one month of therapy againlipid profile
and LFT is done. Either we use same therapy or replace it according to the profile.
The drugs change the lipid profile e.g increase CBC and than check it.
example: biometazone, rosibetasone and ciglitazone.
They have effect in HDL , LDL. They are going to increase level of HDL majority.
Sometimes effect in LDL is more so that is a severe side effect.

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1.sulfonyl urea.

2.biguanides

33. substituted benzoic acid derivative.

4.pioglitazone.
Insulin is not hypoglycemic agent.
Synthetic agent:
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o
o
o

1st one is sulfunyl urea. We have to take general stracture and than mention
modification.
Basic structure of sulfonyl urea is sulfonyl amine.
it has benzene ring having alkyl (-R__) chain other SO 2NH2.
Derived from sulfonyl amide (have number of derivatives and number of activities).

Stimulate secretion of insulin from pancrease or

cells of langerhenes.

o Relate to benzoic acid and has same MOA, only difference in the receptor site.
2. Biguanide:
because of side effects not usually used. But its derivative is used for anti-diabetic purpose.
3.phenformine:
On R1 phenyl grp is present, other is H.
4.metformin:
Both position have CH3.
5.buformin:
One grp is butyl and other is H.
Anti-hyperglycemic agent. Not inc the level of insulin.
Reduces the resistance or increase the insulin sensitivity of cell.
Inhibit hepatic output of glucose.
Reduces the absorption of glucose.
6. thiazolidine dione (glitazone)
Also called betazone e.g thiabutazone, biobutazone,picglitazone.
These are changing the lipid profile.
It has more effect in LDL i.e hepatotoxicity.
Can change enzymatic pattern,.
ANTIVIRAL AGENTS:
It has 1 type of nucleic acid which may be RNA or DNA.
The RNA and DNA has core of protein. In some case that protein is also covered by another
protein called capsid or envelop.
It survives in a host.
It doesnt have well developed enzyme system.
It uses the substances of host cells and also use enzyme of host cells.
It replicates with host cells.
At last stage virus is going to be adsorb into the cell or that cell surface of host
cell=>attachment.
It is going to be adsorb into the cellor that cell surface. After that it is going to encoat. The
protein coat surrounding RNA or DNA is uncoated.
Nucleic acid in virus is released and thus attach with the nucleic acid so other substances of host
cells and different part of viruses are synthesized in different part of the host. They are not
synthesized in single cell but form in different cells.
These parts are assembled now, and we have got the virus.
Release of mature virus effect different cells, these are the targets of all anti-viral agents.
27-aug-2013
The targets of anti-viral agents are different steps of viral life cycle e.g
To inhibit encoding of virus, sometime encoding takes place after adsorption.
Another step is adsorption of virus & other target is to inhibit adsorption of virus.
Virus has to be penetrate (encoded or intact both can penetrate) our target is to be inhibit
penetration.
Other step is inhibition of transcription, translation (etc) or nucleic acid synthesis.
The 1st option is to inhibit the fusion of virus to host ,otherwise we inhibit above steps.
Page 8 of 20

The target will be to inhibit the assembly of viral particles if above steps can be stopped.
Next target is to inhibit the mature virus i.e termed as budding so we inhibit budding.
We have different compound which act at one step or different steps.
May be effective against many broad spectrum anti-viral agent. (more than one mode of action &
active against more than one virus).
The virus are using the system of host cell e.g enzymatic system.
The problem in synthesizing active agent or the requirement for desireable agent or for synthesis
of ideal compound is selectivity of agent i.e they should only act on the virus and should effect
the host cell. This is 1st problem to have the selectivity. This is requirement of ideal viral agent.
They should be active against different virus, should be broad spectrum.
Less toxic to the host cell or without effecting the host cell, they can reach the target cell.

Amantadine & Rimantadine;

These two compounds inhibit the uncoating of virus or they inhibit the penetration.
Rimantadine is the derivative of Amantadine.
They are mainly effective against influenza A virus not B & C.
They can be used prophylactically against influenza A not B & C.
If infection is already there they are not active.

Antimetabolites:
Next step is mainly synthesis of protein. E,g anti-neoplastic are anti-metabolite. They have
similar structure but not similar in activity.
To inhibit synthesis of protein we have anti-metabolites.
We have iodinated or flourinatednucleosidech act as anti-metabolite.
Iodoxyuridine:
Active against hepatitis B.
They can be used topically (0.1 And soln.) in case of herpes & pox virus.
Ophthalmic soln. is available.
Trifloridine:
Also available as topical in 1% soln. for ophthalmic use.
Acyclovir:
Page 9 of 20

 It is also related to same nucleoside. They are active against number of viruses, the brand
name is ZOVIVAX.
Active against herpes simplex, zoaster virus and choice of treatment in the case of genital
herpes, The compound is activated by the kinases and may inhibit the viral DNA polymerase.
Oral, parentral, topical dosages are avalaible.
Ribavarin;
Inhibit synthesis of protein but specifically inhibit RNA virus and active against adeno virus,
vaccine virus, myxema virus and also influenza virus.
The molecule is termed as broad spectrum anti-bacterial agent.
Also termed as pirazol or virazole.
This is also activated by the viral kinase and inhibit the enzyme inosine monophosphate
dehydrogenase and ultimately inhibit the synthesis of formation of guanosine.
Zidovudin:
Active against retrovirus.
Specific against reverse transcriptase. Hence can be used in AIDS, herpes & leukemia.
This molecule is analogue of thymidine.
Miscellaneous compound:
They are not anti-metabolite.
They are not structurally related to nucleotide or nucleoside.
Examples: saquinar, nevirapine.

SULPHONEAMIDE:
Antimicrobial but not anti-biotic.
We have More than 500 derivative of sulphon- amides , although few are used clinically.

DERIVATIVE OF SULPHANIL AMIDE:

Albendazole:

It is an oral dosage form, braod spectrum, slightly soluble in methanol, chloroform poor by
adsorb when taken with diet containing 40 g of fats, will increase the absorbtion. It will be
rapidly metabolized.
Page 10 of 20

DOA: is 8-12 hour.

It is active against tape worms.
They also prevent the multiplication of worms in other animals like dog used in hylatoid
disease (condition in which sacs are foms which are filled with water in different organs.
They interfere with the synthesis of protein, also inhibit the absorbtion of sugar & hence
decrease the essential nutrients & suplly of energy.

Theobendazole:.

Is an anti-fungal agent & also anti-parasitic agent. May be used to control the infection in
vegetables & fruits while it is active against round worms & other species found in wild
animals & also the infection which is transferred to human beings then compound form
chelates & DUE to this action also used in anti-dote in metal poisning.

Mebendazole:

Especially against pin worm & hook worm & also have effect against round worms.
They decrease the mobilization of of parasite, selective & irreversible blocking of uptake of
glucose.
In the case of piperazine derivative mainly we have parental which is depolarizing neuron
mascular blocking agent.
It induces persistant activation of nicotinic receptor, which result in paralysis of worm.
Another pyrazine derivative is directly carbamazine.
It also decrease mascular activity, immobilizes the organism.

Niclosamidic compound:

Active against cestodes, pin worm & round worm, available as chewable tablets having 2 g
active ingredient & it should be taken in empty stomach.
Laxatin is also supplemented. It inhibits the glucose uptake inhibit the generation of energy &
also inhibit inorganic phosphate- incorporation into ATP the drog effects the scolex of the
parasite (head of parasite).
Also other segments of parasite are effective with results in detachment of parasite from the
intestinal wall.

Sulphasiazone:

In this That is replaced by heterocyclic & pyrizidine ring & this ring is withdraw in nature.
The acidic character or protob become strange by being the acidic character & molecule
become stronger & more water soluble.
Sulphanilamide pka 100
Sulphamethoxazole pka=6.1
Sulphadiazine pka 6.48
Sulphacetamide pka -5.4
Just by modification pka value is reduced & solubility is used in crystal formation is reduced. &
proton become stronger. It make molecule more water soluble.

Sulphadiazine:

It is one of the important example. There are some other substitution.ie 5 membered or 6
membered ring. But they all have secondary character i.e thymine going to withdraw the
electron & make molecule more water soluble.
Page 11 of 20

Sulphasoxazole:

Have anti-bacterial effect & going to overcome crystal formation.

It is used specifically in urinary tract infection.
It is 5 membered ring.
They act as with drawing agent.
A molecule in which pka equal to ph of urine.
It is used more safely.

Sulfacetamide:

Pka is 5.411 ie almost equal to urine.

It is also used in UTI & used specifically in ophthalmic preparation.
Topically used compounds are silver salts of sulfadiazine & available in free forms & use in
case of burn therapy & it is because the molecule is active against pseudomonas that
microbe or bacteria is one of the culprit if reduce the healing of burns specifically &
against pseudomonas.

Sulfasalazine:

it is used in ulcerative colitis.

It has sulfa-pyradine & meta amino salicylic acid & hydrolyze in large intestine ie intestinal
bacteria & then we get active compound ie sulphapyradine.

Sulfamethoxazole:

Pka is 6.1.
It is usd in combination with trimethoprim.
Drug is septran. It has 2 molecules trimethoprim +sulphamethoxazole.
Both have got anti-bacterial action used 2 agent to reduce pka value. If increase dose, it
become more toxic, when used in combination, dose is reduced then less side effects.
Combination act in 2 steps or 2 different molecules. One step dihydrofolate reductase &
other tetra hydrofolate & ultimately no formation of folic acid, more allergic reaction,
although it is popular in series of sulphone amide.
Duration of action: short acting- 6 hr.sulphasoxazole, sulfadiazine, sulfamerazine,
sulfanipidine.
Intermediate acting : 8 hr. sulphamethoxazole, sulphapherazole.
Long acting: sulpha-methoxy pyaradine, sulphadimethoxime, sulphadioxine. These may
be used once in a day.
Weakly absorb molecules: include silver salts butane used topically. Sufa sulazine,
succinyle & aryl derivative.
The derivative of pthalic acid, succinic acid, going to hydrolyze & give active i.e 1-succinyl
2- pthalyl 3- sufacelizine 4-silver salts of sulfadine (topical). Dapsone anti-leprotic agent,
structure, MOA problems & have to over come.
Silver salts of sulfadinazine not directly effect

Lecture attended by: NAZIA TABBASSUM

Date: 18-9-2013/wednesday
ANTI-MALARIAL:

Causative organism is plasmodium parasite. We have 4 types.

Page 12 of 20

o Plasmodium falciparum
o Plasmodium ovale
o Plasmodium vivix
o Plasmodium malaria.
In human being infection is due to p. falciperum or p. vivix.
Few compounds are used against malaria but with time. Those compound become resistant
after that cinchona alkaloid, the oldest compound (tea extract was used , highest conc. Is
found in bark of cinchona plant.
Chemicals:
o 4-amino quinolene
o 8-amino quinolenes.
o Biguinides
o 9-amino anthereline derivative.
o Few isolated & extracted compound.
All quinoline derivative have this nucleus with substitute of amino group with side chain in
which 1 hydrogen is replaced by side chains (H-N-H-replace)

QUINOLINE:

Side chain is almost common in all derivative.

We have got 4 carbon i.e butyle side chain with 4 C-N-(C 2H5)2 di-ethyl-amino-butyle (DEAB).
In butyle side chain 1st C is substituted by CH3 called 1-methylbutyl di-ethyl-amino group. In
all we have got same side chain.
If we consider SAR santoquine was !st derivative synthesized by german & thought one of
compound of 4-amino-quinoline.
Substitution of CH3 group dec the activity.
One of the most important & commonly used derivative is chloroquine- chloro group is
substituted in this ring at position & in 4-amino-hydroxy-chloro-quine.
hydroxychloroquine -OH group is attached at N of side chain. It is more active as chloroquine
& is less toxic.

o
Hydro-oxy-chloro-quine sulphate

In amodiaquinine : substitution of cyclic compound on side chain.

Page 13 of 20

In mefloquine is also having cyclic ring

These are related structures & derivatives of quinidine.
They are competitive inhibitor of folic acid.
Malarial organism is parasite but synthesize its own folic acid.
These drugs inhibit conversion of DHF to THF.
In piperidine presence of chlorine on biguanides molecules condense together.
Pyrimidin derivative effective in exo-erythrocytic state. Ewhile in biguinides important
derivatives are proguinine.
This molecule is active in pre-erythrocytic state.
Proguinine is used with atovaquine against the resistant strain.
Halofentine is recently used compound also used in combination of biguanides & pyridine
derivative against the resistant strain.
Artemisinine used in Chinese traditional medecines. Now compound is available as drug of
choice . 2 derivatives are available
o 1-water soluble 2-lipid soluble
This compound have got lactone ring & also have got Oxygen ring i.e cleaved or broken down
to give the superoxide or radical is responsible for its bio-logical activity.
Date: 1-10-2013

LIFE CYCLE OF MALARIAL PARASITE:

Asexual phaseoccur in host (vertebrate or human)

Sexual phase occur in female mosquito .
From anophilus mosquito saliva biting result in transferring infectious agent into the blood
of host.
In blood erhtyrocytic state, in liver hepatic state.
In blood use heamoglobin of host & heamoglobin going to be degraded & use by parasite
for synthesis of its protein.
In 4-6 days symptoms of chills, fever are going to appear. These parasite are going to
burst out erythrocites.
Mosquitoes having sporozoites (prophylactic therapy) by bitting to infection person.
It can cause extra-intestinal amebiasis.
For prophylactically use quinile salt are used even Quinine +table salt=salt of chloro &
hydroxyl quinine.
Attenuated sporozoides: means radiation & use as prophylactic measure.

Artemismine:

O2 radical or super- active form damage at different sites.

Some gene coding have been done & can be used against plasmodium.

Page 14 of 20

PENICILLIN:

Most of the derivative have this nucleus. & substitution at R is there.

Penicillin have got bicyclic structure. One is 5-membrane ring, thiazolizine ring N & S & 4
membered ring.
Lactone ring having And & c=of side chains: acycl R-CO-NH amino side chain.
Structure activity relationship:
o The bicyclic ring is essential for activity.
o S have got 1st position. S is given priority but in some cases S is replaced but
compound is active. S is required but not essential.
o These di-methyl (CH3 )group are characteristic of penicillin.
o In some cases substances at COOH group or derivatized to salt. But in body COOH is
revive after metabolism.
o These bicyclic ring are required as intact. The And is essential & also C=O for such
activity.
o The NH of acyl amine is essential. The molecule is called 6APA & molecule is
intermediary compound & we have number of derivatives. Semisynthetic 6APA is
obtained by hydrolysis of penicillin G & v.
o Main substitution at R.
o Certain problems are essential for penicillin.
1-acid labile cant be taken orally.
2-Degraded by lactamases.
3-Penicillin G & We are the narrow spectrum compound.
4-allergic reaction.
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o
o
o

Now we have got different derivatives that have overcome acid degradation. Thus
modification have been doen to overcome problem 1, 2, 3 but 4- problem or allergic
reaction is still there. So as precausionary step test dose is given.
If we consider unsubstituted bicyclic ring is termed as PENAM RING.
In chemical aspect S is given 1 no. in penam & molecule is peracillanic acid (^APA)
1-R-CO-acyle 2-CO-NHamide 3-COOH is essential.

NATURAL PENICILLIN: (penicillin G)

Fermentation medium , phenyl acetic acid is another ether medium.

From phenyl acedic acid organism produce penicillin G i.e benzyle penicillin in which
R=benzyl.
Penicillin We . in which R=methyl phenoxy group
By adding phenoxy acedic acid .
These are naturally occurring compound but after that we have got synthetic or semisynthetic compound.
Semi-synthetic =in which insulin is hydrolyzed.
6APA is a precursor & no. of derivatives prepared called semi-synthetic derivative .

SEMI-SYNTHETIC DERIVATIVE:

Di-methyl substituted (phenyl aromatic ring. In GAPA above add & form methicillin.
In other molecule heterocyclic ring such as azole, amino phenyl or benzyl group.
Lactose ring will be broken by action of gastric acid.
Thus our strategy is to introduce the with drawing group by action of inductive organism,
provide stability to C=Of group & by this acid cant react at this site.
The hetero-cyclic ring system & halogens, nitro group serve as with drawing group.
With penicillin G nothing to do with with drawing group so it is acid sensitive & cant
administer orally. Infection against gram +ve oraginsm . it is narrow spectrum.
Penicillin We has phenoxy CH2 group having with drawing characters & can serve as resistant
to gastric acid can be taken orally but degradated.
Active against gram +ve . in 1960 serious problem & hospitalized observation that penicillin
dont show organism become resistant & grip to be degradated by -lactamase at that time
this was serious problem & need for penicillin.
Thus research done on penicillin by addition of bulky group give shielding or stearic effect
(physically ) dont allow -lactamase to reach to the site of action.
Thus by introduction of bulky group we overcome the problem of 2 i.e degradation by lactamase.
Then we got oxacillin, cloxacillin, flucloxacillin. These have with draing effects & bulky prevent
degradation.
In 1877 pastuar discovered penicillin i.e obtained from mold but that time it was too toxic to
use it clinically.
In 1928 fleming have got the other substance which is relatively same & less toxic but not
able to isolate because molecule was un-stable.
In 1938 flory & CHAIN have isolated penicillin by freez dryng method..,

Lectures attended by: IFRA HUSSAIN

22-10-2013/teusday
CHLORAMPHENICOL:

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Species of streptomycin.
Approved in 1947 in US to be used as braod spectrum anti-biotics.
S.E:
Aplastic anemiea, blood toxicity so the used was limited in US but still molecule is
available in some countries b/c molecule is cheap.
Has broad spectrum activity against gram ve.
More active as compare to gram +ve.
Molecule has 2 Nitrogen atoms pH is acidic.
The 2 N present in the form of carboxiamide & 2 nd CONH one is in the form.
Moderately soluble in water but solubility cab be increased by forming succynyl derivative
i.e more water soluble.
Molecule also has a bitter taste which can be masked by the formation of palmitate
derivative which also increase water solubility.
Aplastic anemia is due to the formation of certain
metabolite involving the And but the ratio is less.
Other toxicity are also there which are overcome after the
withdrawal of drug i.e they are reversible & are less
common.
The molecules are easily penetrate into CSF & causes
inflammation. In meningitis can cross CSF. Specific use of
drug in meningitis & also can penetrate easily in the
lymph nodes & thus used in the cases of typhoid&
parathyroid fever.
SAR
Substituted aromatic ring is essential.
Propane diole is essential for the activity. These can
be confirmed by the development of strains which
can acetylate the OH- grp i.e OH- grps are not
avalaible in free form & this is not available for
binding to the active site therefore propanediol is
essential.
Dichloroacetamide is also essential.
Almost the whole molecule is required for activity
thus no derivative is present.
MOA
Act at ribosomal level. Bind to 50s ribosomal subunit & they are going to bind to the
subunit of organism.
The binding affinity for microorganism is more as compare to ribosome of host.
Anti-biotic should be selectively toxic for invading organism as compared to the
host.
AMINGLYCOSIDES :

Streptomycin.
Kananmycin.
Gentamycin.
Tpramycin.

Streptomycin :
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Discovered in 1944 by wakesman & collaborators.

The molecules has specific action against organism of mycobacterium tubercolusis.
It is drug of choice for even though it has no. of S.E.
The molecule is going to act at different levels. They are going to act on ribosomes codons &
mRNA. They are not able to recognize the specific codons so abnormal protein synthesized.
In the same way they inhibit the synthesis of protein.
Also inhibit elongation of polypeptide/polymerization of amino acid. They are going to
interfere/ synthesis of protein at different levels.
S.E :
Allergic reaction still there, didnt over that problem.
Effect on 8th cranial nerve & hence result in the loss of hearing which may be
temporary (reversible of parmanant damage)
The effect is also onserved in the form of vertigo & the disturbance in coordination
(imbalance)thus the use is limited.
In Tb used in combination to decrease toxicity.
30s subunit act on this ribosome.
SAR :
It has 3 rings.
1 ring is hexose 9amino glucose)
2nd ring pentose sugar.
Molecule of aglycone 9non-sugar) that can also be a cyclic structure.
Changes in pentose & hexose sugar can occur then different types of streptomycin are
derived.
Lecture attended by: ANUM ZAfar

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