Natural Products as Pharmaceuticals

and Sources of Lead Compounds

Presented by

Qudsia Rehman 606

Kanwal Irshad 620
Natural Product
 A natural product is a chemical compound or
substance produced by a living organism –
found in nature that usually has a
pharmacological or biological activity for use
in pharmaceutical drug discovery and drug
design.
Lead Compound
 A lead compound in drug discovery is a
chemical compound that has pharmacological
or biological activity likely to be
therapeutically useful, but may still have
suboptimal structure that requires
modification to fit better to the target.
Cephalosporins

 Cephalosporins are similar to Penicillins, but more

stable to bacterial β lactamases and therefore have a
broader spectrum of activity.
History

 The 1st source of Cephalosporins, Cephalosporium

acremonium(Fungus), was isolated in 1948 by
Giuseppe from the sea near a sewer outlet of the
Sardinian Coast. The crude filtrates from this fungus
were found to inhibit the in vitro growth of βlactamase
producing S. aureus and to cure the Staphylococcal
infections and typhoid fever in humans.
CEPHALOSPORINS

 Abraham and Newton described the structure of the first cephalosporin,

“cephalosporin C”.
 Cephalosporin C is not potent enough to be a useful antibiotic, but
removal, through chemical means, of the natural side chain produced 7-
aminocephalosporanic acid, which, analogous to 6-APA, could be fitted
with unnatural side chains
Biosynthesis
Biosynthesis

 ACV synthase,condense 3 precursors including L-

aaminoadipic acid, L-cysteine, L-valine to ACV tripeptide
 ACV is then cyclized into isopenicillin N (IPN) by IPN
synthase. Conversion from IPN to penicillin N was
catalyzed by epimerization.
 Deacetyloxycephalosporin C (DAOC) synthase-
hydroxylase which successively transforms penicillin N
into DAOC and deacetyl-cephalosporin C (DAC).
 The last step in CPC biosynthesis is catalyzed by DAC
acetyltransferase (DAC-AT).
Chemistry
 The nucleus of Cephalosporins, 7-
aminocephalosporanic acid bears a close resemblance
to 6-aminopencillanic acid.
 The core of the basic cephalosporin molecule consists
of a two ring system which includes a β-lactam ring
condensed with dihydrothiazine ring. The core itself
can also be referred to as 7- aminocephalosporanic
acid which can be derived by hydrolysis from the
natural compound Cephalosporin C.
Chemistry
 Chemical compounds containing this core are
relatively stable to acid hydrolysis and
tolerance to βlactamases.
 Cephalosporin C ring structure contains a

side-chain.
Modification of side chains
on the relevant positions has
been used to create a whole
new class of cephalosporin
antibiotics.

Modification of side-chains at position 7 of the lactam

ring seems to affect the antibacterial activity while
position 3 of the dihydrothiazine ring alters
pharmacokinetic properties and receptor binding affinity.
Structure activity relationship