This document discusses medicinal chemistry concepts related to chemotherapeutic agents. It provides an introduction to chemotherapy and antimicrobial agents. It then summarizes the structure-activity relationships of several classes of agents: 1) Sulphonamides - The minimum structural requirement is the sulphanilamide skeleton, with essential amino and sulphonyl groups. Activity decreases with substitutions on the benzene ring. 2) Penicillins - The β-lactam ring and thiazolidine ring are essential for activity. Modifications to the acylamino side chain can enhance stability, spectrum of activity, and resistance to β-lactamase. 3) Further sections will discuss the structure-activity relationships

1. PHR 402: MEDICINAL CHEMISTRY II
CHEMOTHERAPEUTIC AGENTS
LECTURER: Dr kabiru Abubakar
2023 trimester one
SYNOPSIS
 Introduction
 SAR of Sulphonamides
 SAR of Penicillins
 SAR of Flouroquonolones

2. INTRODUCTION
• Chemotherapy simply refers to the treatment that involves the use of chemical
substances (particularly, drugs) to destroy rapidly growing cells.
• Antibiotics are microbial metabolites or their synthetic analogs that in small doses
inhibit the growth and survival of microorganisms without serious toxicity to the
host.
• Antimicrobial agents are synthetic compounds that are unrelated to natural products
but still inhibit or kill microorganisms.
• The clinical utility of natural antibiotics has been enhanced through structural
modifications by Medicinal Chemist leading to
 broader antimicrobial spectrum,
 greater potency,
 reduced toxicity,
 more convenient administration & additional pharmacokinetic parameters.

3. SULPHONAMIDES
The lead compound was Prontosil rubrum – a synthetic dye
In 1930s a German scientist by name Domagk Gerhaerd examined a series of dyes based
on hypothesis that;
The dyes might be taken selectively on by certain species of bacteria in a manner
similar to the way Gram-stain works and can therefore selectively kill the bacterial cells
Prontosil was found to possess in-vivo activity against streptococcal infections but was
no active in-vitro.
It was soon discovered that the urine of Prontosil treated animal posses in-vitro
antibacterial activity.
Fractionation of the urine lead to the isolation and identification of p-
aminobenzenesulphonic acid amide (sulfanilamide)
Prontosil therefore acts as a prodrug.
Sulfanilamide was later discovered to possess in-vivo antibacterial activity.

4. Prontosil therefore acts as a prodrug.
Sulfanilamide was later discovered to possess in-vivo antibacterial activity.
This provided the basis for the discovery of sulphonamides class of antibacterial agents.
It ushered in the modern era of anti-infective drug discovery

5. Mechanism of Action of Sulphonamides

6.  The functional groups that differ in the two molecules is the carboxyl of PABA and the
sulphonamide group of sulfanilamide.
 Thus sulfanilamide and other sulphonamides compete with PABA which results in the
production of false dihydropteroate consequently, blocking the bacterial folic acid
synthesis an important intermediate in DNA synthesis

7. Structure Activity Relationship of Sulphonamides
The major features of SAR of sulphonamides include the following;
1
 Sulphanilamide skeleton is the minimum structural requirement for antibacterial activity.
 The amino- and sulphonyl-groups on the benzene ring are essential and should be in 4 and 1
position respectively.
 The free aromatic amino groups should reside para to the sulphonamide group. Its
replacement at ortho or meta position results in compounds devoid of antibacterial activity.

8.  The free aromatic amino groups should reside para to the sulphonamide
group. Its replacement free aromatic amino at ortho or meta position results
in compounds devoid of antibacterial activity.
 Sulphur atom should be directly linked to the benzene ring.
 Replacement of benzene ring by other ring systems or the introduction of
additional substituents on it decreases or abolishes its activity.
 Activity varies with the nature of the substituent at the Sulphonyl-amino
group. Addition of heterocylic substituents lead to highly potent derivatives,
e.g Suphametoxazole, sulphamethizole, sulphadiazine etc

9. The N-4 amino group could be modified to be
prodrugs, which are converted to free amino
function in vivo. Eg. Pthalylsulfathiazole

10. β-LACTAM ANTIBIOTICS
 The β-lactam antibiotics can be
broadly classified into five groups
based on their ring structure namely;
Penicillins, Cephalosporins,oxapenam,
monobactams & Carbapenems
β-lactam ring
 The β-lactam is a cyclic amide with
four atoms in its ring. It is main
component of the pharmacophore.
Classes of β-Lactam antibiotics

11.  The Penicillins are characterized by a
substituted 5-membered thiazolidine ring
fused to a the β-lactam ring.
 The amide in the acylamino side chain is
susceptible to hydrolysis by amidases and
gastric acid
 The β-lactam ring is susceptible to
hydrolysis by β-lactamase (penicillinase)
to produce penicilloic acid which lacks
antibacterial activity
Substituted-6- aminopenicillanic acid
(Basic structure of penicillins)
CHEMISTRY
penicilloic acid

12. Carboxylic acid
It is essential for activity
Activity is decreased
when modified to ester
or alcohol
Sulphur is usual
but not essential
β-lactam
Essential for activity
Activity is lost on
hydrolysis
Acylamino side chain
Susceptible to hydrolysis
 Addition electron
withdrawing group on
the chain enhances
stability.
 Addition of bulky
groups enhances
stability to β-
lactamase
 Addition of polar
groups like NH2, OH,
COOH to carbon α- to
the carbonyl group
enhances stability
and also increase
activity against Gram-
ve bacteria.
Cis stereochemistry is
essential for activity
STRUCTURE ACTIVITY RELATIONSHIP

13. Benzylpenicillin (Penicillin G)
This was the first penicillin that was isolated from the fungi Penicillium by the Scientist
Alexander Fleming in 1928.
This natural product is thus the prototype molecule for the discovery of other penicillins
Although it possess significant antibacterial activity, it has some limitations such as;
I. It is not orally active because of its susceptibility to hydrolysis by gastric acid
II. It is not effective against Gram negative bacteria
III. It is susceptible to inactivation by β-lactamase producing bacteria.
IV. This limitations are addressed through modifications of the structure.

14. • Most of the limitations associated with benzyl penicillin were addressed through
structural manipulations of the acyl amino side chain of the penicillin structure. For
example;
• Addition of electron withdrawing atom on the acylamino side chain enhances it stability
to gastric acid and thus becomes orally active. Eg. Phenoxymethylpenicillin (penicillin V)
• It is orally active but, its spectrum of activity is similar to that of Penicillin G.
• It is also susceptible to inactivation by β-lactamase producing bacteria.
Phenoxymethylpenicillin (penicillin V)

15. If polar groups like NH2, OH, or COOH is attached to the methylene group α- to the
carbonyl group of the side chain acid stability is increased.
In addition, the spectrum of antibacterial activity will be increased such that the compound
will have activity against both Gram +ve and Gram -ve bacteria. For example

16.  Addition of bulky groups enhances stability to β- lactamase. Eg. Methicillin, is resistant to
β-lactamase activity.
 Although resistant to β-lactamase, it is susceptible to hydrolysis by gastric acid, hence it
is not orally active. It has to be administered parenterally.

17.  Addition of isoxazole moiety on the acylamino side chains produced enhanced acid
stability as well as resistance to β-lactamase effect. For example, oxacillin and cloxacillin
are both orally active and resistant to β-lactamase.