Medicinal chemistry of Sulphonamides and quinolones

Medicinal Chemistry of Sulfonamides and Quinolones

Medicinal Chemistry

SPH2153

By: Dr. Rasha Saad

Introduction The fight against bacterial infection is one of the great success

stories of medicinal chemistry. The topic is a large one and there are terms used in this chapter

which are unique to this particular field. Rather than clutter the text with explanations and definitions: staphylococcocci, bacillici, Gram-negative, Gram-positive.

The h

isto

ry o

f an

tibac

teri

al a

gent

s

The history of antibacterial agents

Bacteria were first identified in the 1670s by van Leeuwenhoek, following his invention of the microscope.

This appreciation followed the elegant experiments carried out by the French scientist Pasteur, The possibility that these microorganisms might be responsible for disease began to take hold.

During that latter half of the nineteenth century, scientists such as Koch were able to identify the microorganisms responsible for diseases such as tuberculosis, cholera, and typhoid.

Methods such as vaccination for fighting infections were studied. Research was also carried out to try and find effective antibacterial agents or antibiotics.

However, the scientist who can lay claim to be the father of chemotherapy—the use of chemicals against infection—was Paul Ehrlich. Ehrlich spent much of his career studying histology, then immunochemistry, and won a Nobel prize for his contributions to immunology.

The history of antibacterial agents

By 1910, Ehrlich had successfully developed the first example of a purely synthetic antimicrobial drug. This was the arsenic-containing compound salvarsan (Fig. 10.1).

Although it was not effective against a wide range of bacterial infections, it did prove effective against the protozoal disease sleeping sickness (trypanosomiasis), and the spirochaete disease of syphilis. The drug was used until 1945 when it was replaced by penicillin.

Prolavine (Fig. 10.2) is a yellow-coloured aminoacridine structure which is particularly effective against bacterial infections in deep surface wounds, and was used to great effect during the Second World War.

The history of antibacterial agents

Despite the success of this drug, it was not effective against bacterial infections in the bloodstream and there was still an urgent need for agents which would fight these infections.

This need was answered in 1935 with the discovery that a red dye called prontosil (Fig. 10.3) was effective against streptococci infections in vivo.

prontosil was eventually recognized as being a prodrug for a new class of antibacterial agents—the sulfa drugs (sulfonamides).

The discovery of these drugs was a real breakthrough, since they represented the first drugs to be effective against bacterial infections carried in the bloodstream. They were the only effective drugs until penicillin became available in the early 1940s

The bacterial cell

Site of antibacterial action

Antibacterial agents which act against cell metabolism

(antimetabolites)

Sulfonamides

Sulfonamides

Nomenclature of the Sulfonamides

Sulfonamides

The history of sulfonamides The best example of antibacterial agents acting as antimetabolites are the sulfonamides (sometimes called the sulfa drugs).

Structure-activity relationships (SAR)

The synthesis of a large number of sulfonamide analogues (Fig. 10.7) led to the following conclusions.

The p-amino group is essential for activity and must be unsubstituted (i.e. R = H). The only exception is when R = acyl (i.e. amides). The amides themselves are inactive but can be metabolized in the body to regenerate the active compound. Thus amides can be used as sulfonamide prodrugs (see later). • The aromatic ring and the sulfonamide functional group are both required. • The aromatic ring must be para-substituted only. • The sulfonamide nitrogen must be secondary. • R" is the only possible site that can be varied in sulfonamides. • Changing the nature of the group R" has also helped to reduce the toxicity of

some sulfonamides

Sulfanilamide analogues R" can be varied by incorporating a large range of heterocyclic or aromatic structures which affects the extent to which the drug binds to plasma protein.

To conclude, varying R" can affect the solubility of sulfonamides or the extent to which they bind to plasma protein. These variations are therefore affecting the pharmacodynamics of the drug, rather than its mechanism of action.

Mechanism of action

The sulfonamide molecule is similar enough in structure to p-aminobenzoic acid (PABA) that the enzyme is fooled into accepting it into its active site (Fig. 10.15).

Mechanism of action

The sulfonamide molecule is similar enough in structure to p-aminobenzoic acid (PABA) that the enzyme is fooled into accepting it into its active site (Fig. 10.15).

Applications of sulfonamides

Before the appearance of penicillin, the sulfa drugs were the drugs of choice in the treatment of infectious diseases. However, there has been a revival of interest with the discovery of a new 'breed' of longer lasting sulfonamides. One example of this new generation is sulfamethoxine (Fig. 10.11) which is so stable in the body that it need only be taken once a week.

Applications of sulfonamides

The sulfa drugs presently have the following applications in medicine: • treatment of urinary tract infections • eye lotions • treatment of infections of mucous membranes • treatment of gut infections Sulfonamides have been particularly useful against infections of the intestine and can be targeted specifically to that site by the use of prodrugs. For example, succinyl sulfathiazole (Fig. 10.12) is a prodrug of sulfathiazole.

Applications of sulfonamides

Substitution on the aniline nitrogen with benzoyl groups (Fig. 10.13) has also given useful prodrugs which are poorly absorbed through the gut wall and can be used in the same way.

Mechanism of action

Examples of other antimetabolites

Examples of other antimetabolites

There are other antimetabolites in medical use apart from the sulfonamides. Two examples are trimethoprim and a group of compounds known as sulfones (Fig. 10.16).

Trimethoprim

Trimethoprim is often given in conjunction with the sulfonamide sulfamethoxazole (Fig. 10.17). The latter inhibits the incorporation of PABA into folic acid, while the former inhibits dihydrofolate reductase.

Mechanism of action

Sulfones

The sulfones are the most important drugs used in the treatment of leprosy. It is believed that they inhibit the same bacterial enzyme inhibited by the sulfonamides, i.e. dihydropteroate synthetase.

The spectrum of activity

http://www.youtube.com/watch?v=qBdYnRhdWcQ http://www.youtube.com/watch?v=oC21vLFtsjo

Agents which act on nucleic acid transcription and

replication

Quinolones and fluoroquinolones

Quinolone and Fluoroquinolone

The quinolone and fluoroquinolone antibacterial agents are relatively late arrivals on the antibacterial scene, but are proving to be very useful therapeutic agents.

They are particularly useful in the treatment of urinary tract infections and also for the treatment of infections which prove resistant to the more established antibacterial agents.

In the latter case, microorganisms which have gained resistance to penicillin may have done so by mutations affecting cell wall biosynthesis.

NALIDIXIC ACID

Nalidixic acid was the first therapeutically useful agent in this class of compounds.

It is active against Gram-negative bacteria and is useful in the short-term therapy of urinary tract infections. It can be taken orally, but unfortunately, bacteria can rapidly develop resistance to it.

Various analogues have been synthesized which have similar properties to nalidixic acid, but provide no great advantage.

ENOXACILIN

A big breakthrough was made, however, when a single fluorine atom was introduced at position 6, and a piperazinyl residue was placed at position 7 of the heteroaromatic skeleton.

This led to enoxacilin which has a greatly increased spectrum of activity against Gram-negative and Gram-positive bacteria.

Activity was also found against the highly resistant Pseudomonas aeruginosa.

CIPROFLOXACIN

A Further adjustments led to ciprofloxacin, now the agent of choice in treating travellers' diarrhoea.

It has been used in the treatment of a large range of infections involving the urinary, respiratory, and gastrointestinal tracts as well as infections of skin, bone, and joints.

It has been claimed that ciprofloxacin may be the most active broad-spectrum antibacterial agent on the market.

Furthermore, bacteria are slow in acquiring resistance to ciprofloxacin, in contrast to nalidixic acid. The quinolones and fluoroquinolones are thought to act on the bacterial enzyme

CIPROFLOXACIN