This document discusses sulfasalazine, a drug used to treat rheumatoid arthritis, psoriatic arthritis, Crohn's disease, and ulcerative colitis. Sulfasalazine is a prodrug composed of 5-aminosalicylic acid (5-ASA) linked to sulfapyridine through an azo bond. When ingested, it is partially absorbed in the jejunum and the remainder is reduced in the colon by bacteria into sulfapyridine and 5-ASA, its active components. The document also discusses the pharmacology, structure-activity relationships, and use of prodrug approaches of delivering 5-ASA specifically to the colon to treat inflammatory bowel diseases.

1. Organic Pharmaceutical Chemistry IV
Fifth Stage
Semester 1
2016-2017
Prepared by:
‫صـالـح‬ ‫حـسام‬
‫ــسـن‬‫ح‬ ‫حيـدر‬
‫حيد‬ ‫مصطفى‬‫ر‬

2. Introduction
Sulfasalazine is a combination of an aspirin-like anti-inflammatory component
and a Sulfa antibiotic-like component.
It is a medicine used to treat:
 Rheumatoid arthritis.
 Psoriatic arthritis.
 Crohn’s disease.
 Ulcerative colitis.
 Because sulfasalazine acts to reduce the
damage to the joints, rather than just
relieve the pain, it belongs to the group of
medicines called disease modifying anti-
rheumatic drugs (DMARDs).

3. pharmacology
• Sulfasalazine is a prodrug composed of
5-aminosalicylic acid (5-ASA) linked to sulfapyridine
through an azo bond.
• Partially absorbed in the jejunum after oral
ingestion.
• The remainder reduced in colon by coliform
bacterial enzyme, azoreductase, to sulfapyridine
and 5-ASA.

4. pharmacology
 In vivo studies have indicated that the absolute bioavailability
of orally administered SSZ is less than 15% for parent drug.
 Of the two species, SP is relatively well absorbed from the
intestine and highly metabolized, while 5-ASA is much less
well absorbed.
 Acetylsulfapyridine (AcSP) is principal metabolite of SP,
which 90% bound to plasma proteins.
 SP and 5-ASA and their metabolites are primarily eliminated
in the urine either as free metabolites or as glucuronide
conjugates.
 The majority of 5-ASA stays within the colonic lumen and is
excreted as 5-ASA and acetyl-5-ASA with the feces.

5. pharmacology
5-ASA, suggesting a multifactorial basis of therapeutic action.
These include:
 Inhibition of prostaglandin and leukotriene synthesis ,Free radical
scavenging and Immunosuppressive activity.
While SP;
 competitive inhibitor of the bacterial enzyme dihydropteroate synthetase.
The inhibited reaction is necessary in these organisms for the synthesis of
folic acid by means of processing the substrate para-aminobenzoic acid
(PABA).

6. Structure activity relationship (SAR)
♦ 5-aminosalicylic acid (mesalamine)
has anti-inflammatory activity.

7. Structure activity relationship (SAR)
♦ 4-aminosalicylic acid has antibacterial
activity and most effective against
tuberculosis.
♦ 3-aminosalicylic acid has antioxidant
activity and effect on cell cycle
progression.

8. Structure activity relationship (SAR)
Balsalazide: is a pro-drug of mesalamine that
consists of 5-aminosalicylate with an azo bond to a
phenyl-hydroxybenzoid acid moiety which is cleaved
off in the large intestine by bacterial enzymes,
releasing free mesalamine , it is less toxic and not
associated with urinary problems.
Olsalazine: is a prodrug of mesalamine that consists
of two molecules of 5- aminocsalicylate (5’5’-
azodisalicylate) joined at the amino-terminus with an
azo bond that is cleaved by bacterial action in the
colon, releasing two molecules of mesalamine also
more safe than sulfasalazine.

9. Structure activity relationship (SAR)
1. The amino groups essential for activity and must
be unsubstituted. The only exception is 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.
2. The aromatic ring and the sulfonamide
functional group are both required.
3. The aromatic ring must be para substituted only.
Sulfapyridine

10. Structure activity relationship (SAR)
4. The sulfonamide nitrogen must be secondary.
5. The addition of pyridine ring helped to reduce
toxicity of sulfonamide. HOW?!!
6. Substitution on nitrogen that attach to sulfur affect
on pharmacokinetic of drug and not has effect on
antibacterial activity.
7. SP has PKa 8.4 ,which means high potential to
produce crystalluria. the danger of crystal formation
has been greatly reduced through the use of more
water solube sulfonamide such as sulfisoxazole
,which has PKa 5.
Sulfapyridine

11. Prodrug approach
Colon specific drug delivery system has attracted considerable attention for
the past few years. The colon is a site where both local and systemic
delivery of drugs can take place. To achieve successful colon targeted drug
delivery, a drug need to be protected from degradation, release and
absorption in the upper portion of GIT, and then to be ensured abrupt or
controlled release in the proximal colon.
A large number of anaerobic and aerobic bacteria are present in the entire
length of the human GIT. Intestinal enzymes are used to trigger drug release
in various parts of the GIT. Usually, these enzymes are derived from gut
microflora residing in high numbers in the colon. These enzymes are used to
degrade coatings or matrices as well as to break bonds between an inert carrier
and an active agent (i.e., release of a drug from a prodrug)

12. Prodrug approach
The azo linkages are cleaved to form a pair of amines by the action of
azoreductases produced by anaerobic bacteria in the colon, releasing active
drugs from azo prodrugs. This reduction occurs favorably in the anaerobic
environment created by bacteria in the cecum and colon.

13. Prodrug approach
This approach has been
successfully utilized in
sulfasalazine, which is the
most commonly prescribed
medication for the treatment
of IBD. It is an azo conjugate
of 5- ASA and sulfapyridine.
The active moiety is 5-ASA,
whereas sulfapyridine acts as
a carrier that protects 5-ASA
from the acidic pH of
stomach, and prevents its
absorption from small
intestine, delivering it to
colon.

14. Prodrug approach
A majority of side effects that are associated with sulfasalazine like:
• hepatotoxicity
• hypospermia
• and severe blood disorders.
they are due to sulfapyridine.
Even though few prodrugs of 5-ASA like basalazine, ipsalazine and olsalazine
have been reported, none of them have reached beyond the stage of clinical
trials. Most of them suffer from adverse effects, due to the carriers used with
them. The need for a totally safe, colon specific prodrug of 5-ASA with
nontoxic carrier, still remains.

15. References
• Prodrugs: Challenges and Rewards (Valentino Stella ،Ronald Borchardt ،Michael Hageman ،Reza
Oliyai ،Hans Maag ،Jefferson Tilley ).
• Colon Specific Drug Delivery Systems: A Review on Various Pharmaceutical Approaches (Prasanth
V.V, Jayaprakash. R, Sam T. Mathew).
• Campieri M, Lanfranchi GA, Bazzocchi G, Brignola C, Sarti F, Franzin G, et al. Treatment of
ulcerative colitis with high-dose 5-aminosalicylic acid enemas. Lancet 1981;2:270–1.
• Taffet SL, Das KM. Desensitization of patients with inflammatorybowel disease to sulfasalazine. Am
J Med 1982;73:520–4.
• Holdworth CG. Sulphasalazine desensitization. Br Med J 1981;282:110.

16. Thank U.