This slide was prepared by Tousif Azmain and his group members for the assignment purpose for Department of Pharmacy, East West University, Bangladesh. Uploaded by Tousif Azmain.

1. Oxazole Ring
Containing Drugs
PHRM 412: MEDICINAL CHEMISTRY III
COURSE INSTRUCTOR: NISHAT NASRIN

2. A.B.M Asikur
2014-1-70-013
Presented By
Shabbir Ahmed
2014-1-70-040
Farhana Mazia
2014-1-70-055
Tousif Azmain
2014-1-70-053

3. Outline
 Oxazole ring
 Bengazole A
 Mechanism of Action of Bengazole A
 Structure Activity Relationship of Bengazole A
 Pharmacokinetics of Bengazole A
 Oxaprozine
 Mechanism of Action of Oxaprozine
 Structure Activity Relationship of Oxaprozine
 Pharmacokinetics of Oxaprozine

4. Oxazole
Ring
Heterocyclic
Aromatic
compounds
Present in
numerous
pharmacologically
important
compounds
Different
biological
activities
Used as
diversity scaffolds
in
combinatorial
chemistry
Intermediates for
the preparation
of new
biological
materials

5. Bengazole A
 Bengazoles are rare and
intriguing class of natural
products characterized by
the presence of,
a. Two oxazole groups linked
by a geminal arrangement
and,
b. A polyhydroxylated
appendage

6. Overview
 Marine natural product (Jaspis
Sponge)
 Single stereoisomer
 Family of 22 bengazoles isolated
in 1988
 Potent antifungal activity
 Potent in vitro antifungal activity
against Candida albicans
 Active against fluconazole-
resistant C. krusei and C.
glabrata
 Activity comparable to
amphotericin B
 Ergosterol dependent
antifungal activity
 Sensitive isolated C-10
stereocentre

7. Mechanism of Action
 Fungal cytochrome P450 enzyme 14α-
demethylase catalyzes the conversion of
lanosterol to ergosterol.
 Ergosterol plays an important role in
membrane fluidity.
 Inhibition of 14α-demethylase prevents the
conversion of lanosterol to ergosterol.
Bengazole A

8. Mechanism of Action
 Bengazole A bind with of one of the
oxazole ring to the Fe-heme active site
of the enzyme.
 Subsequent accumulation of 14α-methyl
sterols is fatal for fungi.
Bengazole A

9. Structure Activity Relationship
 The study suggests that antifungal activity of
bengazole A is not accounted for by simple analogs
with one or two oxazole rings alone. At the very
least, activity was correlated with the presence of a
5-monosubstituted oxazole.
 For anti-Candida activity; a long-hydrophobic side-
chain, the polyol side chain, and at least one oxazole
in the heterocyclic core is required.
 2,4-Disubstituted oxazolyl carbinol analogs,
including their long-chain esters, were inactive.

10. Structure Activity Relationship
 The closest heterocyclic analog to bengazole A,
was inactive suggesting abolished biological
activity upon replacement of the hydrophilic polyol
side chain of bengazole A with a shortened n-
propyl carbinol.
 The fatty acyl side chain of Bengazole A is
important for antifungal activity. The fatty acyloxy
chain at C-10 potentiates activity only when the
native polyol chain is present since highly lipophilic
compounds without polyol chain are inactive.

11. Structure Activity Relationship
 Derivatives were prepared by using different aldehydes (oxazole-5-carboxaldehyde,
furfural and benzaldehyde) and generating a small library of analogues that were
completely inactive. This suggests that necessity of polyol side chain in antifungal
activity.

12. Pharmacokinetics
Erratically absorbed
after oral
administration
Absorption is
enhanced by a
fat meal
Metabolized in liver
Primarily excreted
through urine
Half-life
approximately 8.5
hours

13. Oxaprozin
 Oxaprozin (3- (4,5-
diphenyloxazol-2-yl)
propanoic acid) is a non-
steroidal anti-inflammatory
agent (NSAID)
 Used to symptomatically
treat inflammation, pain,
and rheumatoid diseases.

14. Inhibition
of Cox-1
Inhibition of
COX-2
Modulating
Endogenous
Cannabiod
System
Inhibition
of NF-κB
activation
Inhibition of
hydrolase
Action on the
hypothalamus
Mechanism
of
Oxaprozin
anandamide

15. STRUCTURE
ACTIVITY
RELATIONSHIPS
 The compound 3- [4- (4-
fluorophenyl) -5- (4-
aminosulfonyl-3-fluorophenyl)
oxazol-2-yl] propane acid
showed the best activity from
the above group of derivatives.

16.  Derivatives containing a
hydroxy group in one of phenyl
cores of oxaprozine have also
been shown to have the anti-
inflammatory activity. As
example; 3- [5- (4-
Hydroxyphenyl) -4-
phenyloxazol-2-yl], 3- [4- (4-
hydroxyphenyl) -5-
phenyloxazol-2-yl] propane
acid.
STRUCTURE
ACTIVITY
RELATIONSHIPS

17.  Synthesis of the copper
complex of oxaprozin
increased anti-
inflammatory activity. It
was started by forming Na
or K salt of oxaprozin and
then by adding an
aqueous solution Cu
(NO3) 2 in the solution of
the oxazoline salt gets the
desired complex.
STRUCTURE
ACTIVITY
RELATIONSHIPS

18. PHARMACOKINETICS
It has high oral
bioavailability (95%)
Peak plasma
concentrations being
achieved 3 to 5 hours
after dosing
Oxaprozin can diffuse
easily into inflamed
synovial tissue after oral
administration
Metabolized in the liver
oxidative and conjugative
pathways
Readily eliminated by the
renal and fecal routes

19. References
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2691865/
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967228/
 http://www.doiserbia.nb.rs/img/doi/0367-598X/2011/0367-
598X1100040B.pdf
 http://www.sciencedirect.com/topics/neuroscience/oxaprozin
 http://www.sciencedirect.com/topics/biochemistry-genetics-and-
molecular-biology/ergosterol