Design, synthesis and in vivo evaluation of novel

glycosylated sulfonylureas as antihyperglycemic

agents

Dr.Ghadeer Suaifan

Associate Professor of Medicinal Chemistry

and Pharmaceutical Instrumental analysis

3rd Annual Internationalon Pharmaceutical Sciences, 2-5 May 2016 Conference, Athens

Diabetes mellitus (DM) is a major degenerative disease with a

serious cause of maladies in the 21st century.

DM is divided into three main types: Type I, Type II and Gestational

diabetes.

Type II diabetes mellitus (T2DM) accounts for more than 90% of all

diabetic cases.

Extended period of hyperglycemia causes irreversible damage to

the eyes, kidneys, nerves and heart.

3rd Annual Internationalon Pharmaceutical Sciences, 2-5 May 2016 Conference, Athens

* 2012

* 2014

*2030

1.5 million deaths were directly caused by

diabetes.

347 million diabetic cases have been

diagnosed worldwide.

Estemaited to be the 7th leading cause of

death.

World Health Organization Global Status

Report on Non Communicable Diseases 2015

3rd Annual Internationalon Pharmaceutical Sciences, 2-5 May 2016 Conference, Athens

Oral Hypoglycemic agents

Sulfonylurea

First generation

Tolbutamide

Sulfonylurea

Second generation

Gliclazide

Sulfonylurea

Third generation

Glimepride

Biguanides

Metformine

Increasing insulin release from β islet cells.

Reduce excessive

hepatic glucose

production

3rd Annual Internationalon Pharmaceutical Sciences, 2-5 May 2016 Conference, Athens

5

Hypoglycemia GIT

disturbance

Weight

gain Hypersensetivity

3rd Annual Internationalon Pharmaceutical Sciences, 2-5 May 2016 Conference, Athens

Reactive Unit

Homing Unit

Streptozotocin

3rd Annual Internationalon Pharmaceutical Sciences, 2-5 May 2016 Conference, Athens

Must have an aromatic ring

next to sulfoxide

Should have a substituent at the

para position enhance glycemic

activity

Has some size constrains

N-propyl to N-hexyl are most potent

7

3rd Annual Internationalon Pharmaceutical Sciences, 2-5 May 2016 Conference, Athens

3rd Annual Internationalon Pharmaceutical Sciences, 2-5 May 2016 Conference, Athens

9

-40

-30

-20

-10

0

10

20

30

40

0 30 60 90 120 150 180

Ch

ange

in b

loo

d g

luco

se le

vel

(%)

Time (min) -40

-30

-20

-10

0

10

20

30

40

0 30 60 90 120 150 180

Chan

geinbloodglucoselevel

(%)

Time(min)

Negtive Control

Compound 8b 60mg/kg b.wt

Compound 8a 60mg/kg b.wt

Compound 8c 60mg/kg b.wt

Glimepride 1mg/kg b.wt

-40

-30

-20

-10

0

10

20

30

40

0 30 60 90 120 150 180

Chan

geinbloodglucoselevel

(%)

Time(min)

Negtive Control

Compound 8b 60mg/kg b.wt

Compound 8a 60mg/kg b.wt

Compound 8c 60mg/kg b.wt

Glimepride 1mg/kg b.wt

-40

-30

-20

-10

0

10

20

30

40

0 30 60 90 120 150 180 Chan

geinbloodglucoselevel

(%)

Time(min)

Negtive Control

Compound 8b 60mg/kg b.wt

Compound 8a 60mg/kg b.wt

Compound 8c 60mg/kg b.wt

Glimepride 1mg/kg b.wt

-40

-30

-20

-10

0

10

20

30

40

0 30 60 90 120 150 180

Chan

geinbloodglucoselevel

(%)

Time(min)

Negtive Control

Compound 8b 60mg/kg b.wt

Compound 8a 60mg/kg b.wt

Compound 8c 60mg/kg b.wt

Glimepride 1mg/kg b.wt

-40

-30

-20

-10

0

10

20

30

40

0 30 60 90 120 150 180

Chan

geinbloodglucoselevel

(%)

Time(min)

Negtive Control

Compound 8b 60mg/kg b.wt

Compound 8a 60mg/kg b.wt

Compound 8c 60mg/kg b.wt

Glimepride 1mg/kg b.wt

-40

-30

-20

-10

0

10

20

30

40

0 30 60 90 120 150 180

Chan

geinbloodglucoselevel

(%)

Time(min)

Negtive Control

Compound 8b 60mg/kg b.wt

Compound 8a 60mg/kg b.wt

Compound 8c 60mg/kg b.wt

Glimepride 1mg/kg b.wt -60

-50

-40

-30

-20

-10

0

10

20

30

40

0 30 60 90 120 150 180

Ch

ange

in b

loo

d g

luco

se le

vel (

%)

Time (min) -60

-50

-40

-30

-20

-10

0

10

20

30

40

0 30 60 90 120 150 180

Chan

geinblood

glucoselevel(%)

Time(min)

ChartTitle

Neg veControl

Compound8b60mg/kgb.wt

Compound8b30mg/kgb.wt

Compound8b7.5mg/kgb.wt

Glimepride1mg/kgb.wt

-60

-50

-40

-30

-20

-10

0

10

20

30

40

0 30 60 90 120 150 180

Chan

geinblood

glucoselevel(%)

Time(min)

ChartTitle

Neg veControl

Compound8b60mg/kgb.wt

Compound8b30mg/kgb.wt

Compound8b7.5mg/kgb.wt

Glimepride1mg/kgb.wt

-60

-50

-40

-30

-20

-10

0

10

20

30

40

0 30 60 90 120 150 180

Chan

geinblood

glucoselevel(%)

Time(min)

ChartTitle

Neg veControl

Compound8b60mg/kgb.wt

Compound8b30mg/kgb.wt

Compound8b7.5mg/kgb.wt

Glimepride1mg/kgb.wt

-60

-50

-40

-30

-20

-10

0

10

20

30

40

0 30 60 90 120 150 180

Chan

geinblood

glucoselevel(%)

Time(min)

ChartTitle

Neg veControl

Compound8b60mg/kgb.wt

Compound8b30mg/kgb.wt

Compound8b7.5mg/kgb.wt

Glimepride1mg/kgb.wt

-60

-50

-40

-30

-20

-10

0

10

20

30

40

0 30 60 90 120 150 180 Ch

angeinblood

glucoselevel(%)

Time(min)

ChartTitle

Neg veControl

Compound8b60mg/kgb.wt

Compound8b30mg/kgb.wt

Compound8b7.5mg/kgb.wt

Glimepride1mg/kgb.wt

-60

-50

-40

-30

-20

-10

0

10

20

30

40

0 30 60 90 120 150 180

Chan

geinblood

glucoselevel(%)

Time(min)

ChartTitle

Neg veControl

Compound8b60mg/kgb.wt

Compound8b30mg/kgb.wt

Compound8b7.5mg/kgb.wt

Glimepride1mg/kgb.wt

3rd Annual Internationalon Pharmaceutical Sciences, 2-5 May 2016 Conference, Athens

Conclusion

Chloro-substituted glycosylated sulfonylurea prove to be potent hypoglycemic

agents. (Molecules 2015)

Importance of these novel class as a potential antihyperglycemic agents

Future work synthesis of more potent derivatives

3rd Annual Internationalon Pharmaceutical Sciences, 2-5 May 2016 Conference, Athens

Thank You

Dr Ghadeer Suaifan

3rd Annual Internationalon Pharmaceutical Sciences, 2-5 May 2016 Conference, Athens