‫من طلب العلم تک ّفل اللَّه برزقه‬

Synthesis of 2-((3-(1H-benzo[d]imidazol-2-yl)quinolin-2-yl)thio)-N-
arylacetamide derivatives as new alpha-glycosidase inhibitors in the
treatment of diabetes

Supervisors:
Dr. Massoud Amanlou
Dr. Mohammad Mahdavi
By:
Ali Davodi
Contents:
▪ Introduction
▪ Types of diabetes
▪ Alpha-glucosidase inhibitor
▪ Development alpha glucose inhibitors
▪ experimental section
▪ NMR spectroscopy
▪ inhibitory activity of the compounds
▪ Docking study

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Introduction
Global prevalence

https://publichealthupdate.com/diabetes-around-the-world-in-2021-key-global-findings/ 5/39
U.S. Prevalence

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https://www.cdc.gov/diabetes/data/statistics-report/index.html
Prediabetes

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https://www.cdc.gov/diabetes/data/statistics-report/index.html
Types of diabetes
Diabetes

▪ Definition: A metabolic disease in which the body’s inability to produce any or

enough insulin causes elevated levels of glucose in the blood.

▪ Types of diabetes:

Lancet (London, England) vol. 375,9733 (2010): 2215-22.

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Gestational diabetes mellitus (GDM):
▪ Having diabetes during pregnancy
▪ Having gestational diabetes puts you at risk for diabetes type 2
▪ Giving birth to a baby >9 lbs also puts you at risk for type 2
▪ 18 out of every 100 pregnant females will develop GDM

Gestational diabetes mellitus. Nat Rev Dis Primers 5, 47 (2019)

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Type 1 diabetes
▪ Also known as juvenile diabetes
▪ Usually diagnosed in children and young adults
▪ When body’s own immune system destroys the insulin producing cells of the
pancreas – beta cells – which produce insulin
▪ Only 5% of people have this disease
▪ Body does not produce insulin
▪ Is not preventable
▪ Causes?
▪ Predisposition to diabetes – genetics - and something (i.e. weather, virus ...
etc ) in environment triggers the disease

Diabetes Care 2014;37(7):2034–2054 11/39

Type 2 diabetes:
▪ Most common form of diabetes – about 90% of cases
▪ Used to be called adult onset, non insulin dependent diabetes
▪ Body produces insulin, but does not use it properly
▪ glucose doesn’t move into cells, they pile up in the bloodstream
▪ when they do occur are often ignored because they may not seem serious

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Ann Intern Med, 163(11), pp.861-868.
Complications for uncontrolled Type 2 diabetes :

Journal of diabetes research 2018 (2018). 13/39

Alpha glucosidase
inhibitor
Alpha glucosidase enzyme
▪ are oral anti-diabetic drugs used for diabetes
mellitus type 2 that work by preventing the
digestion of carbohydrates .Carbohydrates are
normally converted into simple sugars
(monosaccharides) by alpha-glucosidase enzymes
present on cells lining the intestine, enabling
monosaccharides to be absorbed through the
intestine. Hence, alpha-glucosidase inhibitors
reduce the impact of dietary carbohydrates on
blood sugar.

J. Med. Chem. 2012, 55, 23, 10345–10346 15/39

Alpha glucosidase inhibitor mechanism of action:

Scientific reports 6.1 (2016): 1-13. 16/39

Alpha glucosidase inhibitor mechanism of action:

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Clin Invest Med. 1995 Aug;18(4):303-11. PMID: 8549017.
Alpha glucosidase inhibitors drugs:

Miglitol

Acarbose Voglibose

https://www.drugs.com/drug-class/alpha-glucosidase-inhibitors 18/39
Cost of Diabetes (US):

Updated 2021:

$327 billion : Total costs of diagnosed diabetes in the united states

in 2021

Medical costs for people with diabetes are More than twice as high
60% risk of only deat for adults with diabetes

https://www.cdc.gov/diabetes/data/statistics-report/index.html
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Development alpha
glucose inhibitors
drug
Diphenyl imidazole derivatives as alpha glucosidase inhibitors
Acarbose
Ic50:750

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Quinoline derivatives as alpha glucosidase inhibitors
Acarbose
Ic50:750

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Structural Hybridization: A Useful Tool in the Design of New Drug

N
N O Cl
NH H N
N OH
Br
O
S
A, IC50 = 37.94 ± 1.86 µM N
N
D, IC50 = 9.1 ± 2.3 µg/mL H

H O O
N N G, IC50 = 80.0 ± 2.0 µM
N
N H OH

O
O O
E, IC50 = 10.6 ±1.4 µg/mL O
B, IC50 = 2.09 ± 0.04 µM
S
N
N H
N
O N
O O HO
H
N O N N HN N OH
N H, IC50 = 70.1 ± 0.6 µM
OH
F, IC50 = 2.60 ± 0.01 µM

C, IC50 = 0.71 ± 0.02 µM

N
Newly designed compound
N
H H
N
N S n
O R
experimental section
Synthesis of diphenyl imidazole thio quinoline N-phenylacetamide
O 1-DMF/POCL 3,0°C Na2S
O O
N 2-D,80-90°C,5h DMF,rt,1h N SH
H N Cl

O
H2 N Na2S2O5 N

DMF, 5h N
H2 N H
N SH
N SH
O O
H
Cl N Cl
Cl n
NH2
R n
DMF,rt,2h n=0,1
R
n=0,1

HN

O N
H K2CO3
N N Cl
n N S
N DMF,rt,2h
H nN
R
H R 25/39
N SH O
n=0,1 n=0,1
Derivatives of diphenyl imidazole thio quinoline N-phenylacetamide
N
NH

R NH S N
O
9i 4-Nitrophenyl 453 188-190 oC
Compound R Mw m.p
9j 2-Methylphenyl 424 180-182 oC
9a Phenyl 410 180-182 C o

9k 4-Methylphenyl 424 179-181 oC

9b 2-Fluorophenyl 428 183-185 oC
9l 4-Methoxyphenyl 440 181-183oC
9c 4-Fluorophenyl 428 189-191 oC
9m 4-Ethylphenyl 438 191-193oC
9d 3-Chlorophenyl 444 190-192 oC 9n 2,3-Dimethylphenyl 438 178-180 oC
9e 4-Chlorophenyl 444 185-187 oC 9o 2,6-Dimethylphenyl 438 185-187 oC

9f 2-Bromophenyl 489 181-183 oC 9p Naphthalene 535 185-187 oC

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9g 4-Bromophenyl 489 185-187 oC 9q Benzyl 500 182-184 oC
NMR spectroscopy
1
H-NMR spectroscopy

12- H-Aromatic

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13
C-NMR spectrum

18- H-Aromatic

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inhibitory activity of the compounds
Compound R IC50 (μM) [a] Concentrations of Precipitation (µM)

9a Phenyl 30.2 ± 0.4 ≥ 200

9b 2-Fluorophenyl 61.3 ± 0.4 ≥ 200

9c 4-Fluorophenyl 13.5 ± 0.6 ≥ 200

9d 4-Chlorophenyl 3.2 ± 0.3 ≥ 200

9e 3-Chlorophenyl 110.4 ± 0.2 ≥ 200

9f 2-Bromophenyl 23.4 ± 0.2 ≥ 200

9g 4-Bromophenyl 185.0 ± 0.3 ≥ 200

9h 2,6-Dichlorophenyl 100.8 ± 0.1 ≥ 200

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9i 4-Nitrophenyl 19.7 ± 0.2 ≥ 200
inhibitory activity of the compounds
Compound R IC50 (μM) [a] Concentrations of Precipitation (µM)

9j 2-Methylphenyl 16.5 ± 0.4 ≥ 200

9k 4-Methylphenyl 12.3 ± 0.2 ≥ 200

9l 4-Methoxyphenyl 5.7± 0.3 ≥ 200

9m 4-Ethylphenyl 55.6 ± 0.2 ≥ 200

9n 2,3-Dimethylphenyl 9.8 ± 0.5 ≥ 200

9o 2,6-Dimethylphenyl 147.0 ± 0.2 ≥ 200

9p Naphthalene 17.7 ± 0.8 ≥ 200

9q Benzyl 750 < ≥ 200

9r 4-Fluorobenzyl 33.0 ± 0.1 ≥ 200

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Acarbose - 750.0 ± 5.0 -
Docking study
Cl
O
N S
N
H
N

HN

2-((3-(1H-benzo[d]imidazol-2-yl)quinolin-2-yl)thio)-N-(4-chlorophenyl)acetamide (9d)

IC50 (µM)=3.2

O OH
HO

O OH
OH HO
OH
HO O O OH
OH
HO N OH
H
OH OH

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IC50 (µM)=750
Thank you for your
attention
😉
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