Menu

Natural H H S 58% 8 4-NO2

0 Comment

Natural
plants: There are many plants whose extracts show
anti-dengue property.

Carica
papaya is a very common plant whose leaf extract is used in
this disease. It was used in a mid-age patient where it was found that 5 days treatment
of the extract led to increase in WBC as well as platelet count. Other plants
extrants which have significant role in the treanment of dengue are listed in the
table below.

We Will Write a Custom Essay Specifically
For You For Only $13.90/page!


order now

 

SAR
of methionine–proline anilides:

Two methionine–proline anilides have been found to
inhibit NS2B-NS3
efficiently. Their Ki
values are found to be 4.9 and 10.5 respectively.

 

Table 1 Chemical structures of dipeptides and their activities
against DENV 2 NS2B-NS3 protease.

Sr. No.

R

X

Z

Ki  (µM)

Remaining activity of DENV 2 NS2B-NS3

1

4-NO2

H

S

4.9

31%

 

2

4-NO2

Boc

S

10.5

45%

 

3

3-NO2

H

S

 

37%

 

4

2-NO2

H

S

 

96%

 

5

H

H

S

 

60%

 

6

4-NO2

H

S

 

36%

 

7

H

H

S

 

58%

 

8

4-NO2

H

S(O)

 

71%

 

9

4-NO2

H

S(O)2

 

99%

 

10

4-NO2

H

S

 

103%

 

11

4-NO2

CF3CO

S

 

54%

 

12

4-NO2

No2-Bn

S

 

38%

 

13

4-NO2

MeO-Bn

S

 

90%

 

 

As it can be seen
clearly from the table that no significant change in activity is found if the S
at Z is replaced by S(O)2 but activity got decreased upto 45% when X
group was replaced by Boc but

 replacement with H gave the most potent
compound which decreased the activity for upto 31%. Further if methionine is
replaced by phenylalanine, the activity remains only upto 25% but it has higher
inhibitory concentration (200 µM).

 

1.      X=
H

2.      X=Boc

SAR
of tetrapeptide aldehyde inhibitors:

They started with the following aldehyde derivative
(Ki =5.8 µM) to determine
the pharmacophoric features of the NS3 active site.

Figure 1 A tetrapetide aldehyde derivative

Table 2 Results from different scans (alanine, phenylalanine,
lysine, and proline, D- and N-Me amino acids) and varying the inhibitor

Sr.
No.

Aldehyde
inhibitors

Ki (µM)

1

Bz-Nle-Lys-Arg-Arg-H

5.8

2

Bz-Nle-Lys-Arg-Ala-H

193.0

3

Bz-Nle-Lys-Ala-Arg-H

>500

4

Bz-Nle-Ala-Arg-Arg-H

22.1

5

Bz-Ala-Lys-Arg-Arg-H

5.3

6

Bz-Nle-Lys-Arg-Phe-H

15.9

7

Bz-Nle-Lys-Phe-Arg-H

40.7

8

Bz-Nle-Phe-Arg-Arg-H

15.8

9

Bz-Phe-Lys-Arg-Arg-H

6.8

10

Bz-Nle-Lys-Arg-Lys-H

20.5

11

Bz-Nle-Lys-Lys-Arg-H

41.3

12

Bz-Nle-Lys-Pro-Arg-H

109.0

13

Bz-Nle-Pro-Arg-Arg-H

61.4

14

Bz-Nle-Lys-N-Me-Arg-Arg-H

47.4

15

Bz-Nle-N-Me-Lys-Arg-Arg-H

113.3

16

Bz-N-Me-Nle-Lys-Arg-Arg-H

43.7

17

Bz-Nle-Lys-Arg-D-Arg-H

51.0

18

Bz-Nle-Lys-D-Arg-Arg-H

115.0

19

Bz-Nle-D-Lys-Arg-Arg-H

28.6

20

Bz-D-Nle-Lys-Arg-Arg-H

9.4

21

Bz-Lys-Arg-Arg-H

1.5

22

Bz-Arg-Arg-H

12.0

23

Bz-Nle-Lys-Arg-(p-guanidinyl)Phe-H

2.8

 

When they replaced Arg at
P1 with Lys, They found that the activity of the inhibitor was increased four
times but the activity increased eight fold when they replaced Arg at P2. The
most potent compound was obtained when P1 was replaced with (p-guanidinyl)Phe with Ki = 2.8 µM. When P2 and P3 were replaced
with proline a huge loss in activity was found which indicated that turn
geometry was unfavourable in binding.

            Replacement of P1 gave some active compound but the Ki is not that much good. The
most effective replacement at P1 was fount to be Trp which gave compound with  Ki
=7.5
µM.

Table 3 Effect of modifications in the P1 position of the
tetrapeptide

P1

Ki
(µM)

Phe

15.9

Phg

33.0

homoPhe

>500

(p-Cl)Phe

138.0

(p-CN)Phe

18.6

(p-Me)Phe

6.0

(p-Ph)Phe

11.6

Trp

7.5

 

Phe alone at P1 gave lesser
potent compound as compared to the compound which was obtained by replacing P1
with -(p-guanidinyl)Phe.

x

Hi!
I'm Rick!

Would you like to get a custom essay? How about receiving a customized one?

Check it out