SEMINAR HÓA DƯỢC

Thiết kế, tổng hợp và đánh giá hoạt tính sinh học của
acid (E)-3-(4-methansulfonylphenyl)-2-(aryl)acrylic
là chất ức chế kép cyclooxygenase và lipoxygenase
GV: ThS. Nguyễn Thị Yến Nhi
SV: 19140343-Kim Minh Dương
Đặng Thị Hiền Diệu
19140306-Ngô Thị Thanh Bình
19140333-Nguyễn Lê Phương Đình
TỔNG QUAN
 TỔNG QUAN
MeO2S
HO NH2
N N
O
CO2H S
O
O Cl
Rofecoxib (1) Licofelone (2) Zileuton (3)

OH MeO2S
O
t-Bu
HO O S O
OH
N R1
HO R2
HO OH
t-Bu
O
Quercetine (4) S-2474 (5) 6a, R1 = n-alkyl, R2 = phenyl
6b, R1 = phenyl, R2 = n-alkyl

Moreau A., Chen Q. H., Rao P. P., Knaus E. E., Design, synthesis, and biological evaluation of (E)-3-(4-methanesulfonylphenyl)-2-(aryl) acrylic acids as dual
inhibitors of cyclooxygenases and lipoxygenases, Bioorganic & medicinal chemistry, 14(23), 7716-7727, 2006.
 ĐIỀU CHẾ
Phản ứng ngưng tụ Perkin
CHO R1
MeO2S R1
R2
+ Et3N, Ac2O R2
90°C, 12h
SO2Me CO2H
CO2H
4-methylsufonylbenzaldehyde (7) Acid phenylacetic (8)
Acid (E)-3-(4-methanesulfonylphenyl)-2-
phenylacrylic (9)
9a, R1=R2=H
9b, R1=Br, R2=H
9c, R1=F, R2=H
10% w/v dd NaOH,
9d, R1=OH, R2=H 25ºC, 5h
9e, R1=OAc, R2=H
9f, R1=Ome, R2=H
9g, R1=NHAc, R2=H (from 8 (R1=NH2))
9h, R1=H, R2=Br
Moreau A., Chen Q. H., Rao P. P., Knaus E. E., Design, synthesis, and biological evaluation of (E)-3-(4-methanesulfonylphenyl)-2-(aryl) acrylic acids as dual
inhibitors of cyclooxygenases and lipoxygenases, Bioorganic & medicinal chemistry, 14(23), 7716-7727, 2006.
 ĐIỀU CHẾ
Phản ứng ghép mạch Suzuki R1 11a, R1= OPr-i, R2= H
MeO2S
4
biphenyl-4-yl 11b, R1= R2= F
Pd(PPh3)4, Na2CO3, DME 3 11c, R1= SMe, R2= H
R2
Hồi lưu,12h 12a, R1= OPr-i, R2= H
MeO2S CO2H biphenyl-3-yl 12b, R1= R2= F
4 R2
Br 12c, R1= SMe, R2= H
3

+ R1 B(OH)2

CO2H
SO2Me
9b (4-Br) 10, R1= H, F, OPr-i, SMe MeO2S
9h (3-Br) 4
R2= H, F 1) Pd(PPh3)4, Na2CO3, biphenyl-4-yl 11d, R1= SO2Me, R2= H
3
DME, hồi lưu, 12h
2) Oxone , MeOH, THF,
biphenyl-3-yl 12d, R1= SO2Me, R2= H
25°C, 15h CO2H

Moreau A., Chen Q. H., Rao P. P., Knaus E. E., Design, synthesis, and biological evaluation of (E)-3-(4-methanesulfonylphenyl)-2-(aryl) acrylic acids as dual
inhibitors of cyclooxygenases and lipoxygenases, Bioorganic & medicinal chemistry, 14(23), 7716-7727, 2006.
 MeO2S
4
R
KẾT QUẢ 3

CO2H

Dữ liệu thử nghiệm in vitro ức chế enzyme COX-1/COX-2 và 5-LOX/15-LOX của

acid (E)-2-(phenyl hoặc biphenyl)-3-(4-methansulfonylphenyl)acrylic (9, 11 và 12)

Moreau A., Chen Q. H., Rao P. P., Knaus E. E., Design, synthesis, and biological evaluation of (E)-3-(4-methanesulfonylphenyl)-2-(aryl) acrylic acids as dual
inhibitors of cyclooxygenases and lipoxygenases, Bioorganic & medicinal chemistry, 14(23), 7716-7727, 2006.
 KẾT QUẢ

Acid (E)-2-[4-(2,4-Difluorophenyl)phenyl]-3-(4-methansulfonylphenyl)acrylic (11b)

(hình cầu và que) được gắn vào vị trí hoạt động của COX-2 chuột.

Moreau A., Chen Q. H., Rao P. P., Knaus E. E., Design, synthesis, and biological evaluation of (E)-3-(4-methanesulfonylphenyl)-2-(aryl) acrylic acids as dual
inhibitors of cyclooxygenases and lipoxygenases, Bioorganic & medicinal chemistry, 14(23), 7716-7727, 2006.
 KẾT QUẢ

Acid (E)-2-[4-(2,4-difluorophenyl)phenyl]-3-(4-methansulfonylphenyl)acrylic (11b) (hình cầu

và que) được gắn vào vị trí hoạt động của 15-LOX đậu tương.
Moreau A., Chen Q. H., Rao P. P., Knaus E. E., Design, synthesis, and biological evaluation of (E)-3-(4-methanesulfonylphenyl)-2-(aryl) acrylic acids as dual
inhibitors of cyclooxygenases and lipoxygenases, Bioorganic & medicinal chemistry, 14(23), 7716-7727, 2006.
 KẾT QUẢ

Acid (E)-2-(4-Hydroxyphenyl)-3-(4-methansulfonylphenyl)acrylic (9d)

(hình cầu và que) được gắn vào vị trí hoạt động của 15-LOX đậu tương

Moreau A., Chen Q. H., Rao P. P., Knaus E. E., Design, synthesis, and biological evaluation of (E)-3-(4-methanesulfonylphenyl)-2-(aryl) acrylic acids as dual
inhibitors of cyclooxygenases and lipoxygenases, Bioorganic & medicinal chemistry, 14(23), 7716-7727, 2006.
 KẾT QUẢ
MeO2S R

H CO2H

Thử nghiệm in vivo về hoạt tính kháng viêm và giảm đau của acid (E)-2-(4-hydroxyphenyl)-3-(4-
methansulfonylphenyl)acrylic (9d), acid (E)-2-(4- acetylaminophenyl)-3 -(4-methansulfonylphenyl)acrylic (9g) và
acid (E)-2-[4-(2,4-diflophenyl)phenyl]-3-(4-methansulfonylphenyl)acrylic (11b).

Moreau A., Chen Q. H., Rao P. P., Knaus E. E., Design, synthesis, and biological evaluation of (E)-3-(4-methanesulfonylphenyl)-2-(aryl) acrylic acids as dual
inhibitors of cyclooxygenases and lipoxygenases, Bioorganic & medicinal chemistry, 14(23), 7716-7727, 2006.
KẾT LUẬN