Synthesis and antiviral activity of new indole-based heterocycles

Article abstract of DOI:10.1248/cpb.58.1529

New 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine and 1,3-thiazole derivatives incorporating indole nucleus were prepared using 3-acetylindole as precursor and evaluated for their antiviral activity against herpes simplex type 1 (HSV-1).

Full text of DOI:10.1248/cpb.58.1529

November 2010
Note
Chem. Pharm. Bull. 58(11) 1529—1531 (2010)
1529
Synthesis and Antiviral Activity of New Indole-Based Heterocycles
Hassan ABDEL-GAWAD,*,a Hanan Ahmed MOHAMED,a Kamal Mohamed DAWOOD,b and
c
Farid Abdel-Rahem BADRIA
a Applied Organic Chemistry Department, National Research Centre; Dokki, Giza 12622, Egypt: b Chemistry Department,
Faculty of Science, Cairo University; Giza 12613, Egypt: and c Pharmacognosy Department, Faculty of Pharmacy,
Mansoura University; Mansoura 35516, Egypt. Received May 31, 2010; accepted August 2, 2010
New 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine and 1,3-thiazole derivatives incorporating indole nucleus were
prepared using 3-acetylindole as precursor and evaluated for their antiviral activity against herpes simplex type
1 (HSV-1).
Key words 3-aetylindole; 1,3-thiazole; hydrazonoyl halide; antiviral activity; herpes simplex type 1
Indole, the potent basic pharmacodynamic nucleus has
Treatment of the salt 3 with hydrazine hydrate in aqueous
been reported to possess a wide variety of biological proper- ethanol afforded the corresponding 4-amino-1,2,4-triazole-5-
ties such as antiviral agents which inhibits of Herpes Sim- thione 4, subsequent treatment of 4 with phenacyl bromide in
plex Virus replication,1—3) Fungicidal,4) anti-inflammatory,5) dry ethanol and in the presence of a catalytic amount of tri-
anticonvulsant,6) and antibacterial.7) Other compounds de- ethylamine afforded 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine
rived from 3-acetylindoles used in the treatment of gastroin- derivative 5 in good yield. The reaction of potassium salt 3
testinal,8) antiproliferative agent,9,10) potential antiviral with phenacyl bromide or hydrazonoyl chlorides 7a, b in
agents,11) cardiovascular and central nervous system (CNS) aqueous ethanol led to the formation of 1-phenyl-N-(4-
disorders,12) and also used as Herpes simplex type 1 (HIV-1) phenyl-2-thioxothiazol-3(2H)-yl)-1H-pyrazole-3-carboxam-
1
integrase inhibitors.13) Encouraged by these observations and ides 6 and 8a, b, respectively (Chart 1). The H-NMR spec-
in continuation of our previous work in the synthesis of bio- trum of compound 6 contained a new singlet, not present in
logically active heterocycles,14—17) we synthesized newer het- the spectrum of the starting material, at dϭ7.03 ppm, attrib-
1
erocyclic indole derivatives with the hope to get better antivi- uted to CH of the 2-thioxothiazole ring, whereas the H-
ral agents.
NMR spectrum of compound 5 contained a singlet signal at
dϭ5.25 ppm corresponding to the two protons of –S–CH2 in
the thiadiazine ring.
Results and Discussion
Treatment of 5-(1H-indol-3-yl)-1-phenyl-1H-pyrazole-3-
The target compounds 11—14 were obtained by reaction
carbohydrazide 118) with tetrachlorophthalic anhydride in of equimolar quantities of thiosemicarbazide 919) with 4-
refluxing glacial acetic acid afforded imide 2 in excellent methoxyphenacyl bromide 10, hydrazonoyl chlorides 7a—c,
yield. While, the reaction of nucleophile 1 with carbon disul- chloroacetic acid or chloroacetic acid and 4-flurobenzalde-
fide resulted in the formation of the potassium salt of hyde. The alternative synthesis of 5-(4-fluorobenzylidene)-
hydrazinecarbodithioate 3 in moderate yield (Chart 1).
thiazolidin-4-one derivative 14 has been proceeded via reac-
Chart 1
∗ To whom correspondence should be addressed. e-mail: abdelgawadhassan@hotmail.com
© 2010 Pharmaceutical Society of Japan

1530
Vol. 58, No. 11
Chart 2
Table 1. Results of in Vitro Anti-herpes Simplex-1 Virus (HSV-1) and thiazoles 8a, b and thiazolidin-4-one 13 showed no antiviral
Cytotoxicity
activity. But 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine 5; thia-
zoles 11; 12a, b and 5-(4-fluorobenzylidene)thiazolidin-4-
c)
Compound
% Reductiona)
MACb)
CD50
one 14 showed a weak to moderate activity in reducing the
number of plaques at the same concentration (0.1 mg/ml).
Compounds 12c and 2 were the best among the tested com-
pounds; they reduced the number of viral plaques of herpes
simplex type-1 (HSV-1) by 62% and 45% respectively with
respect to Aphidicolin.
2
4
5
6
8a
8b
11
12a
45
None
35
None
None
None
28
17
27
62
None
37
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.005
0.05
0.02
0.01
0.03
0.03
0.03
0.04
0.03
0.04
0.18
0.03
0.05
0.2
Experimental
Chemistry All melting points were taken on Electrothermal IA 9000
series digital melting point apparatus. Elemental analytical data (in accord
with the calculated values) were obtained from the microanalytical unit, Na-
tional Research Centre, Dokki, Giza, Egypt. The IR spectra (KBr) were
12b
12c
13
14
1
recorded on a Shimadzu CVT-04 spectrophotometer. The H-NMR spectra
Aphidicolind)
100
were recorded at 270 MHz on a Varian EM-360 spectrometer using tetram-
ethylsilane (TMS) as an internal standard. Chemical shift (d) values are
given in parts per million. The mass spectra were determined using a Varian
MAT CH-5 spectrometer (70 eV). 5-(1H-Indol-3-yl)-1-phenyl-1H-pyrazole-
a) Percent (%) reduction in the number of viral plaques. b) Minimum antiviral
concentration (in mg/ml). c) Cytotoxicity (compound concentration caused 50% loss
of the monolayer present around the viral plaques) (in mg/ml). d) Positive antiviral
control.
3-carbohydrazide 118)
; 2-(1-(1H-indol-3-yl)ethylidene)hydrazinecarbothio-
amide 919) and hydrazonoyl chlorides 723) were prepared according to the
reported procedures.
tion of thiazolidin-4-one 13 with 4-flurobenzaldehyde in gla-
cial acetic acid and presence of excess anhydrous sodium
acetate (Chart 2).
5-(1H-Indol-3-yl)-1-phenyl-N-(4,5,6,7-tetrachloro-1,3-dioxoisoindolin-
2-yl)-1H-pyrazole-3-carboxamide (2)24) Yield 87%; mp Ͼ300 °C; IR
1
(KBr) nmax/cmϪ1 3403, 3138 (2NH), 1781, 1736, 1656 (3CϭO); H-NMR
(DMSO-d6) d: 5.85 (s, 1H, CH-pyrazole), 7.45—8.61 (m, 9H, Ar-H), 12.31,
13.67 (2s, 2H, 2NH, D2O-exchangeable); MS m/z (%): 585 (Mϩ, 2), 59
(100).
1
The H-NMR spectra data were also consistent with the
assigned structures; thiazole CH proton of 11 was observed
as a broad singlet at about d 6.99 ppm, thiazolidinone CH2
protons of 13 appeared at d 3.93 ppm and all the other aro-
matic and aliphatic protons were observed at the expected
regions.
In-Vitro Anti-herpes Simplex-1 Virus (HSV-1) and Cy-
totoxicity Assays All new compounds were tested for their
possible antiviral activity against herpes simplex type 1
(HSV-1) grown on Vero African green monkey kidney
cells.20—22) Aphidicolin was used as a positive control.
From the results obtained in Table 1, we can conclude that,
Potassium 2-[5-(1H-Indol-3-yl)-1-phenyl-1H-pyrazole-3-carbonyl]hy-
drazinecarbodithioate (3)25) Yield 76%; IR (KBr) nЈϭ3380—3028
(3NH), 1653 (CϭO) cmϪ1
.
3-[5-(1H-Indol-3-yl)-1-phenyl-1H-pyrazol-3-yl]-4-amino-1H-1,2,4-tri-
azole-5(4H)-thione (4)25) Yield 38%; mp 216—218 °C; IR (KBr) nmax
/
cmϪ1: 3393—3291 (NH2, 2NH), 1496 (CϭS); 1H-NMR (DMSO-d6) d: 6.02
(s, 2H, NH2, D2O-exchangeable), 7.03 (s, 1H, CH-pyrazole), 7.21—7.48 (m,
9H, Ar-H), 11.57, 14.00 (2s, 2H, 2NH, D2O-exchangeable); MS m/z (%):
373 (Mϩ, 9), 359 (100).
3-[5-(1H-Indol-3-yl)-1-phenyl-1H-pyrazol-3-yl]-6-phenyl-7H-1,2,4-
1
triazolo[3,4-b]-1,3,4-thiadiazine (5)25) Yield 59%; mp 196—198 °C; H-
NMR (DMSO-d6) d: 6.02 (s, 2H, NH2, D2O-exchangeable), 5.25(s, 2H, S-
compounds 1,2,4-triazole-5(4H)-thione 4, 2-thioxothiazole 6, CH2), 7.03 (s, 1H, CH-pyrazole), 7.23—8.15 (m, 14H, Ar-H), 11.57, (s, H,

November 2010
1531
NH, D2O-exchangeable); MS m/z (%): 493 (Mϩ, 1.7), 105 (100).
5-(1H-Indol-3-yl)-1-phenyl-N-(4-phenyl-2-thioxothiazol-3(2H)-yl)-1H-
pyrazole-3-carboxamide (6)25) Yield 48%; mp 194—195 °C; 1H-NMR
(DMSO-d6) d: 5.25 (s, H, pyrazole-CH), 7.03 (s, H, CH, thiazole-CH),
7.24—8.14 (m, 14H, Ar-H), 11.56 (s, H, NH, D2O-exchangeable); MS m/z
(%): 473 (Mϩ, 21), 359 (100).
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indol-3-yl)-1-phenyl-1H-pyrazole-3-carbohydrazide (8a)25 Yield 50%;
mp 257—258 °C; IR (KBr) nmax/cmϪ1 3284 (NH), 1666, 1602 (2CϭO); 1H-
NMR (DMSO-d6) d: 2.56 (s, 3H, CH3), 7.03 (s, 1H, CH-pyrazole), 7.16—
8.08 (m, 13H, Ar-H), 11.30, 11.49 (2s, 2H, 2NH, D2O-exchangeable); MS
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N؅-[5-Acetyl-3-(4-fluorophenyl)-1,3,4-thiadiazol-2(3H)-ylidene]-5-(1H-
indol-3-yl)-1-phenyl-1H-pyrazole-3-carbohydrazide (8b)25) Yield 43%;
mp 273—274 °C; IR (KBr) nmax/cmϪ1 3387 (NH), 1679, 1605 (2CϭO); 1H-
NMR (DMSO-d6) d: 2.54 (s, 3H, CH3), 7.01 (s, 1H, CH-pyrazole), 7.17—
8.01 (m, 13H, Ar-H), 11.29, 11.56 (2s, 2H, 2NH, D2O-exchangeable); MS
m/z (%): 573 (Mϩ, 1.2), 91 (100).
2-{2-[1-(1H-Indol-3-yl)ethylidene]hydrazinyl}-4-(4-methoxyphenyl)thia-
zole (11)26) Yield 62%; mp 241—242 °C; IR (KBr) nmax/cmϪ1 3388, 3343
(2NH); 1H-NMR (DMSO-d6) d: 2.51 (s, 3H, CH3), 4.44 (s, 3H, OCH3), 6.99
(s, 1H, CH-thiazole), 7.17—8.12 (m, 8H, Ar-H), 8.46, 11.52 (2s, 2H, 2NH,
D2O-exchangeable); MS m/z (%): 362 (Mϩ, 100).
2-{2-[1-(1H-Indol-3-yl)ethylidene]hydrazinyl}-4-methyl-5-(phenyl-
diazenyl)thiazole (12a)27) Yield 44%; mp 240—242 °C; IR (KBr) nmax
/
cmϪ1 3424, 3239 (2NH); 1H-NMR (DMSO-d6) d: 2.50 (s, 3H, CH3), 2.59 (s,
3H, CH3), 6.59—8.52 (m, 9H, Ar-H), 10.54, 11.79 (2s, 2H, 2NH, D2O-ex-
changeable); MS m/z (%): 374 (Mϩ, 100).
2-{2-[1-(1H-Indol-3-yl)ethylidene]hydrazinyl}-5-[(4-bromophenyl)di-
azenyl]-4-methylthiazole (12b)27) Yield 53%; mp 260—261 °C; IR (KBr)
n
max/cmϪ1 3426, 3236 (2NH); 1H-NMR (DMSO-d6) d: 2.50 (s, 3H, CH3),
2.59 (s, 3H, CH3), 6.89—8.32 (m, 8H, Ar-H), 10.54, 11.79 (2s, 2H, 2NH,
D2O-exchangeable); MS m/z (%): 454, 453 (Mϩ, 42, 41).
2-{2-[1-(1H-Indol-3-yl)ethylidene]hydrazinyl}-5-((4-chlorophenyl)di-
azenyl)-4-methylthiazole (12c)27) Yield 56%; mp 258—259 °C; IR (KBr)
n
max/cmϪ1 3417, 3230 (2NH); 1H-NMR (DMSO-d6) d: 2.51 (s, 3H, CH3),
2.60 (s, 3H, CH3), 6.87—8.30 (m, 8H, Ar-H), 10.35, 11.71 (2s, 2H, 2NH,
D2O-exchangeable); MS m/z (%): 408 (Mϩ, 62), 91(100).
2-{[1-(1H-Indol-3-yl)ethylidene]hydrazono}thiazolidin-4-one
(13)16)
Yield 67%; mp 280—282 °C; IR (KBr) nmax/cmϪ1 3377, 3315 (2NH), 1751
1
(CϭO); H-NMR (DMSO-d6) d: 2.54 (s, 3H, CH3), 3.93 (s, 2H, thiazilidi-
none-CH2), 7.20—8.49 (m, 4H, Ar-H), 11.57, 11.93 (2s, 2H, 2NH, D2O-ex-
changeable); MS m/z (%): 272 (Mϩ, 27), 98 (100).
2-{[1-(1H-Indol-3-yl)ethylidene]hydrazono}-5-(4-fluorobenzylidene)thi-
azolidin-4-one (14). Method A; Method B16) Yield A: 57%; B: 63%; mp
298—299 °C; IR (KBr) nmax/cmϪ1 3415, 3040 (2NH), 1713 (CϭO); 1H-
NMR (DMSO-d6) d: 2.51 (s, 3H, CH3), 3.90 (s, 1H, NH, D2O-exchange-
able), 7.20—7.85 (m, 8H, Ar-H), 8.42 (s, 1H, CHϭN–), 12.00 (s, H, NH,
D2O-exchangeable); MS m/z (%): 378 (Mϩ, 0.7), 236 (100).
Antiviral and Cytotoxicity Assays The antiviral activity was deter-
mined applying our reported method.28)
28) Abdel-Aziz H. A., Abdel-Wahab B. F., Badria F. A., Arch. Pharm.
(Weinheim), 343, 152—159 (2010).
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