New sulphonamide and carboxamide derivatives of acyclic C-nucleosides of triazolo-thiadiazole and the thiadiazine analogues. Synthesis, anti-HIV, and antitumor activities. Part 2

Article abstract of DOI:10.1080/15257770802271771

A new series of acyclic C-nucleosides 1′,2′-O-isopropylidene-D- ribo-tetritol-1-yl)[1,2,4] triazolo[3,4-b][1,3,4]thiadiazoles bearing arylsulfonamide (5-8) and arylcarboxamide (9-12) residues have been synthesized under microwave irradiation. Thiadiazines 13-15 have been analogously prepared, and upon acid hydrolysis, afforded the free nucleosides 16-18. The new synthesized compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compound 7 was also screened against a panel of tumor cell lines consisting of CD4 human T-cells. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770802271771

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New Sulphonamide and Carboxamide
Derivatives of Acyclic C-Nucleosides of
Triazolo-Thiadiazole and the Thiadiazine
Analogues. Synthesis, Anti-HIV, and
Antitumor Activities. Part 2
Najim A. Al-Masoudi a & Yaseen A. Al-Soud b
a Fachbereich Chemie , Universität Konstanz , Konstanz, Germany
(formerly)
b Department of Chemistry, College of Science , University of Al al-
Bayt , Al-Mafraq, Jordan
Published online: 18 Aug 2008.
To cite this article: Najim A. Al-Masoudi & Yaseen A. Al-Soud (2008) New Sulphonamide and
Carboxamide Derivatives of Acyclic C-Nucleosides of Triazolo-Thiadiazole and the Thiadiazine
Analogues. Synthesis, Anti-HIV, and Antitumor Activities. Part 2, Nucleosides, Nucleotides and Nucleic
Acids, 27:9, 1034-1044, DOI: 10.1080/15257770802271771
To link to this article: http://dx.doi.org/10.1080/15257770802271771
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Nucleosides, Nucleotides and Nucleic Acids, 27:1034–1044, 2008
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770802271771
NEW SULPHONAMIDE AND CARBOXAMIDE DERIVATIVES OF
ACYCLIC C-NUCLEOSIDES OF TRIAZOLO-THIADIAZOLE AND THE
THIADIAZINE ANALOGUES. SYNTHESIS, ANTI-HIV, AND
ANTITUMOR ACTIVITIES. PART 2
Najim A. Al-Masoudi1 and Yaseen A. Al-Soud2
1Fachbereich Chemie, Universita¨t Konstanz, Konstanz, Germany (formerly)
2Department of Chemistry, College of Science, University of Al al-Bayt, Al-Mafraq, Jordan
A
new series of acyclic C-nucleosides 1ꢁ,2ꢁ-O-isopropylidene-D-ribo-tetritol-1-yl)[1,2,4]
2
triazolo[3,4-b][1,3,4]thiadiazoles bearing arylsulfonamide (5–8) and arylcarboxamide (9–12)
residues have been synthesized under microwave irradiation. Thiadiazines 13–15 have been
analogously prepared, and upon acid hydrolysis, afforded the free nucleosides 16–18. The new
synthesized compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compound 7 was
also screened against a panel of tumor cell lines consisting of CD4 human T-cells.
Keywords
anti-HIV activity; acyclic C-nucleosides; microwave-assisted synthesis;
triazolo-thiadiazoles and -thiadiazines; sulphonamides; carboxamides
INTRODUCTION
The use of acyclonucleoside analogues as potent antiviral agents (such
as the antiherpetic drug ACV (Acyclovir, Zovirax),[1,2] DHPA,[3] PMEA,
HPMPA,[4] HBG, and DHPG[5,6]) has stimulated extensive research in
the synthesis of this class of compounds. Structure-activity relationship
studies have shown that the side chains of acyclonucleosides play a crucial
Received 28 November 2007; accepted 22 May 2008.
We thank Professor E. De Clercq and Professor C. Pannecouque of Rega Institute of Medical
Research, Katholieke Universiteit, Leuven (Belgium) for the anti-HIV screening. Miss Firemel of
Konstanz University (Germany) is gratefully acknowledged for the two-dimensional NMR experiments.
We are grateful for Professor P. La Colla and Dr. R. Loddo of Cagliari University (Italy) for the antitumor
screening. Mr. Galtesky of Konstanz University (Germany) is gratefully acknowledged for the 2D-NMR
experiments and mass measurements, respectively.
Address correspondence to Najim A. Al-Masoudi, P.O. Box 10 05 52, 78405 Konstanz, Germany.
E-mail: Najim.Al-Masoudi@gmx.de
1034

New Sulphonamide and Carboxamide Derivatives
1035
S
N
R
N
N
N
O
O
OH
OH
SCHEME 1 6-Alkyl/aryl-3-(1,2-O-isopropylidene-d-ribo-tetritol-1-yl)[1,2,4]triazolo[3,4-b][1,3,4] thiadia-
zoles (1).
role in the interaction of the acyclonucleosides with their antiviral target
enzymes[7] (phosphorylation).
Various substituted 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines and Schiff’s
bases are associated with diverse pharmacological activities, such as anal-
gesic, antihelminthic, antitubercular, plant growth regulating, antiviral,
antifungal, and anticancer properties.[9–16] Recently, we synthesized various
acyclic C-nucleosides of 6-alkyl/aryl-3-(1,2-O-isopropylidene-d-ribo-tetritol-1-
yl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (1), and the corresponding 6-
aryl-thiomethyl as their free nucleosides analogues from the treatment
of 2,3-O-isopropylidine-d-ribono-1,4-lactone with thiocarbohydrazide.[17] As
a continuation of our research programs on the development of com-
pounds potentially active against HIV, we synthesized and evaluated new
acyclic C-nucleosides of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole nucleosides
bearing sulfonamide and carboxamide as well as thiadiazine residues.
Sulphonamides are used for treatment of certain bacterial infections, e.g.
the anticonvulsant sultiame[18] as well as other kinds of infections.[19]
Further, some sulphonamides are considered as competitive folic acid
inhibitors in microorganisms, with their activity as bacteriostatic.[20]
RESULTS AND DISCUSSION
We recently synthesized a new series of acyclic C-nucleosides of 3-(D-
ribo-tetritol-yl)-5-mercapto-1,2,4-triazoles as well as their [1,2,4]triazolo[3,4-
b][1,3,4]thiadiazole analogues[17] from the opening of a δ-lactone 2 with
thiocarbohydrazide in pyridine under microwave irradiation (MWI). In
the present work, 6-(4-aminophenyl)-3-(1,2-O-isopropylidene-d-ribo-tetritol-
1-yl)-7H-1,2,4-triazolo [3,4-b][1,3,4]thiadiazole (4), prepared from the cor-
responding C-nucleoside 3,[17] was selected as the parent compound

1036
N. A. Al-Masoudi and Y. A. Al-Soud
for the preparation of a new series of arylsulphonamides and arylcar-
boxamides as potential derivatives, and antitumor agents. Thus, treat-
ment of 4 with the appropriate arylsulphonyl chlorides (4-chloro,
4-nitro, 4-methylbenzenesulphonyl- and 3-furylsulphonyl chlorides) as
well as the appropriate acyl chlorides, (furan-2-carbonyl, thiophene-2-
carbonyl, 2-fluorobenzoyl, and quinoline-4-carbonyl chlorides), afforded
sulphonamides 5–8 (43–58%) and 9–12 (49–86%), respectively.
1
The structures of 5–12 were assigned from their H, 13C NMR, and
1
mass spectra. The HNMR spectra (in CDCl3) of 5–12 showed similar
patterns for the sugar protons. H-1ꢁ and H-2ꢁ appeared as doublets or
ꢁ
ꢁ
broad singlets in the δ 4.77–4.89 region and at δ 4.75–4.78 (J 1 ,2 ∼5.5 Hz,
J 2 ,3 ∼5.5), respectively. H-3ꢁ appeared as triplet in the δ 4.52–4.63 region
ꢁ
ꢁ
(J 3 ,4 b ∼ 2.3 Hz, J 3 ,4 a ∼ 4.2 Hz). The 13C NMR spectra of 5–12 were fully
established (Experimental section), and they contained similar resonance
signals for the sugar carbons C-1ꢁ–C-4ꢁ as well as for the triazolo-thiadiazole
ring carbons C-3 (C N)–C-8 (C N). In the 13C NMR spectra of 5–12, the
C-6 resonated relatively at higher field (δ 174.3–174.8), while C-3 and C-8
resonated at the δ 161.6–167.1 and δ 146.4–151.1 regions, respectively. The
phenyl, furan, thiophene, coumarin, and the isopropylidene carbon atoms
were fully assigned (see Experimental section).
ꢁ
ꢁ
ꢁ
ꢁ
SH
S
S
3
N
N
N
NHS
O2R
NH2
HO
1
O
N
N
N
NH2
N
N
N
N
N
O
5
i
O
O
O
O
O
O
O
O
OH
OH
OH
OH
R
OH
OH
4
2
5
6
7
8
4-Cl-Ph
4-NO2-Ph
4-Me-Ph
3-furan
3
ii
O
S
S
N
Me
N
NHS
O
NHCOR
N
N
N
N
N
N
O
O
O
O
OH
OH
OH
OH
R
7
9
furan
10 thiophene
11 2-F-Ph
4-quinoline
12
SCHEME 2 Ragents and conditions: (i) RSO2Cl, Et3N, CH2Cl2, 23◦C, 3–4 h; (ii) RCOCl, Et3N, 23◦C,
CH2Cl2.
Compound 7 was selected for further NMR study. From the gradient
selected HMBC[21] spectrum of 7, C-3 at δC 162.1 showed a 2J C,H couplings
with H-1ꢁ at δH 4.84, and 3J C,H coupling with H-3ꢁ at δH 4.63. Furthermore,
a 3J C,H coupling between C-6 at δC 174.7 and NAr-H-3 and -H-5 at δH 6.73.

New Sulphonamide and Carboxamide Derivatives
1037
S
S
SH
N
N
N
R
R
N
N
N
N
N
N
NH2
N
N
ii
O
i
O
OH
OH
OH
OH
O
O
OH
OH
OH
OH
R
R
3
Ph
13
14
15
Ph
16
17
18
2,4-Cl2-Ph
CO2Et
2,4-Cl2-Ph
CO2Et
SCHEME 3 Ragents and conditions: (i) BrCH2COAr, EtOH, 20 min, MWl, 80◦C; (ii) 80% HOAc, 80◦C,
12 h.
Next, our work was modified by selecting 4-amino-3-(1,2-O-
isopropylidene-d-ribo-tetritol-1-yl)-5-mercapto-1,2,4-triazole (3)[17] as
a
precursor for the synthesis of new triazolothiadiazine derivatives to
examine their antiviral activity in comparison to the triazolo-thiadiazole
analogues 5–12. Thus, heating 3 with phenacyl bromide, 2-bromo-1-(3,4-
dichlorophenyl)ethanone, or ethyl 3-bromo-2-oxopropanoate under MWI
gave, after purification, the desired acylic C-nucleosides 13–15 in 73, 56,
and 87% yield, respectively. Acid hydrolysis of 13–15 with 80% HOAc
furnished free nucleosides 16–18 in 88, 81 and 78% yield, respectively.
The structural assignment of 13–18 were made from their 1H-, 13C NMR
and mass spectra.
The sugar protons and carbons showed similar patterns to those of
compounds 5–12. CH2S protons resonated as singlets in the δH 3.31–4.39
region, while the carbons resonated in the δC 29.0–35.5 region. The
formation of the thiadiazine derivative was determined from the HMBC
2
spectrum of 13, which showed a J C,H coupling between CH2S protons at
δH 4.39 and C-6 at δC 163.2 as well as a 3J C,H coupling with C-9a (C N) at δC
1
146.2. Further, the gradient-selected H,13C-HSQC[22] spectrum in CDCl3
showed coupling between CH2S protons at δH 4.39 and carbon at δC 35.4,
as well as coupling between H-1ꢁ–4ꢁa,b at δH 4.97 (d, J 1 ,2 = 5.2 Hz), 4.23 (d,
ꢁ
ꢁ
= 5.4 Hz), 4.17 (t, J 3 ,4 = 2.2 Hz), 3.58 (m, H-4ꢁa, H-4ꢁb) and C-1ꢁ–C-4ꢁ
ꢁ
ꢁ
2ꢁ,3ꢁ
at δC 72.8, 79.2, 64.3, respectively.
In Vitro Anti-HIV-Assay
All new synthesized compounds were evaluated for their in vitro anti-
HIV activity by using the IIIB strain for HIV-1 and the ROD strain for HIV-2
in human T-lymphocyte (MT-4) cells. All the tested compounds are inactive,

1038
N. A. Al-Masoudi and Y. A. Al-Soud
except 16, which found to be the only compound from the series inhibiting
HIV-2 replication in cell culture (EC50 of 17.4 µg/mL), in comparison to
the standard antiviral drugs efavirenz[23] and capravirine.[24]
In Vitro Antitumor Assay
Compound 7 was tested in vitro against a panel of tumor cell lines con-
sisting of CD4 human T-cells containing an integrated leukaemia (CCRF-
CEM); human acute T-lymphoblastic leukaemia (WIL-2NS); human splenic
B-lymphoblastoid cells (CCRF-SB); human acute B-lymphoblastic leukaemia
(SK-MEL-28); human skin melanoma (SK-MEL-28); human breast adeno-
carcinoma (MCF-7); human lung squamous carcinoma (SK-MES-1); human
hepatocellular carcinoma (HepG2); human prostate carcinoma (DU-145);
human foreskin fibroblast (CRL7065); and human lung fibroblast (MRC-5),
using the Microculture Tetrazolium Assay (MTT) method[25] for estimation
of the in vitro tumor-inhibiting activity. Compound 7 was inactive against all
tumor cell lines (CC50 > 100 µg/mL).
EXPERIMENTAL
Melting points are uncorrected and were measured on a Bu¨chi melting
point apparatus B-545 (Bu¨chi Labortechnik AG, Switzerland). Microana-
lytical data were obtained with a Vario, Elementar apparatus (Shimadzu,
Japan). NMR spectra were recorded on 300 and 600 MHz (1H) and at
62.9 MHz (13C) spectrometers (Bruker, Germany) with TMS as the internal
standard and on δ scale in ppm. Heteronuclear assignments were verified by
1H-13C HMBC experiments. Mass spectra were recorded at 70 eV on EI and
FAB mass spectra were measured on a MAT 8200 spectrometer (Finnigana
MAT, USA) using 3-nitrobenzyl alcohol (NBOH) or glycerol as matrices.
Some molecular ions were detected by doping the sample with Na+ ion.
General Procedure of Arylsulphonamide Derivatives of 1ꢁ,2ꢁ-O-isopropylidene-
D-ribo-tetritol-1-yl)[1,2,4] triazolo[3,4-b][1,3,4] thiadiazols (5–8)
To a solution of 4 (75 mg, 0.20 mmol) in CH2Cl2 (10 mL) containing
Et3N (20 mg, 0.20 mmol) was added arylsulphonyl chloride (0.20 mmol)
with stirring at 23◦C for 3–4 hours. The solution was evaporated to dryness
and the residue was partitioned between CH2Cl2 (3×15 mL) and water (15
mL). The combined organic extracts were dried (Na2SO4), filtered and
concentrated to 2 mL, then applied to a SiO2 column. Gradient elution with
MeOH (0–10%) and CH2Cl2 afforded the desired sulphonamide products.
N-(4-(3-(1,2-O-Isopropylidene-D-ribo-tetritol-1-yl)[1,2,4]triazolo[3,4-b][1,
3,4]thiadiazol-6-yl)phenyl)-4-chlorobenzenensulphonamide
(5).
From
4-chlorobenzenesulphonyl chloride (42 mg). Yield: 52 mg (47%); m.p.

New Sulphonamide and Carboxamide Derivatives
1039
1
134–138◦C. H NMR (CDCl3): δ 10.08 (s, 1H, NH); 7.68–7.38 (m, 6H,
ꢁ
ꢁ
Ar-H); 6.51 (dd, 2H, J = 5.7 Hz, 3.0 Hz, Ar-H); 4.86 (d, 1H, J 1 ,2 = 5.5 Hz,
H-1ꢁ); 4.70 (d, 1H, J 2 ,3 = 5.6 Hz, H-2ꢁ); 4.59 (t, 1H, J 3 ,4 b = 2.1 Hz, H-3ꢁ);
ꢁ
ꢁ
ꢁ
ꢁ
4.04 (dd, 1H, J 3 ,4 a = 4.2 Hz, H-4ꢁa); 3.95 (dd, 1H, J 4a ,4 b = 12.0 Hz H-4ꢁb);
1.45, 1.34 (2xs, 6H, CMe2). 13C NMR (CDCl3): δ 174.6 (C-6); 167.1 (C-3);
151.1 (C8 N); 138.8 (Ar-C-SO2 + Ar-C-Cl); 130.1, 128.8, 128.1, 127.1, 116.6
(Ar-C); 112.2 (CMe2); 82.3 (C-2ꢁ); 69.4 (C-1ꢁ); 75.9 (C-3ꢁ); 62.1 (C-4ꢁ); 26.5,
25.5 (CMe2). Anal. calc. for C22H22ClN5O6S2 (552.02): C, 47.87; H, 4.02; N,
12.69. Found; C, 47.62; H, 3.92; N, 12.45. MS: m/z (FAB) 552/554 (M+H)+.
N-(4-(3-(1,2-O-Isopropylidene-D-ribo-tetritol-1-yl)[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazol-6-yl)phenyl)-4-nitrobenzenensulphonamide (6). From
4-nitrobenzenesulphonyl chloride (44 mg). Yield: 48 mg (43%); semi-solid.
1H NMR (CDCl3): δ 8.11 (dd, 2H, J = 5.8 Hz, 3.1 Hz, p-NO2-Ar-H); 7.92
(d, 2H, J = 5.8 Hz, 3.1 Hz, p-NO2-Ar-H); 7.57 (dd, 2H, J = 5.6 Hz, 3.0 Hz,
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
Ar-H); 6.51 (dd, 2H, J = 5.6 Hz, 3.0 Hz, Ar-H); 4.89 (d, 1H, J 1 ,2 = 5.3 Hz,
H-1ꢁ); 4.75 (d, 1H, J 2 ,3 = 5.5 Hz, H-2ꢁ); 4.57 (t, 1H, J 3 ,4 b = 2.2 Hz, H-3ꢁ);
ꢁ
ꢁ
ꢁ
ꢁ
4.11 (dd, 1H, J 3 ,4 a = 4.3 Hz, H-4ꢁa); 3.97 (dd, 1H, J 4a ,4 b = 12.1 Hz H-4ꢁb);
1.43, 1.33 (2xs, 6H, CMe2). 13C NMR (CDCl3): δ 174.8 (C-6); 167.0 (C-3);
150.3 (Ar-C-NO2); 149.8 (C8 N); 143.9 (Ar-C-SO2); 128.3, 128.0, 116.7
(Ar-C); 112.5 (CMe2); 82.6 (C-2ꢁ); 69.6 (C-1ꢁ); 76.2 (C-3ꢁ); 62.3 (C-4ꢁ); 26.4,
25.3 (CMe2). Anal. calc. for C22H22N6O8S2 (562.58): C, 46.97; H, 3.94; N,
14.94. Found; C, 46.77; H, 3.86; N, 14.72. MS: m/z (FAB) 563 (M+H)+.
N-(4-(3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazol-6-yl)phenyl)-4-methylbenzenensulphonamide (7). From
4-methylbenzenesulphonyl chloride (38 mg). Yield: 58 mg (54%); m.p.
ꢁ
ꢁ
ꢁ
ꢁ
1
128–131◦C. H NMR (CDCl3): δ 7.70 (dd., 1H, J = 5.4 Hz, 3.3 Hz, Ar-H);
7.53 (dd, 2H, J = 5.4 Hz, 3.3 Hz, Ar-H); 6.73 (dd, 2H, J = 5.5 Hz, 3.2 Hz,
Ar-H); 4.84 (d, 1H, J 1 ,2 = 5.6 Hz, H-1ꢁ); 4.78 (d, 1H, J 2 ,3 = 5.6 Hz, H-2ꢁ);
ꢁ
ꢁ
ꢁ
ꢁ
4.63 (t, 1H, J 3 ,4 b = 2.0 Hz, H-3ꢁ); 4.10 (dd, 1H, J 3 ,4 a = 4.3 Hz, H-4ꢁa); 3.99
ꢁ
ꢁ
ꢁ
ꢁ
(dd, 1H, J 4a ,4 b = 12.0 Hz H-4ꢁb); 2.00 (s, 3H, Ar-Me); 1.47, 1.38 (2xs, 6H,
CMe2). 13C NMR (CDCl3): δ 174.7 (C-6); 162.1 (C-3); 148.1 (C8 N); 141.1
(Ar-CH3); 135.9 (Ar-C-SO2 + Ar-C-NH); 130.9, 128.8, 127.1, 116.5 (Ar-C);
113.1 (CMe2); 82.5 (C-2ꢁ); 69.4 (C-1ꢁ); 75.6 (C-3ꢁ); 62.0 (C-4ꢁ); 26.7, 25.4
(CMe2). Anal. calc. for C23H25N5O6S2 (531.60): C, 51.96; H, 4.74; N, 13.17.
Found; C, 51.73; H, 4.59; N, 12.93. MS: m/z (FAB) 532 (M+H)+.
ꢁ
ꢁ
N-(4-(3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)[1,2,4]triazolo[3,4-b][1,
3,4]thiadiazol-6-yl)phenyl)furansulphonamide (8). From furan-3-sulphonyl
chloride (33 mg). Yield: 59 mg (58%); m.p. 128–131◦C. 1H NMR
(DMSO-d6): δ 10.48 (s, 1H, NH); 7.97–7.16 (m., 3H, furan-H + Ar-H); 4.77
(s, 2H, H-1ꢁ, H-2ꢁ); 4.61 (t, 1H, J 3 ,4 b = 2.2 Hz, H-3ꢁ); 3.62 (m, 2H, H-4ꢁa;
H-4ꢁb); 1.35, 1.30 (2xs, 6H, CMe2). 13C NMR (DMSO-d6): δ 174.3 (C-6);
162.9 (C-3); 146.4 (C8 = N); 142.7, 130.2, 125.5, 112.5, 112.2 (furan-C +
Ar-C); 111.6 (CMe2); 82.2 (C-2ꢁ); 78.1 (C-1ꢁ); 74.9 (C-3ꢁ); 66.9 (C-4ꢁ); 26.5,
ꢁ
ꢁ

1040
N. A. Al-Masoudi and Y. A. Al-Soud
25.1 (CMe2). Anal. calc. for C20H21N5O7S2 (507.54): C, 47.33; H, 4.17; N,
13.80. Found; C, 47.11; H, 4.08; N, 13.58. MS: m/z (FAB) 508 (M+H)+.
Arylcarboxamide derivatives of 1,2-O-isopropylidene-D-ribo-tetritol-1-
yl)[1,2,4] triazolo[3,4-b][1,3,4]thiadiazols (9–12). These compounds were
prepared following the same method for the preparation of 5–8, from 4
(94 mg, 0.25 mmol) and acyl chloride (0.25 mmol).
3-(1,2-O-Isopropylidene-D-ribo-tetritol-1-yl)-6-(4-(N-phenylfuran-2-
carboxamido)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (9). From furan-2-
carbonyl chloride (32 mg). Yield: 100 mg (86%); m.p. 165–166◦C. 1H NMR
(CDCl3): δ 10.12 (s, 1H, NH); 7.95–6.70 (m, 7H, Ar-H + furan-H); 4.89
(d, 1H, J 1 ,2 = 5.3 Hz, H-1ꢁ); 4.77 (br s, 1H, H-2ꢁ); 4.55 (t, 1H, J 3 ,4 b = 2.0
Hz, H-3ꢁ); 3.60 (m, 2H, H-4ꢁa, H-4ꢁb); 1.32, 1.27 (2xs, 6H, CMe2). 13C NMR
(CDCl3): δ 173.8 (C-6); 161.8 (C-3 + C O); 146.8 (C8 N + furan-C-CO);
135.7; 130.2, 128.1, 122.1, 111.2 (Ar-C + furan-C); 111.0 (CMe2); 82.3
(C-2ꢁ); 74.3 (C-1ꢁ); 69.2 (C-3ꢁ); 65.3 (C-4ꢁ); 26.3, 25.2 (CMe2). Anal. calc.
for C21H21N5O6S (471.49): C, 53.50; H, 4.49; N, 14.85. Found; C, 53.32; H,
4.41; N, 14.61. MS: m/z (FAB) 472 (M+H)+.
ꢁ
ꢁ
ꢁ
ꢁ
3-(1,2-O-Isopropylidene-D-ribo-tetritol-1-yl)-6-(4-N-phenylthiophene-2-
carboxamido)[1,2,4]-triazolo[3,4-b][1,3,4]thiadiazole
(10).
From
thiophene- 2-carbonyl chloride (37 mg). Yield: mg (86%); oil. 1H NMR
(CDCl3): δ 7.95–7.621 (m, 6H, Ar-H + thiophene-H); 7.31 (t, 1H, J = 5.3
Hz, thiophene-H); 4.90 (d, 1H, J 1 ,2 = 5.2 Hz, H-1ꢁ); 4.72 (d, 1H, J 2 ,3
=
ꢁ
ꢁ
ꢁ
ꢁ
5.3 Hz, H-2ꢁ); 4.52 (t, 1H, J 3 ,4 b = 2.3 Hz, H-3ꢁ); 3.63 (m, 2H, H-4ꢁa, H-4ꢁb);
1.34, 1.29 (2xs, 6H, CMe2). 13C NMR (CDCl3): δ 174.5 (C-6); 161.6 (C-3
+ C O); 146.7 (C8 N); 136.9; 135.3, 128.1, 122.1 (Ar-C + thiophene-C);
111.2 (CMe2); 82.4 (C-2ꢁ); 74.6 (C-1ꢁ); 69.1 (C-3ꢁ); 65.5 (C-4ꢁ); 26.6, 25.3
(CMe2). MS: m/z (FAB) 510 (M+Na)+.
ꢁ
ꢁ
6-(2-Fluoro-4-N-Phenylbenzamido)-3-(1,2-O-isopropylidene-D-ribo-
tetritol-1-yl)[1,2,4]-triazolo[3,4-b][1,3,4]thiadiazole
(11).
From
2-
fluorobenzoyl chloride (40 mg). Yield: (49%); oil. 1H NMR (CDCl3):
ꢁ
ꢁ
δ 10.21 (s, 1H, NH); 7.97–7.20 (m., 8H, Ar-H); 4.79 (d, 1H, J 1 ,2 = 5.3 Hz,
H-1ꢁ); 4.78 (br s, 1H, H-2ꢁ); 4.55 (t, 1H, J 3 ,4 b = 2.5 Hz, H-3ꢁ); 3.63 (m,
2H, H-4ꢁa; H-4ꢁb); 1.37, 1.32 (2xs, 6H, CMe2). 13C NMR (CDCl3): δ 174.7
(C-6); 163.2 (C O); 162.9 (C-3); 158.1 (d, J C,F = 218 Hz, Ar-C-F); 146.7
(C8 N); 132.7, 130.0, 127.1, 125.5, 122.2, 112.5, (Ar-C); 111.9 (CMe2);
82.7 (C-2ꢁ); 78.3 (C-1ꢁ); 75.2 (C-3ꢁ); 66.6 (C-4ꢁ); 26.2, 25.0 (CMe2). MS: m/z
(FAB) 499/501 (M+H)+.
ꢁ
ꢁ
3-(1,2-O-Isopropylidene-D-ribo-tetritol-1-yl)-6-(4-N-phenylquinolon-4-
carboxamido)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (12). From quinoline-
1
4-carbonyl chloride (48 mg). Yield: (53%); semi-solid. H NMR (600 MHz,
CDCl3): δ 7.93–7.60 (m, 5H, Ar-H); 7.35–7.18 (m., 3H, Ar-H); 4.82 (d, 1H,
J 1 ,2 = 5.2 Hz, H-1ꢁ); 4.65 (d, 1H, J 1 ,2 = 5.4 Hz, H-2ꢁ); 4.57 (t, 1H, J 3 ,4 b
=ꢁ 2.6 Hz, H-3ꢁ); 3.69 (m, 2H, H-4ꢁa; H-4ꢁb); 1.35, 1.33 (2xs, 6H, CMe2).
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ

New Sulphonamide and Carboxamide Derivatives
1041
13C NMR (CDCl3): δ 174.3 (C-6); 172.0 (N-C O), 162.2 (C-3); 160.1 (C O,
coumarin); 151.7 (C-4, coumarin), 149.8 (C-8a, coumarin); 146.9 (C8 N);
134.8, 129.1, 128.1, 127.7, 127.1, 122.0, 115.9 (Ar-C); 112.0 (CMe2); 82.1
(C-2ꢁ); 78.0 (C-1ꢁ); 75.4 (C-3ꢁ); 66.5 (C-4ꢁ); 26.0, 25.2 (CMe2). Anal. calc.
for C26H23N5O7S (549.56): C, 56.82; H, 4.22; N, 12.74. Found; C, 56.50; H,
4.05; N, 12.64. MS: m/z (FAB) 572 (M+Na)+.
General Preparation of 6-Aryl or Alkyl-3-(1,2-O-isopropylidene-D-ribo-tetritol-
1-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines (13–15).
A solution of 3 (69 mg, 0.25 mmol) and phenacyl bromide, 2-
bromo-1-(3,4-dichlorophenyl)ethanone, or ethyl 3-bromo-2-oxopropanoate
(0.25 mmol) in EtOH (5 mL) was heated at 80◦C under MWI for 20 minutes.
After cooling, the solution was evaporated to dryness and the residue was
partitioned between CHCl3 (3 × 30 mL) and water (30 mL). The combined
organic extracts was dried, filtered and evaporated to dryness to give the
desired products.
3-(1,2-O-Isopropylidene-D-ribo-tetritol-1-yl)-6-phenyl-[1,2,4]triazolo[3,4-
b] [1,3,4] thiadiazine (13). From phenacyl bromide (50 mg). Yield: 69 mg
(73%) as yellow powder; m.p. 132–136◦C. 1H NMR (DMSO-d6): δ 7.86 (m,
2H, Ar-H); 7.55–7.42 (m., 3H, Ar-H); 4.97 (d, 1H, J 1 ,2 = 5.2 Hz, H-1ꢁ); 4.23
ꢁ
ꢁ
(d, 1H, J 2 ,3 = 5.4 Hz, H-2ꢁ); 4.17 (t, 1H, J 3 ,4 = 2.2 Hz, H-3ꢁ); 3.58 (m,
2H, H-4ꢁa, H-4ꢁb); 4.39 (s, 2H, SCH2); 1.37, 1.33 (2xs, 6H, CMe2). 13C NMR
(DMSO-d6): δ 163.2 (C-6); 154.2 (C-3); 146.2 (C9 N); 134.0, 131.2, 129.2,
127.8 (Ar-C); 110.6 (CMe2); 79.2 (C-2ꢁ); 72.8 (C-1ꢁ); 70.0 (C-3ꢁ); 64.3 (C-4ꢁ);
35.5 (SCH2): 25.3, 22.6 (CMe2). Anal. calc. for C17H20N4O4S (376.43): C,
54.24; H, 5.36; N, 14.88. Found; C, 54.02; H, 5.27; N, 14.68. MS: m/z (FAB)
377 (M+H)+.
ꢁ
ꢁ
ꢁ
ꢁ
6-(2,4-Chlorophenyl)-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)-[1,2,4]
triazolo[3,4-b][1,3,4]thiadiazine (14). From 2-bromo-1-(3,4-dichlorophenyl)
ethanone (67 mg). Yield: 62 mg (56%) as a white solid; m.p. 106–108◦C.
1H NMR (DMSO-d6): δ 7.50–7.26 (m, 3H, Ar-H); 4.98 (d, 1H, J 1 ,2 = 5.1
ꢁ
ꢁ
Hz, H-1ꢁ); 4.25 (d, 1H, J 3 ,4 = 2.1 Hz, H-2ꢁ); 4.17 (t, 1H, J 3 ,4 = 2.3 Hz,
H-3ꢁ); 3.58 (m, 2H, H-4ꢁa, H-4bꢁ); 4.38 (s, 2H, SCH2); 1.40, 1.37 (2xs, 6H,
CMe2). 13C NMR (DMSO-d6): δ 164.2 (C-6); 153.7 (C-3); 146.9 (C9 N);
137.7 (Ar-Cl-Cl); 135.3 (Ar-C-Cl + ArC); 131.0, 128.4, 127.7 (Ar-C); 11.2
(CMe2); 84.8 (C-2ꢁ); 69.1 (C-1ꢁ); 68.4 (C-3ꢁ); 60.3 (C-4ꢁ); 35.3 (SCH2); 25.7,
22.5 (CMe2). Anal. calc. for C17H18Cl2N4O4S (445.32): C, 45.85; H, 4.07; N,
12.58. Found; C, 45.66; H, 4.01; N, 12.37. MS: m/z (FAB) 445/447 (M+H)+.
Ethyl 3-(1,2-O-isopropylidene-d-ribo-tetritol-1-yl)-[1,2,4]triazolo[3,4-b]
ꢁ
ꢁ
ꢁ
ꢁ
[1,3,4]thiadiazine -6-carboxylate (15). From ethyl 3-bromo-2-oxopropanoate
1
ꢁ
ꢁ
(45 mg). Yield: 81 mg (87%); oil. H NMR (CDCl3): δ 4.91 (d, 1H, J 1 ,2
=
5.2 Hz, H-1ꢁ); 4.41 (d, 1H, J 2 ,3 = 5.3 Hz, H-2ꢁ); 4.18 (q, 2H, J = 7.0 Hz,
ꢁ
ꢁ
CO2CH2CH3); 3.70 (d, 1H, J 2 ,3 = 5.1 Hz, H-3ꢁ); 3.62 (m, 2H, H-4ꢁa, H-4bꢁ);
ꢁ
ꢁ

1042
N. A. Al-Masoudi and Y. A. Al-Soud
3.31 (s, 2H, SCH2); 1.46, 1.36 (2xs, 6H, CMe2); 1.28 (t, 3H, CO2CH2CH3).
13C NMR (DMSO-d6): δ 163.7 (C-6); 163.1 (C
O); 154.5 (C-3); 146.6
(C9 N); 113.2 (CMe2); 83.6 (C-2ꢁ); 68.8 (C-1ꢁ); 68.2 (C-3ꢁ); 64.0 (C-4ꢁ); 29.0
(SCH2). 26.5, 25.4 (CMe2). MS: m/z (FAB) 373 (M+H)+.
General Procedure of Preparation of Free C-Nucleosides (16–18)
A solution of 13–15 (0.50 mmol) in 80% HOAc (10 mL) was stirred at
80◦C for 12 hours. The solution was evaporated to dryness and the residue
was co-evaporated with EtOH (4 × 20 mL), and the residue was extracted
between water (15 mL) and ether (3×15 mL). The aq. layer was evaporated
to dryness to give the desired product as oil, semi-solid, or crystalline solid.
3-(D-Ribo-tetritol-1-yl)-6-phenyl-[1,2,4]-triazolo[3,4-b][1,3,4]thiadiazine
1
(16). From 13 (173 mg). Yield: 148 mg (88%); m.p.75–78◦C. H NMR
(DMSO-d6): δ 7.87 (m, 2H, Ar-H); 7.51–7.41 (m., 3H, Ar-H); 4.38 (d, 1H,
J 1 ,2 = 5.3 Hz, H-1ꢁ); 4.21 (d, 1H, J 2 ,3 = 5.3 Hz, H-2ꢁ); 4.12 (t, 1H, J 3 ,4
=
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
2.3 Hz, H-3ꢁ); 3.57 (m, 2H, H-4ꢁa, H-4ꢁb); 4.31 (s, 2H, SCH2). 13C NMR
(DMSO-d6): δ 162.9 (C-6); 154.8 (C-3); 147.1 (C9 = N); 133.8, 128.4, 127.7,
125.9 (Ar-C); 85.1 (C-2ꢁ); 69.2 (C-1ꢁ); 68.4 (C-3ꢁ); 60.3 (C-4ꢁ); 35.3 (SCH2).
Anal. calc. for C14H16N4O4S (336.37): C, 49.99; H, 4.79; N, 16.66. Found;
C, 49.72; H, 4.69; N, 16.46. MS: m/z (FAB) 358/360 (M+Na)+.
6-(2,4-Dichlorophenyl)-3-(D-ribo-tetritol-1-yl)-[1,2,4]-triazolo[3,4-b][1,3,
4]thiadiazine (17). From 14 (222 mg). Yield: 180 mg (81%); amorphous.
1H NMR (DMSO-d6): δ 7.51–7.29 (m., 3H, Ar-H); 4.41 (d, 1H, J 1 ,2 = 5.2
ꢁ
ꢁ
Hz, H-1ꢁ); 4.23 (d, 1H, J 2 ,3 = 5.2 Hz, H-2ꢁ); 4.19 (t, 1H, J 3 ,4 = 2.3 Hz,
H-3ꢁ); 3.56 (m, 2H, H-4ꢁa, H-4ꢁb); 4.36 (s, 2H, SCH2). 13C NMR (DMSO-d6):
δ 163.6 (C-6); 154.5 (C-3); 146.5 (C9 N); 137.5 (Ar-Cl-Cl); 135.2 (Ar-C-Cl,
ArC); 131.1, 128.7, 127.7 (Ar-C); 85.0 (C-2ꢁ); 69.0 (C-1ꢁ); 68.5 (C-3ꢁ); 60.1
(C-4ꢁ); 35.0 (SCH2). Anal. calc. for C14H14Cl2N4O4S (404.04): C, 41.49; H,
3.48; N, 13.83. Found; C, 41.27; H, 3.40; N, 13.62. MS: m/z (FAB) 426/428
(M+Na)+.
ꢁ
ꢁ
ꢁ
ꢁ
Ethyl
3-(D-ribo-tetritol-1-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-6-
1
carboxylate (18). From 15 (186 mg). Yield: 145 mg (78%); semi-solid. H
NMR (DMSO-d6): δ 4.55 (d, 1H, J 1 ,2 = 5.0 Hz, H-1ꢁ); 4.16 (q, 2H, J = 7.1
ꢁ
ꢁ
Hz, CO2CH2CH3); 3.76 (d, 1H, J 2 ,3 = 5.2 Hz, H-2ꢁ); 3.39 (t, 1H, J 3 ,4
=
ꢁ
ꢁ
ꢁ
ꢁ
2.2 Hz, H-3ꢁ); 3.61 (m, 2H, H-4ꢁa, H-4ꢁb); 3.33 (s, 2H, SCH2); 1.27 (t, 3H,
CO2CH2CH3). 13C NMR (DMSO-d6): δ 163.2 (C-6); 162.9 (C O); 154.3
(C-3); 146.8 (C9 N); 83.9 (C-2ꢁ); 69.0 (C-1ꢁ); 68.9 (C-3ꢁ); 64.2 (C-4ꢁ); 29.2
(SCH2). Anal. calc. for C11H16N4O6S (323.33): C, 39.75; H, 4.85; N, 16.86.
Found; C, 39.49; H, 4.78; N, 16.62. MS: m/z (FAB) 346 (M+Na)+.
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