Synthesis of acyclovir and HBG analogues having nicotinonitrile and its 2-methyloxy 1,2,3-triazole

Article abstract of DOI:10.1080/15257770.2011.582850

Reaction of pyridin-2(1H)-one 1 with 4-bromobutylacetate (2), (2-acetoxyethoxy)methyl bromide (3) gave the corresponding nicotinonitrile O-acyclonucleosides, 4 and 5, respectively. Deacetylation of 4 and 5 gave the corresponding deprotected acyclonucleosi

Full text of DOI:10.1080/15257770.2011.582850

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Synthesis of Acyclovir and HBG
Analogues Having Nicotinonitrile and Its
2-methyloxy 1,2,3-triazole
Ahmed H. Moustafa a , Hassan A. El-Sayed a , Abd El-Fattah Z. Haikal
a & El Sayed H. El Ashry b
a Department of Chemistry, Faculty of Science, Zagazig University,
Zagazig, Egypt
b Department of Chemistry, Faculty of Science, Alexandria
University, Alexandria, Egypt
Published online: 20 Jul 2011.
To cite this article: Ahmed H. Moustafa , Hassan A. El-Sayed , Abd El-Fattah Z. Haikal & El
Sayed H. El Ashry (2011) Synthesis of Acyclovir and HBG Analogues Having Nicotinonitrile and
Its 2-methyloxy 1,2,3-triazole, Nucleosides, Nucleotides and Nucleic Acids, 30:5, 340-352, DOI:
10.1080/15257770.2011.582850
To link to this article: http://dx.doi.org/10.1080/15257770.2011.582850
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Nucleosides, Nucleotides and Nucleic Acids, 30:340–352, 2011
Copyright ꢀC Taylor and Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770.2011.582850
SYNTHESIS OF ACYCLOVIR AND HBG ANALOGUES HAVING
NICOTINONITRILE AND ITS 2-METHYLOXY 1,2,3-TRIAZOLE
Ahmed H. Moustafa,1 Hassan A. El-Sayed,1 Abd El-Fattah Z. Haikal,1
and El Sayed H. El Ashry2
1Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
2Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
Reaction of pyridin-2(1H)-one 1 with 4-bromobutylacetate (2), (2-acetoxyethoxy)methyl bromide
2
(3) gave the corresponding nicotinonitrile O-acyclonucleosides, 4 and 5, respectively. Deacetylation
of 4 and 5 gave the corresponding deprotected acyclonucleosides 6 and 7, respectively. Treatment
of pyridin-2(1H)-one 1 with 1,3-dichloropropan-2-ol (8), epichlorohydrin (10) and allyl bromide
(12) gave the corresponding nicotinonitrile O-acyclonucleosides 9, 11, and 13, respectively. Fur-
thermore, reaction of pyridin-2(1H)-one 1 with the propargyl bromide (14) gave the corresponding
2-O-propargyl derivative 15, which was reacted via [3+2] cycloaddition with 4-azidobutyl acetate
(16) and [(2-acetoxyethoxy)methyl]azide (17) to give the corresponding 1,2,3-triazole derivatives 18
and 19, respectively. The structures of the new synthesized compounds were characterized by using
1
IR, H, 13C NMR spectra, and microanalysis. Selected members of these compounds were screened
for antibacterial activity.
Keywords Pyridin-2(1H)-one; acyclonucleosides; 1,2,3-triazole; [3+2] cycloaddition
INTRODUCTION
3-Cyanopyridin-2-(1H)-one and their fused heterocyclic analogues have
diverse biological and pharmacological activities, particularly as inhibitors
of farnesyl transferase,[1] HIV-integrase strand transfer,[2] insulin-like growth
factor-1 receptor (IGF-1R) kinase,[3] anaplastic lymphoma kinase (ALK),[4]
and hepatitis B virus (HBV).[5] Pyridin-2-(1H)-one have been also reported
as antimicrobial,[6–8] antidepressant, cardiotonic,[9] anticancer,[10] and an-
timalarial.[11] Moreover, amrinone has been established as a positive in-
otropic and vasodilatatory agent used in the clinic for the treatment of heart
failure.[12,13]
3-Cyanopyridine derivatives have been described as intermediates in
the synthesis of pyrido[2,3-d]pyrimidines as antihistaminic agents[14,15]
Received 6 February 2011; accepted 18 April 2011.
Address correspondence to Ahmed H. Moustafa, Department of Chemistry, Faculty of Science,
Zagazig University, Zagazig 1234, Egypt. E-mail: ah hu mostafa@yahoo.com
340

Synthesis of Acyclovir and HBG Analogues
341
O
O
N
N
N
N
HN
HN
H2N
HO
N
H2N
HO
N
O
ACV
HBG
FIGURE 1 Structure of acyclovir and HBG.
and acyclo-3-deazapyrimidine S-nucleosides that are active toward HIV.[16]
Acyclic nucleosides[17–19] and their chemotherapeutic value have attracted
the attention toward the synthesis of various analogues with variant chemical
modifications. The above aspects attracted our attention to the synthesis of
the acyclic nucleoside of nicotinonitrile derivatives of the well-known an-
tiviral agent acyclovir [18–20] having the (hydroxyethoxy)methyl residue and
its analogues. Moreover, these glycone residues have been linked to the
pyridine ring via a triazole ring acyclic nucleosides using a click chemistry
approach (Figure 1).
RESULTS AND DISCUSSION
Pyridin-2-(1H)-one and azinones in general are weak acids that form
mesomeric anions that react with an electrophilic reagent on the oxygen,
nitrogen, or carbon atom. The anion from pyridin-2(1H)-one can be mainly
alkylated on nitrogen; Na and K salts predominantly undergo N -alkylation
(Figure 2).[20]
Reaction of pyridin-2(1H)-one 1 with 4-bromobutyl acetate (2) and (2-
acetoxyethoxy)methyl bromide (3)[21] in the presence of potassium carbon-
ate in anhydrous acetone/DMF at room temperature gave the correspond-
ing 2-(acetoxybutyloxy)-4-(4-chlorophenyl)-6-(thien-2-yl)nicotinonitrile (4)
and 2-[(acetoxyethoxy)methyloxy]-4-(4-chlorophenyl)-6-(thien-2-yl)nicotin-
onitrile (5), in good yields (Scheme 1), but not the expected N -acyclic nu-
cleosides 4a and 5a.
O
N
H
FIGURE 2 Alkylation profile of pyridine-2(1H)-one.

342
A. H. Moustafa et al.
Ar
Ar
N
CN
CN
OH
O
N
H
S
S
1
AcO
Br
X
Acetone/DMF
K2CO3, r.t.
2
3
; X = CH2
; X = O
Ar
N
Ar
N
CN
CN
O
O
S
d
AcO
S
X
b
c
AcO
a
X
4; X = CH2
5; X = O
4a; X = CH2
5b; X = O
Et3N/H2O
CH3OH
Ar
CN
O
N
S
d X
b
HO
a
c
6
; X = CH2
Ar = p.Cl-C6H4
7
; X = O
SCHEME 1 Acyclovir analogues.
The infrared (IR) spectra of compounds 4 and 5 agreed with absorption
bands at 2214–2216 and 1737–1738 cm−1 for C N and C O of acetoxy
groups. The absence of a band that can be due to an N C O group agreed
1
with the structures 4 and 5 and not 4a and 5a. H NMR spectra of 4 and
5 showed the structure. The 13C NMR spectra showed the characteristic
bands for C N and C O of acetoxy groups at δ 115.5 and 170.7 ppm,
respectively.

Synthesis of Acyclovir and HBG Analogues
343
OH
Cl
Ar
CN
(8)
Cl
O
N
K2CO3/DMF, heat
OH
Hb
Cl
Hc
S
Hc'
9
Ha'
Ha
Ar
Ar
O
CN
CN
Cl
(10)
K2CO3/DMF, r.t.
O
N
O
N
H
Hb
Hc
S
S
11
Hc'
O
1
Ha
Ha'
Ar
N
CN
Br
(12)
O
K2CO3/DMF, r.t.
S
Hc
13
Hb
Ha
SCHEME 2 Alkylation with functionalized alkyl halides.
Deacetylation of compound 4 and 5 by using triethylamine/methanol
and a few drops of water [22–24] gave the corresponding deacetylated deriva-
tives 6 and 7, respectively (Scheme 1). The IR spectra of 6 and 7 revealed the
absence of band at 1737–1738 cm−1 for the acetoxy groups and presence of
bands at 3410–3426 cm−1 for OH groups.
Similarly, alkylation of pyridin-2(1H)-one 1 has been investigated using
functionalized alkyl halides that are suitable for further chemical modifi-
cation to provide acyclic nucleoside analogues. Thus, reaction of pyridin-
2(1H)-one 1 with 1,3-dichloropropan-2-ol (8) in the presence of potas-
sium carbonate in dry acetone/DMF for overnight at room temperature,
then at reflux for 6 hours, afforded 2-(3-chloro-2-hydroxyprop-1-yloxy)-4-
(4-chlorophenyl)-6-thien-2-yl)nicotinonitrile (9) as one isomer in moder-
ate yield (48%) (Scheme 2). Its IR spectrum showed bands at 3424 and
2217 cm−1 characteristic for OH and C N groups. 1H and 13C NMR spectra
of 9 showed the characteristic signals corresponding to the presence of one
isomer.
Reaction of pyridin-2(1H)-one 1 with epichlorohydrin (10) and allyl
bromide (12) in the presence of potassium carbonate in dry acetone/DMF at

344
A. H. Moustafa et al.
room temperature afforded 4-(4-chlorophenyl)-2-(oxiran-2-ylmethyloxy)-6-
(thien-2-yl)nicotinonitrile (11) and 2-(allyloxy)-4-(4-chlorophenyl)-6-(thien-
2-yl)nicotinonitrile (13), respectively (Scheme 2). The 1H NMR spectrum of
11 showed signals at δ 2.83, 2.89, and 4.29 ppm as triplet and doublet of
doublets corresponding to Ha, Haꢁ, and Hb, in addition to doublet signals
at δ 4.38 and 4.88 ppm for Hc and Hcꢁ of (OCH2), respectively. Its 13C NMR
spectrum showed signals at δ 44.6 and 49.5 ppm corresponding to CH2O
and CHO of oxiran ring and δ 68.5 ppm for OCH2 group. The IR spectra
of compounds 9, 11, and 13 revealed the absence of N C O groups; this
confirmed that the alkylation occured on the oxygen atom and not on the
nitrogen.
The next target is the acyclonucleoside 19 and its C-analogues 18,
which required two synthons, the propargyl derivative as 15 and the
azide derivatives 16 and 17. Thus, reaction of pyridin-2(1H)-one 1
with propargyl bromide (14) in the presence of anhydrous potassium
carbonate gave the corresponding 2-(prop-2-yloxy)-4-(4-chlorophenyl)-6-
(thien-2-yl)nicotinonitrile (15). The 4-azidobutyl acetate (16) and [(2-
acetoxyethoxy)methyl]azide (17) were prepared from 4-bromobutylacetate
(2) and (2-acetoxyethoxy)methyl bromide (3) by replacement of the halide
with azide ion as reported in the literature[25,26] (Scheme 3).
Applying click chemistry for the reaction of 15 with 16 and 17 to
achieve the [3+2] cycloaddition reaction in the presence of CuSO4.5H2O
and sodium ascorbate[27] gave 4-(4-((4-(4-chlorophenyl)-3-cyano-6(thien-2-
yl)pyridine-2-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butyl acetate (18) and
2-((4-((4-(4-chlorophenyl)-3-cyano-6(thiophen-2yl)pyridine-2-yloxy)methyl)
-1H-1,2,3-triazol-yl)methoxy)ethyl acetate (19), respectively. The dipolar
cycloaddition had taken place regiospecifically because of the steric factor.
The structures of 18 and 19 were proven on the basis of spectroscopic
1
analysis (IR and 1H, 13C NMR). H NMR spectrum of 18 showed multi-
plets at δ 1.52 and 1.85 ppm for CH2(c) and CH2(b), with other signals at
1.95, 4.32, and 4.51 ppm characteristic for CH3 of acetoxy group, CH2OCO
(d) and NCH2(a), in addition to a singlet at 5.62 ppm for CH2O-pyridine,
respectively. Its 13C NMR spectrum showed signals at 22.0, 25.5, 26.8, 49.4,
63.1, and 68.9 ppm corresponding to CH3CO, 2CH2, NCH2, CHOCO and
OCH2-pyridine, respectively. The spectroscopic analysis data for compound
19 was in agreement with the structure.
Antimicrobial Activity
Acyclic nucleosides 6, 7, 9, 11, 13, 18, and 19 were evaluated for an-
tibacterial activity against Staphylococcus aureus and Bacillus subtilis as Gram
(+ve) bacteria and Pseudomonas aeruginosa and Escherichia coli as Gram (−ve)
bacteria, using a cup plate agar diffusion method.[28] Ampicillin was used
as a reference to evaluate the potency of tested compounds. Nucleosides

Synthesis of Acyclovir and HBG Analogues
345
TABLE 1 Antimicrobial activity of tested compounds (inhibition zones mm, minimum inhibitory
concentration µg/mL)
Compound
no.
Staphylococcus
aureus
Bacillus
subtilis
Pseudomonas
aeruginosa
Escherichia
coli
6
7
9
11
13
18
19
13
11
0
8.5
5
15
10
7
7
10
0
8
4.5
8
27
28
0
25
14
24
23.5
23
4
9
1
3
2
6
5
2
6
6
Ampicillin
SCHEME 3 Synthesis of triazole analogues.

346
A. H. Moustafa et al.
6, 7, and 18 showed higher antibacterial activity compared to the standard
drug (ampicillin). Compounds 11 and 19 showed moderate antibacterial
activity compared to the standard drug, whereas the allyloxy nicotinonitrile
13 showed lower antibacterial activity compared to the standard drug (ampi-
cillin). Compound 9 did not show any activity against tested micro-organisms.
The results of the biological activities encourage further work on such a ring
system (Table 1).
CONCLUSION
The alkylation of 4-(4-chlorophenyl)-2-oxo-6-(thien-2-yl)-1,2-dihydropy-
ridine-3-carbonitrile with 4-bromobutyl acetate, (2-acetoxyethoxy)methyl
bromide, 1,3-dichloro-2-propanol, epichlorohydrin, allyl, and propargyl
bromide afforded O-alkyl products and not the expected N -alkylated ana-
logues. The 1,2,3-triazole acyclonucleosides were obtained by the reaction
of 2-(prop-2-yloxy)nicotinonitrile with the azide derivatives 2 and 3 via click
chemistry. The glycosides 6, 7, 11, 13, 18, and 19 showed significant antibac-
terial activity and futher evaluation against other pathogens is underway.
EXPERIMENTAL
All melting points are uncorrected and were measured using an Electro
thermal IA 9100 apparatus. TLC was performed on Merck Silica Gel 60F254
with detection by ultraviolet (UV) light and by the charring with 10% EtOH
solution of H2SO4. The IR spectra (KBr disc) were recorded on a Pye Unicam
Sp-3-300 or a Shimadzu FTIR 8101 PC infrared spectrophotometer. The
operation frequency was 300 MHz for 1H and 75.5 MHZ for 13C NMR using
JOEL-JNM-LA 300 MHz spectrometer. The coupling constants (J) are given
in hertz. The chemical shifts are expressed on the δ (ppm) scale using TMS
as the standard reference. Elemental analyses were determined on a Perkin
Elmer 240 (microanalysis; Cairo University, Cairo, Egypt).
General Procedure for Alkylation of Pyridin-2(1H)-one (1)
A mixture of pyridin-2(1H)-one 1 (0.01 mol) and potassium carbonate
(0.01 mol) was stirred in dry acetone/DMF (15 mL) for 1 hour; then the
alkylating agent (0.011 mol) was added. The reaction mixture was stirred
for overnight at room temperature, filtered off, and the solvent was evapo-
rated under reduced pressure. The residue was dried and crystallized from
ethanol. In the case of 1,3-dichloropropan-2-ol, the reaction mixture re-
quired heating under reflux for 6 hours.
2-(Acetoxybutyloxy)-4-(4-chlorophenyl)-6-(thien-2-yl)nicotinonitrile (4).
83% yield; Pale yellow crystals; m.p. 145–146◦C; IR (KBr) 2215 cm−1 (C N)
and 1737 cm−1 (C O, acetoxy); 1H NMR spectrum (300 MHz; DMSO-d6) δ

Synthesis of Acyclovir and HBG Analogues
347
1.63 (m, 2H, CH2(c)), 1.71 (m, 2 H, CH2(b)), 1.89 (s, 3 H, CH3CO), 3.95
(t, 2H, J = 5.76 Hz, OCH2(a)), 4.37 (t, 2H, J = 5.89 Hz, CH2OCO(d)),
7.09 (t, 1H, J = 3.96, 4.46 Hz, thiophene-H), 7.51 (d, 2H, J = 8.40 Hz,
Ar-H), 7.60 (d, 2H, J = 8.40 Hz, Ar-H), 7.62 (s, 1H, pyridine-H-5), 7.68 (d,
1H, J = 4.46 Hz, thiophene-H), 7.93 (d, 1H, J = 3.96 Hz, thiophene-H); 13C
NMR (75 MHz DMSO-d6) δ 21.1 (CH3CO), 25.2, 25.4 (2CH2), 63.9 (OCH2),
67.3 (CH2OCO), 91.9, 112.4, 115.5 (C N), 129.1, 129.3, 129.4, 130.8, 131.7,
134.9, 135.5, 142.9, 153.4, 155.3, 164.3 (Ar-C) and 170.7(C O). Anal. Calcd
for C22H19ClN2O3S (426.92): C, 61.89; H, 4.49; N, 6.56. Found: C, 61.88; H,
4.47; N, 6.55.
2-[(Acetoxyethoxy)methyloxy]-4-(4-chlorophenyl)-6-(thien-2-yl)nicotino-
nitrile (5). 78% yield; Pale yellow crystals; m.p. 105–106◦C; IR (KBr) 2214
cm−1 (C N) and 1738 cm−1 (C O, acetoxy); 1H NMR spectrum (300 MHz;
DMSO-d6) δ 1.92 (s, 3 H, CH3CO), 4.32 (t, 2H, J = 5.4 Hz, OCH2(c)),
4.58 (t, 2H, J = 5.4 Hz, CH2OCO(d)), 6.12 (s, 2H, OCH2O(a)), 7.1 (t,
1H, J = 4.03, 4.10 Hz, thiophene-H), 7.52 (d, 2H, J = 8.32 Hz, Ar-H),
7.61 (d, 2H, J = 8.32 Hz, Ar-H), 7.65 (s, 1H, pyridine-H-5), 7.70 (d, 1H,
J = 4.10 Hz, thiophene-H), 7.95 (d, J = 4.03 Hz, 1H, thiophene-H); 13C
NMR (75 MHz DMSO-d6) δ 21.1 (CH3CO), 62.3, 65.7 and 69.9 (2CH2 and
OCH2O), 92.1, 112.8, 115.4 (C N), 129.3, 129.5, 130.9, 131.9, 132.1, 134.8,
135.5, 142.7, 153.3, 155.5, 164.0 (Ar-C) and 170.7 (C O). Anal. Calcd for
C21H17ClN2O4S (428.89): C, 58.81; H, 4.00; N, 6.53. Found: C, 58.80; H,
4.02; N, 6.55.
4-(4-Chlorophenyl)-2-(hydroxybutyloxy)-6-(thien-2-yl)nicotinonitrile (6).
Triethylamine (0.5 mL) was added to a solution of 4 (0.01 mol, 4.26 g) in
MeOH (20 mL) and a few drops of water. The mixture was stirred overnight
at room temperature, then refluxed for 4 hours, evaporated under reduced
pressure and the residue was co-evaporated with MeOH until the triethy-
lamine was removed. The residue was crystallized from ethanol to give pale
yellow crystals. 86% yield; m.p. 201–203◦C, IR (KBr) 2214 cm−1 (C N)
and 3410 cm−1 (OH); 1H NMR spectrum (300 MHz; DMSO-d6) δ 1.61 (m,
2H,CH2(c)), 1.85 (m, 2H, CH2(b)), 3.49 (q, 2H, J = 6.34 Hz, CH2OH(d)),
4.47 (t, 2H, J = 5.09 Hz, OCH2(a)), 4.53 (t, 1H, J = 4.49 Hz, OH), 7.24 (t,
1H, J = 3.87, 4.01 Hz, thiophene-H), 7.66 (d, 2H, J = 8.52 Hz, Ar-H), 7.75 (d,
2H, J = 8.52 Hz, Ar-H), 7.80 (s, 1H, pyridine-H-5), 7.83 (d, 1H, J = 4.01 Hz,
thiophene-H), 8.09 (d, 1H, J = 3.87 Hz, thiophene-H). 13C NMR (75 MHz
DMSO-d6) δ 25.57, 29.35 (2CH2), 60.84 (CH2OH), 67.72 (OCH2), 112.3,
115.6 (C N), 129.1, 129.2, 129.3, 129.5, 130.9, 131.8, 135.0, 135.5, 143.0,
153.4, 155.4 and 164.4 (Ar-C). Anal. Calcd for C20H17ClN2O2S (384.88): C,
62.41; H, 4.45; N, 7.28. Found: C, 62.43; H, 4.43; N, 7.25.
2-[(Hydroxyethoxy)methyloxy]-4-(4-chlorophenyl)-6-(thien-2-yl)
nicotinonitrile (7). Triethylamine (0.5 mL) was added to a solution of
5 (0.01 mol, 4.28 g) in MeOH (20 mL) and a few drops of water. The
mixture was prepared as above to give pale yellow crystals. 88% yield; m.p.

348
A. H. Moustafa et al.
196–198◦C. IR (KBr): 3426 cm−1 (OH) and 2217 cm−1 (C N); 1H NMR
spectrum (300 MHz; DMSO-d6) δ 3.81 (q, 2H, J = 5.29 Hz, CH2OH(d)),
4.54 (t, 2H, J = 5.01 Hz, OCH2(c)), 4.93 (t, 1H, J = 5.29 Hz, OH), 6.01
(s, 2H, OCH2O(a)), 7.23 (t, 1H, J = 3.99, 4.56 Hz, thiophene-H), 7.65
(d, 2H, J = 8.45 Hz, Ar-H), 7.73 (d, 2H, J = 8.45 Hz, Ar-H), 7.77 (s, 1H,
pyridine-H-5), 7.85 (d, 1H, J = 4.56 Hz, thiophene-H), 8.07 (d, J = 3.99 Hz,
1H, thiophene-H); 13C NMR (75 MHz DMSO-d6) δ 59.46, 69.4, (2CH2),
69.8 (OCH2O), 112.4, 115.6 (C N), 129.2, 129.3, 129.5, 130.6, 130.9,
131.8, 135.0, 135.5, 142.9, 153.3, 155.5 and 164.4 (Ar-C). Anal. Calcd. for
C19H15ClN2O3S (386.85): C, 58.99; H, 3.91; N, 7.24. Found: C, 59.01; H,
3.92; N, 7.26.
2-(3-Chloro-2-hydroxypropoxy)-4-(4-chlorophenyl)-6-(thien-2-yl)nicotino
nitrile (9). 48% yield; Pale yellow crystals; m.p. 99–100◦C; IR (KBr) 3424
cm−1 (OH) and 2217 cm−1 (C N). 1H NMR spectrum (300 MHz; DMSO-d6)
δ 3.61 (dd, 1H, J = 5.43 Hz, J = 11.13 Hz, H-a’), 3.67 (dd, 1H, J = 5.64 Hz,
J = 11.17 Hz, H-a), 3.96 (dd, 1H, J = 5.81 Hz, J = 10.23 Hz, H-c’), 4.05
(dd, 1H, J = 5.15 Hz, J = 10.23 Hz, H-c), 4.40 (m, 1H, H-b), 5.53 (d, 1H, J
= 5.23 Hz, OH), 7.11 (t, 1H, J = 4.14, 5.62 Hz, thiophene-H), 7.46 (d, 2H,
J = 8.50 Hz, Ar-H), 7.52 (d, 2H, J = 8.50 Hz, Ar-H), 7.61 (s, 1H, pyridine-
H-5), 7.70 (d, 1H, J = 5.62 Hz, thiophene-H), 7.96 (d, 1H, J = 4.14 Hz,
thiophene-H); 13C NMR (75 MHz DMSO-d6) δ 47.01 (CH2Cl), 68.4
(CHOH), 68.64 (OCH2), 92.1, 112.7, 115.4 (C N), 129.3, 129.5, 130.9,
131.9, 134.9, 135.5, 136.0, 142.8, 153.3, 155.5 and 164.1 (Ar-C). Anal. Calcd
for C19H14Cl2N2O2S (405.30): C, 56.31; H, 3.48; N, 6.91. Found: C, 56.30;
H, 3.46; N, 6.90.
4-(4-Chlorophenyl)-2-(oxiran-2-ylmethoxy)-6-(thien-2-yl)nicotinonitrile
(11). 71% yield; Pale yellow crystals; m.p. 185–187◦C; IR (KBr) 2216 cm−1
1
(C N); H NMR spectrum (300 MHz; DMSO-d6) δ 2.83 (t, 1H, J = 1.50,
4.50 Hz, H-a), 2.89 (t, 1H, J = 4.20, 4.50 Hz, H-a’), 4.29 (dd, 1H, J = 6.30
Hz, H-b), 4.83 (d, 1H, J = 2.17 Hz, H-c’), 4.88 (d, 1H, J = 2.27 Hz, H-c),
7.24 (t, 1H, J = 3.95, 4.07 Hz, thiophene-H), 7.66 (d, 2H, J = 8.43 Hz,
Ar-H), 7.74 (d, 2H, J = 8.43 Hz, Ar-H), 7.79 (s, 1H, pyridine-H-5), 7.82 (d,
1H, J = 4.07 Hz, thiophene-H), 8.10 (d, 1H, J = 3.95 Hz, thiophene-H); 13
C
NMR (75 MHz DMSO-d6) δ 44.6 (CH2O, oxiran), 49.5 (CHO, oxiran), 68.5
(OCH2), 91.8, 113.1, 115.5 (C N), 129.2, 129.4, 129.7, 130.8, 131.9, 134.4,
135.4, 142.7, 153.2, 157.7 and 163.8 (Ar-C). Anal. Calcd for C19H13ClN2O2S
(368.84): C, 61.87; H, 3.55; N, 7.60. Found: C, 61.85; H, 3.54; N, 7.61.
2-(Allyloxy)-4-(4-chlorophenyl)-6-(thien-2-yl)nicotinonitrile (13). 82%
yield; Pale yellow crystals; m.p. 201–203◦C; IR (KBr) 2216.7 cm−1 (C N); 1H
NMR spectrum (300 MHz; DMSO-d6) δ 5.08 (d, 2 H, J = 5.10 Hz, OCH2),
5.33 (d, 1H, J = 10.2 Hz, H-a), 5.52 (d, 1H, J = 17.4 Hz, H-b), 6.16 (m, 1 H,
H-c), 7.24 (t, 1H, J = 4.03, 4.56 Hz, thiophene-H), 7.67 (d, 2H, J = 8.40 Hz,
Ar-H), 7.76 (d, 2H, J = 8.40 Hz, Ar-H), 7.80 (s, 1H, pyridine-H-5), 7.83 (d,
1H, J = 4.56 Hz, thiophene-H), 8.11 (d, 1H, J = 4.03 Hz, thiophene-H);

Synthesis of Acyclovir and HBG Analogues
349
13C NMR (75 MHz DMSO-d6) δ 68.0 (OCH2), 112.6 ( CH2), 115.5
(C N), 119.1 (CH ), 128.3, 128.9, 129.3, 129.5, 130.9, 131.9, 133.1, 134.9,
135.5, 142.8, 153.3, 155.5 and 163.9 (Ar-C). Anal. Calcd for C19H13ClN2OS
(352.84): C, 64.68; H, 3.71; N, 7.94. Found: C, 64.69; H, 3.70; N, 7.93.
2-(Prop-2-ynyloxy)-4-(4-chlorophenyl)-6-(thien-2-yl)nicotinonitrile (15).
87% yield; Pale yellow crystals; m.p. 218–220◦C; IR (KBr) 2211 cm−1 (C N);
1H NMR spectrum (300 MHz; DMSO-d6) δ 3.64 (t, 1H, J = 1.80 Hz, CH),
5.21 (dd, 2H, J = 1.80, 10.5 Hz, OCH2), 7.23 (t, 1H, J = 3.88, 5.09 Hz,
thiophene-H), 7.67 (d, 2H, J = 9.04 Hz, Ar-H), 7.76 (d, 2H, J = 9.04 Hz,
Ar-H), 7.78 (s, 1H, pyridine-H-5), 7.81 (d, 1H, J = 5.09 Hz, thiophene-H),
8.09 (d, 1H, J = 3.88 Hz, thiophene-H); 13C NMR (75 MHz DMSO-d6) δ 52.2
(OCH2), 78.3, 78.9 (C C), 91.9, 113.2, 115.4 (C N), 129.3, 129.5, 130.9,
131.0, 132.2, 134.8, 135.6, 142.6, 153.3, 155.7 and 163.0 (Ar-C). Anal. Calcd
for C19H11ClN2OS (350.82): C, 65.05; H, 3.16; N, 7.99. Found: C, 65.03; H,
3.14; N, 8.00.
General Procedure for Preparation of Triazoles 18 and 19
4-Azidobutyl acetate (16) or 2(azidomethoxy)ethyl acetate (17)
(0.011 mol) and 2-(prop-2-ynyloxy)-4-(4-chlorophenyl)-6-(thien-2-yl)-
nicotinonitrile (15) (0.01 mol) were dissolved in water/tetrahydrofuran
(30:70 (10 mL)). The reaction mixture was stirred at room temperature
for 10 minutes, while an aqueous solution of CuSO4·5H2O (2.0 mL, 5%)
and an aqueous solution of (+)-sodium L-ascorbate (2.0 mL, 10%) were
added. The reaction mixture was stirred until complete consumption of
the starting material indicated by thin layer chromatography (TLC; 3–5
hours). The reaction mixture was evaporated under reduced pressure,
extracted with dichloromethane and the organic phase was dried over
anhydrous Na2SO4. After filtration, the solvent was evaporated to dryness
under reduced pressure[27] and the residue was crystallized from ethanol.
4-(4-((4-(4-Chlorophenyl)-3-cyano-6-(thien-2-yl)pyridine-2-yloxy)methyl)-
1H-1,2,3-triazol-1-yl)butyl acetate (18). 54% yield; Pale yellow crystals; m.p.
108–110◦C; IR (KBr) 2216 cm−1 (C N) and 1731 cm−1 (C O, acetoxy);
1H NMR spectrum (300 MHz; DMSO-d6) δ 1.52 (m, 2 H, CH2(c)), 1.85 (m,
2 H, CH2(b)), 1.95 (s, 3 H, CH3CO), 4.32 (t, 2H, J = 5.51 Hz, CH2OCO
(d)), 4.51 (t, 2H, J = 5.74 Hz, NCH2 (a)), 5.62 (s, 2H, OCH2), 7.24 (t,
1H, J = 3.12, 3.96 Hz, thiophene-H), 7.66 (d, 2H, J = 8.35 Hz, Ar-H),
7.71 (d, 2H, J = 8.35 Hz, Ar-H), 7.80 (s, 1H, pyridine-H-5), 7.82 (s, 1H,
triazole-H), 8.11 (d, 1H, J = 3.96 Hz, thiophene-H), 8.23 (d, 1H, J = 3.12 Hz,
thiophene-H); 13C NMR (75 MHz DMSO-d6) δ 22.0 (CH3CO), 25.5, 26.8
(2CH2), 49.4 (NCH2), 63.1 (CH2OCO), 68.9 (OCH2-pyridine), 92.1,
113.0, 115.5 (C N), 128.3, 128.9, 129.3, 129.6, 130.9, 131.8, 133.9, 135.2,
141.7, 142.5, 152.8, 155.1, 162.0 (Ar-C) and 170.0 (C O). Anal. Calcd for

350
A. H. Moustafa et al.
C25H22ClN5O3S (507.99): C, 59.11; H, 4.37; N, 13.79. Found: C, 59.13; H,
4.36; N, 13.78.
2-((4-((4-(4-Chlorophenyl)-3-cyano-6-(thien-2yl)pyridine-2-yloxy)methyl)-
1H-1,2,3-triazol-yl)methoxy)ethyl acetate (19). 61% yield; Pale yellow
crystals; m.p. 95–97◦C. IR (KBr) 2212 cm−1 (C N) and 1737 cm−1 (C O,
acetoxy); 1H NMR spectrum (300 MHz; DMSO-d6) δ 1.89 (s, 3 H, CH3CO),
3.86 (t, 2H, J = 5.28 Hz, OCH2(c)), 4.37 (t, 2H, J = 5.28 Hz, CH2OCO(d)),
5.10 (s, 2H, OCH2), 5.65 (s, 2H, NCH2O(a)), 7.25 (t, 1H, J = 3.39, 4.17 Hz,
thiophene-H), 7.60 (d, 2H, J = 8.35 Hz, Ar-H), 7.72 (d, 2H, J = 8.35 Hz,
Ar-H), 7.78 (s, 1H, pyridine-H-5), 7.97 (s, 1H, triazole-H), 7.81 (d, 1H, J =
4.17 Hz, thiophene-H), 8.12 (d, 1H, J = 3.39 Hz, thiophene-H); 13C NMR
(75 MHz DMSO-d6) δ 21.08 (CH3CO), 60.27 (OCH2). 62.72 (CH2OCO),
65.44 (NCH2O), 74.5 (OCH2), 92.3, 112.8, 115.5 (C N), 125.8, 129.3,
129.5, 130.9, 132.0, 134.8, 135.5, 142.2, 142.4, 142.8, 153.3, 155.6, 163.7
(Ar-C) and 170.4 (C O). Anal. Calcd for C24H20ClN5O4S (509.96): C,
56.52; H, 3.95; N, 13.73. Found: C, 56.54; H, 3.96; N, 13.72.
Antimicrobial Activity
The antimicrobial activities of some newly synthesized compounds were
screened for their antibacterial activity against six species of bacteria and
one fungi, namely, Staphylococcus aureus and Bacillus subtilis as Gram +ve and
Pseudomonas aeruginosa and Escherichia coli as Gram −ve using a cup plate
agar diffusion method.[28] The tested compounds were dissolved in dimethyl
sulfoxide to obtain a solution of 1 µg/mL concentration. The inhibition
zones were measured in (mm) at the end of an incubation period of 48
hours at 37◦C. Dimethyl sulfoxide showed no inhibition zones. Ampicillin
was used as reference.
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