Synthesis of some novel hydrazono acyclic nucleoside analogues

Article abstract of DOI:10.3762/bjoc.6.49

The syntheses of novel hydrazono acyclic nucleosides similar to miconazole scaffolds are described. In this series of acyclic nucleosides, pyrimidine as well as purine and other azole derivatives replaced the imidazole function in miconazole and the ether

Full text of DOI:10.3762/bjoc.6.49

Synthesis of some novel hydrazono acyclic
nucleoside analogues
Mohammad N. Soltani Rad*1, Ali Khalafi-Nezhad2 and Somayeh Behrouz1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2010, 6, No. 49. doi:10.3762/bjoc.6.49
1Department of Chemistry, Faculty of Basic Sciences, Shiraz
University of Technology, Shiraz 71555-313, Iran, Fax:
+98-711-7354523 and 2Department of Chemistry, College of
Sciences, Shiraz University, Shiraz 71454, Iran
Received: 16 February 2010
Accepted: 23 April 2010
Published: 17 May 2010
Email:
Associate Editor: D. Y. Gin
Mohammad N. Soltani Rad* - soltani@sutech.ac.ir;
nsoltanirad@gmail.com
© 2010 Soltani Rad et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
acyclic nucleoside; chemotherapeutic agent; hydrazone; ketone;
miconazole
Abstract
The syntheses of novel hydrazono acyclic nucleosides similar to miconazole scaffolds are described. In this series of acyclic
nucleosides, pyrimidine as well as purine and other azole derivatives replaced the imidazole function in miconazole and the ether
group was replaced with a hydrazone moiety using phenylhydrazine. To interpret the dominant formation of (E)-hydrazone deriva-
tives rather than (Z)-isomers, PM3 semiempirical quantum mechanic calculations were carried out which indicated that the (E)-
isomers had the lower heats of formation.
Introduction
In recent years, fungal infections have become an important Some of the best known antifungal azole drugs having rational
complication and a major cause of morbidity and mortality in versatility in structures are miconazole (A), oxiconazole (B) and
immune-compromised individuals who suffer from tuber- related compounds, namely aryl azoles (Figure 1).
culosis, cancer or AIDS, and who undergo organ transplants
[1,2]. Up to now, there has been an increase in the number of Pharmacokinetic properties and cellular permeability of a drug
antifungal drugs available with various structures and scaffolds. can be modulated by derivatization to bio-reversible forms of
However, their clinical value has been limited by the emerg- the drug, namely hydrazones [3]. Hydrazone derivatives are
ence of drug resistance, high risk of toxicity, insufficiencies in prominent structural motifs in numerous pharmaceutically
their antifungal activity as well as undesirable side effects. This active compounds. Many well known drugs with various clini-
situation has led to an ongoing search for safe and efficient cal activities, such as chemotherapeutic (e.g. nitrofurantoin
chemotherapeutic agents with potent broad-spectrum antifungal [4,5]), antihypertensive (e.g. endralazine [4,6]), antibiotic (e.g.
activities.
rifampicin [4]), tuberculostatic (e.g. glyconiazide [4,7,8]),
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Beilstein J. Org. Chem. 2010, 6, No. 49.
Figure 1: Chemical structures of miconazole (A), oxiconazole (B) and hydrazono acyclic nucleoside analogue (C).
skeletal muscle relaxant and antispasmodic (e.g. dantrolene and the ether bond in miconazole (i.e. CHOCH2) was replaced
[4,9]), antiseptic (e.g. nitrofural [4]) and intercalating antineo- with hydrazono bond (i.e. C=NNH) in the newly synthesized
plastic (e.g. bisantrene [4,10]), contain a hydrazone moiety in compounds. Figure 1 shows the general structure of hydrazono
their structure. Furthermore, various structurally related acyclic nucleoside compound C.
miconazole bioactive hydrazones are known as antimicrobial
and antifungal agents [11,12].
Results and Discussion
The synthetic pathways for compounds 2a–2g and 2h–2o are
The significance of nucleoside chemistry in drug discovery is outlined in Scheme 1 and Scheme 2. Two different strategies
well-known and fully established in medicinal chemistry [13- were considered for the synthesis of the title compounds taking
16]. Acyclic nucleosides constitute a special class of nucleoside into account the differences in chemical behavior of purine and
analogues which have attracted great interest due to their broad- pyrimidine nucleobases compared to azoles. Because of their
spectrum chemotherapeutic activities against cancer and infec- better solubility, reactivity and ease of separation of products,
tions caused by viruses, microbes and other pathogenic the reactions of the azole derivatives were conducted according
microorganisms. Moreover, antitumor and antiviral activities of to Scheme 1.
various hydrazone derivatives of nucleosides have also been
reported [16-18].
As shown in Scheme 1, condensation of imidazole, 2-phenylim-
idazole, hydantoin, benzimidazole and benzotriazole with
Inspired by the miconazole scaffold and also as an extension of 2-bromoacetophenone and 4′-methoxy-2-bromoacetophenone
our ongoing research in the design and synthesis of novel gave the key intermediates, ketones 1a–1g. Based on our litera-
acyclic nucleosides [19-25], hereby, we wish to report the syn- ture survey, we recognized that among published methods for
thesis of some novel hydrazono acyclic nucleosides having N-alkylation of imidazole derivatives [26-34], the method
similar scaffolds to the miconazole framework. In these com- developed by Liu et al. [35] was the most appropriate one for
pounds, the nucleobases including pyrimidines, purines and N-alkylation of azoles and their derivatives, since in this
other azole derivatives were substituted as heterocyclic cores method the formation of quaternary imidazolium salts is largely
Scheme 1: Synthetic pathway for hydrazono acyclic nucleoside 2a–2g.
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Beilstein J. Org. Chem. 2010, 6, No. 49.
prevented. However, from our experience, using triethylamine derivatives with 2-bromoacetophenones and TEA in the pres-
(TEA) as a homogeneous base instead of K2CO3 (which was ence of a catalytic amount of n-tetrabutylammonium bromide
previously employed by Liu et al.) produced more satisfactory (TBAB) in refluxing anhydrous acetonitrile (MeCN) provided
results. Hence, the reaction of imidazole or benzimidazole ketones 1a–1g in good yields (60–70%). Subsequently, the
Table 1: Synthesized hydrazono acyclic nucleoside analogues.
Entry
Product (2)
mp (°C)
Yielda (%)
a
169.2
87
b
171.3
84
c
d
e
174.5
200.1
165.9
82
89
75
f
148.4
81
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Beilstein J. Org. Chem. 2010, 6, No. 49.
Table 1: Synthesized hydrazono acyclic nucleoside analogues. (continued)
g
137.9
82
h
300.1
78
i
213.8
80
j
k
l
205.1
181.5
173.9
75
79
74
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Beilstein J. Org. Chem. 2010, 6, No. 49.
Table 1: Synthesized hydrazono acyclic nucleoside analogues. (continued)
m
100.1
81
n
104.7
71
o
209.3
84
aIsolated yield.
ketones 1a–1g were converted to the pure hydrazone deriva- using similar method as outlined in Scheme 1. This proved to be
tives 2a–2g by treatment with phenylhydrazine in the presence the case, and the corresponding ketones 1h–1o could not be
of a catalytic amount of acetic acid in ethanol, followed by obtained satisfactorily by this method. The main limitation of
heating at reflux (Scheme 1).
using the aforementioned pathway for purines and pyrimidines
is their low solubility in acetonitrile, which results in low yields
For the synthesis of the purine and pyrimidine analogues of of the corresponding ketones 1h–1o. Thus, we have modified
target compounds 2h–2o, we envisaged that there might be Scheme 1 by using DMF as the solvent of choice for nucleo-
substantial problems in the synthesis of the desired ketones bases (Scheme 2).
Scheme 2: Synthetic pathway for hydrazono acyclic nucleoside 2h–2o.
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Beilstein J. Org. Chem. 2010, 6, No. 49.
Thus, the condensation of purine and pyrimidine nucleobases as the energy difference between the (Z)- and (E)-isomer (ΔE = EZ
well as theophylline and theobromine with 2-bromoaceto- − EE (kcal/mol)). As can be seen in Table 2, calculated ΔE
phenones using K2CO3 in anhydrous DMF under reflux condi- values for all hydrazone derivatives 2a–2o are positive. There is
tions provides the N-alkylation adducts 1h–1o in moderate accord between the experimental observations and calculated
yields (Scheme 2). Subsequently, treatment of the obtained data (Table 2) which supports the greater stability of the (E)-
ketones 1h–1o with phenylhydrazine in refluxing ethanol in the isomers over the (Z)-isomers and hence predominant formation
presence of a catalytic amount of acetic acid afforded the of the (E)-products.
desired compounds 2h–2o. The structures of synthesized com-
pounds are shown in Table 1. As Table 1 indicates, the N-alky- Conclusion
lation reactions of nucleobases were achieved regioselectively. In summary, we have synthesized novel acyclic nucleosides
In the case of pyrimidine nucleobases, N(1)-alkylated com- 2a–2o containing a miconazole-like scaffold as well as hydra-
pounds 1h–1l were the major products (43%, 40%, 51%, 47% zone moiety. In this series of acyclic nucleosides, we employed
and 28%); however, N(1),N(3)-dialkylated adduct was also various nucleobases and other imidazole derivatives in place of
observed in trace amounts (<10%). Moreover, N-benzyl adenine the imidazole in miconazole. To interpret the dominant forma-
derivative 1o was obtained as the N(9)-isomer in 76% yield, tion of the (E)-hydrazone derivatives rather than the (Z)-
while theophylline was mostly alkylated at N(7) to afford 1m isomers, PM3 semiempirical quantum mechanical calculations
(69%).
were carried out which showed that the heats of formation of
the (E)-isomers were lower.
All compounds were fully characterized and their structures
confirmed by 1H and 13C NMR, elemental analysis, mass and The biological studies of compounds 2a–2o are currently under
IR spectroscopy. Although compounds 2a–2o are expected to investigation and will be reported in due course.
be produced as two geometrical isomers ((E)- or (Z)-isomer),
Experimental
1H and 13C NMR analysis indicated that the (E)-isomer was
obtained as major product; the minor (Z)-isomer was detected in General
trace amounts (<5%). To interpret the preference for the (E)- All chemicals were purchased from Fluka or Merck. Solvents
isomers, PM3 semiempirical quantum mechanical calculations were purified and dried according to the reported methods [36]
were carried out using MOPAC in CS Chem 3D Ultra 8 and stored over 0.3 nm molecular sieves. The progress of reac-
(Cambridge Soft, 2004) or Hyperchem (Hypercube Inc., tion was followed by TLC using silica gel SILG/UV 254 plates.
Version 7). The results are summarized in Table 2; ΔE refers to Silica gel 60, 0.063–0.200 mm (70–230 mesh ASTM) was used
for column chromatography. IR spectra were run on a Shimadzu
FTIR-8300 spectrophotometer. The 1H NMR (250 MHz) and
Table 2: Calculated heat of formation of synthesized hydrazones
13C NMR (62.5 MHz) were run on a Bruker Avance DPX-250,
FT-NMR spectrometer (δ in ppm, J in Hz). Mass spectra were
recorded on a Shimadzu GC MS-QP 1000 EX apparatus.
Microanalyses were performed on a Perkin-Elmer 240-B micro-
analyzer. Melting points (mp) were recorded on a Büchi 510
apparatus in open capillary tubes and are uncorrected.
2a–2o using PM3.
Entry
EEa
EZb
ΔEc
2a
2b
2c
2d
2e
2f
123.87244
85.14540
148.47301
14.42535
142.60529
103.74787
183.57186
26.07071
−13.34542
21.58339
17.75077
52.80499
21.96581
52.57276
176.15539
129.56016
91.62108
153.04860
21.51980
146.16960
117.44982
198.25266
28.66346
−9.56043
24.58239
20.31085
55.83149
45.90909
60.37796
185.18056
5.68772
6.47568
4.57559
7.09445
3.56431
13.70195
14.68080
2.59275
3.78499
2.99900
2.56008
3.02560
23.94328
7.80520
9.02517
General procedure for the synthesis of ketones
1a–1g
2g
2h
2i
In a two-neck round-bottom flask (100 mL) equipped with a
condenser, a mixture of the appropriate N-heterocycle
(0.01 mol), the 2-bromoacetophenone (0.012 mol), anhydrous
TEA (1.01 g, 0.01 mol) and a catalytic amount of TBAB (0.1 g)
was dissolved in dry acetonitrile (40 mL). The mixture was then
heated at reflux for 10 h (TLC control). The solvent was evapo-
rated at reduced pressure, the residue dissolved in CHCl3 (200
mL) and washed with H2O (2 × 100 mL). The organic layer was
dried (10 g of Na2SO4) and concentrated to afford the crude
product, which was purified by column chromatography on
silica gel eluting with an appropriate solvent.
2j
2k
2l
2m
2n
2o
aHeat of formation of (E)-isomer (kcal/mol).
bHeat of formation of (Z)-isomer (kcal/mol).
cΔE = EZ − EE (kcal/mol).
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Supporting Information
Supporting information features physical and spectroscopic
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data for all novel compounds 2a–2o.
doi:10.1002/hlca.200790073
Supporting Information File 1
Synthesis of some novel hydrazono acyclic nucleoside
analogues
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