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Bioorganic & Medicinal Chemistry Letters
Synthesis and quantitative structure-activity relationship (QSAR) analysis of
some novel oxadiazolo[3,4-d]pyrimidine nucleosides derivatives as antiviral
agents
Xiaojuan Xua, ∗, Jun Wang a and Qizheng Yaob
aSchool of Chemistry and Chemical Engineering, Yancheng Teachers University, Yancheng 210054,China
b Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
We have synthesized a series of 4H,6H-[1,2,5]oxadiazolo[3,4-d]pyrimidine-5,7-dione 1-oxide
nucleoside and their anti-vesicular stomatitis virus (VSV) activities in Wish cell were also
investigated in vitro. It was found that most compounds showed obvious anti-VSV activities and
compound 9 with ribofuranoside improved the anti-VSV activity by approximately 10 times and
18 times compared to didanosine (DDI) and acyclovir, respectively. A quantitative structure-
activity relationship (QSAR) study of these compounds as well as previous reported oxdiazolo
[3,4-d]pyrimidine nucleoside derivatives indicated that compounds with high activity should
have small values of log P(o/w), vsurf_G and a large log S value. These findings and results
provide a base for further investigations.
Revised
Accepted
Available online
Keywords:
Pyrimidofuroxan nucleoside
vesicular stomatitis virus
Nitric oxide
Quantitative structure–activity relationship
(QSAR)
Nitric oxide (NO) is an important gas messenger molecular in
organisms, which can modulate many physiological.1
Endogenous NO is synthesized from L-arginine under the action
of a family of the enzyme called NO synthase (NOS).2 It has
been implicated in various regulatory mechanisms ranging from
wasodilation and blood-pressure control to immune response, and
it acts as neuro transmission in central and peripheral nervous
systems.3 NO is also involved in non-specific host defense, which
may inhibit an early stage in viral replication and thus prevent
viral spread, promote viral clearance and recovery of the host.4
As NO in-depth study, more and more results complicated that
activated macrophage cells have an extensive killing effect on
tumor cells while during which NO is the toxicity molecular.5
Due to the comprehensive effects in organisms of NO, it attracts
more and more interest in the past years. There is much interest
today in drugs related to NO, especially in structures able to
release NO. These products are collectively called NO donors,
which are widely used in biological, physical and pharmaceutical
fields.6
donor, which can generate NO and three kinds of non-nature
nucleoside-pyrimidine-base in physiological conditions.5 The
antivirus and anticancer activities of non-nature nucleosides have
been suggested by many evidences. So it is obvious that
oxadiazolo[3,4-d]pyrimidine combined with modified sugars will
possess antivirus and antitumor activities, for they can release
both NO and non-nature nucleosides in physiological conditions.
O
O
R1
7
N
N
6
O
2
N
3
O
N
4
5
R2
Fig. 1 The structure of oxadiazolo[3,4-d]purimidine ring.
Although some pyrimidofuroxan-nucleoside compounds have
been reported by our collaborative laboratory,5 these studies did
not investigate comprehensively and, overall, they were limited
to relatively simple compounds. In this work, we have concluded
the reported 14 derivatives and synthesized another 11 novel
oxdiazolo[3,4-d]pyrimidine nucleoside derivatives. In addition,
the antivirus activities and toxicities of all these compounds were
also studied (Table 1). As is known to us, the biological activity
correlates greatly with the structure of the compound. For a
detailed understanding of the structure-activity relationship of all
Among NO donors, derivatives of a minor heterocycle system,
the oxadiazolo[3,4-d]purimidine, are also included (Fig. 1). By
the interaction of [3,4-d]pyrimidine-5,7-dione 1-oxide derivatives
with thiol such as N-acetylcysteamine, cysteine and glutathione
in vivo, they can produce uracil derivatives and release NO.5
These compounds have been proved to be a sort of effective NO
———
reported
and
synthesized
pyrimidofuroxan-nucleoside
∗ Corresponding author. Tel/fax: +86-0515-8823-3186;
e-mail: xxjyctu@gmail.com (Xiaojuan Xu)
Xu, Xiaojuan
