Bioorganic & Medicinal Chemistry Letters
Dihydropyrimidinones and -thiones with improved activity against
human polyomavirus family members
Alexandra Manos-Turvey a,b,y, Hiba A. Al-Ashtal a, Patrick G. Needham a, Caroll B. Hartline c,
Mark N. Prichard c, Peter Wipf b,d, Jeffrey L. Brodsky a,
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a Department of Biological Science, University of Pittsburgh, A320 Langley Hall, Pittsburgh, PA 15260, USA
b Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
c Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA
d Center for Chemical Methodologies and Library Development, University of Pittsburgh, Pittsburgh, PA 15260, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Human polyomaviruses are generally latent but can be reactivated in patients whose immune systems
are suppressed. Unfortunately, current therapeutics for diseases associated with polyomaviruses are
non-specific, have undefined mechanisms of action, or exacerbate the disease. We previously reported
on a class of dihydropyrimidinones that specifically target a polyomavirus-encoded protein, T antigen,
and/or inhibit a cellular chaperone, Hsp70, that is required for virus replication. To improve the antiviral
activity of the existing class of compounds, we performed Biginelli and modified multi-component reac-
tions to obtain new 3,4-dihydropyrimidin-2(1H)-ones and -thiones for biological evaluation. We also
compared how substituents at the N-1 versus N-3 position in the pyrimidine affect activity. We discov-
ered that AMT580-043, a N-3 alkylated dihydropyrimidin-2(1H)-thione, inhibits the replication of a dis-
ease-causing polyomavirus in cell culture more potently than an existing drug, cidofovir.
Received 17 June 2016
Revised 22 August 2016
Accepted 24 August 2016
Available online xxxx
Keywords:
BKPyV
JCPyV
SV40
Molecular chaperone
Biginelli
T antigen
Hsp70
Ó 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
Hsp40
Thiourea
Polyomaviruses are double stranded DNA viruses that are ende-
mic in the human population but are usually not disease-causing.
However, in individuals who are immune-compromised, select
members of this virus family can be reactivated and cause serious
ailments.1,2 For example, BK virus reactivation in renal transplant
patients undergoing immunosuppressive therapies leads to BK
virus associated nephropathy (BKVAN), which is observed in 5–
10% of all kidney transplant recipients. More than half of these
individuals will ultimately lose the donated organ. BK virus reacti-
vation is also evident in cancer patients who undergo bone marrow
transplants and are given immunosuppressants, leading to hemor-
rhagic cystitis. Similarly, 5–10% of HIV-infected individuals ulti-
mately succumb to progressive multifocal leukoencephalopathy
(PML), which arises from JC virus reactivation. Due to recent
improvements in virus identification and sequencing techniques,
the number of known polyomaviruses has increased, such that
there are now 12 human polyomavirus types. Several of these
new polyomavirus family members have also been linked to dis-
ease.3 Unfortunately, existing therapeutics to treat polyomavirus
infections are non-specific and/or exhibit unwanted side-effects.4
Cidofovir (CDV), an FDA approved treatment for cytomegalovirus
(CMV) retinitis in AIDS patients, is an acyclic dCMP analog that
inhibits DNA polymerase and is commonly used off-label to treat
polyomavirus infections (Fig. 1).4 Brincidofovir (BCV, CMX001) is
a prodrug of CDV and shares its mechanism of action.5 A cell based
high-throughput screen for simian virus 40 (SV40) and poly-
omavirus (BK and JC) inhibitors also detected activity with ellagic
acid and spiperone.6
We previously reported on the synthesis, screening, and
preliminary structure–activity relationship (SAR) studies of
multi-component reaction-derived dihydropyrimidinones that
inhibit the growth of polyomaviruses, in particular MAL2-11B,
BQU015242, LR340-006, ML282-56, and ML282-86 (SMAL)
(Fig. 1); we also identified hexachlorophene and bithionol as poly-
omavirus inhibitors.7–11 The most specific dihydropyrimidinone
compounds were identified based on their ability to inhibit the
ATPase activity of T antigen, which is a polyomavirus-encoded
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Corresponding author. Tel.: +1 412 624 4831; fax: +1 412 624 4759.
Present address: Laboratory of Pharmaceutical Chemistry, Department of
y
Pharmacy, University of Liège, 4000, Belgium.
0960-894X/Ó 2016 The Authors. Published by Elsevier Ltd.