In vivo antimalarial activity of novel 2-hydroxy-3-anilino-1,
4-naphthoquinones obtained by epoxide ring-opening reaction
Lucas Cunha Dias de Rezende
, Fernando Fumagalli
, Marraiana Schiavon Bortolin
Marianne Garcia de Oliveira
, Murilo Helder de Paula
, Valter Ferreira de Andrade-Neto
Flavio da Silva Emery
Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, 14040-903 Ribeirão Preto-SP, Brazil
Laboratório de Biologia da Malária e Toxoplasmose, Departamento de Microbiologia e Parasitologia, Centro de Biociências, Universidade Federal do Rio Grande do Norte, 59000-000
Natal, RN, Brazil
Received 26 April 2013
Revised 7 June 2013
Accepted 11 June 2013
Available online 20 June 2013
1,4-Naphthoquinone derivatives are known to have relevant activities against several parasites. Among
the treatment options for malaria, atovaquone, a 1,4-naphthoquinone derivative, is widely applied in
the treatment and prophylaxis of such disease. Based on the structure simpliﬁcation of atovaquone,
we designed and synthesized four novel naphthoquinoidal derivatives. The compounds were obtained
by the underexplored epoxide-opening reaction of 1,4-naphthoquinone using aniline derivatives as
nucleophiles. The antiplasmodial activity of the synthesized compounds was performed in vivo using
Peter’s 4 days suppression test. Signiﬁcant parasitemia reduction and increased survival were observed
for some of the compounds.
Ó 2013 Elsevier Ltd. All rights reserved.
1,4-Naphthoquinones are a class of compounds broadly studied
in organic synthesis, medicinal chemistry and natural products
Within these studies, the antimalarial activity has been
widely reported for several 1,4-naphthoquinones.
sitic activity of the quinones is related to several mechanisms such
as the competitive inhibition of the cytochrome bc1 complex, gen-
eration of reactive oxygen species, enzymatic inhibition (e.g., glu-
tathione reductase, dihydroorotate dehydrogenase and glycerol
glyceraldehyde-3-phosphate dehydrogenase) alkylation of biomol-
ecules, depletion of glutathione, among others.
Lawsone derivatives containing the 2-hydroxy-1,4-naphthoqui-
none scaffold are highly explored for the development of novel
antiparasitics. Atovaquone, parvaquone and buparvaquone are
3-substituted-2-hydroxy-1,4-naphthoquinones clinically applied
as antimalarial (atovaquone) and antipneumocystic (parvaquone
and buparvaquone) agents, which exempliﬁes the potentiality of
such scaffold in the development of novel drugs. Additionally,
some studies indicate the potential application of natural or syn-
thetic 2-amino-1,4-naphthoquinones and 2-amino-1,2-naphtho-
quinones as antiplasmodial agents.
Despite the pharmacological relevance of aminated and
hydroxylated naphthoquinoidal derivatives and the wide
structural diversity of 1,4-naphthoquinones, 2-amino-3-hydroxy-
1,4-naphthoquinone is an uncommon structural fragment only
observed in few examples of natural products and bioactive
which can be seen as a ring bioisostere
of atovaquone, was shown to have inhibitory effects against
Based on the structures of atovaquone and 1, we propose the
simpliﬁcation of the common scaffold by modifying the spacer
group (SG) between the naphthoquinoidal moiety and the benzene
ring (Atovaquone, SG = cyclohexane; and 1, SG = piperazine). In our
proposal, the aliphatic rings of these two compounds are substi-
tuted by a nitrogen atom to produce 3-anilino-substituted
hydroxynaphthoquinones (Fig. 1).
The most common synthetic methodology for obtaining 2-
amino-3-hydroxy-1,4-naphthoquinones and derivatives involves
the nucleophilic substitution of halonaphthoquinones, followed
by hydrolysis depending on the starting material.
nitro or hydrazine reduction,
amination of aryliodionium
ylides of 2-hydroxy-1,4-naphthoquinones,
and oxidation of
2-amino-1,4-naphthoquinones are somewhat useful strategies.
In this work, we describe a two-step method to synthesize
novel 2-hydroxy-3-amino-1,4-naphthoquinone derivatives from
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
Corresponding author. Tel.: +55 16 3602 0658; fax: +55 16 3602 4178.
E-mail addresses: ﬂavioemery@fcfrp.usp.br, ﬂavioemery@qhetem.com (Flavio da
Bioorganic & Medicinal Chemistry Letters 23 (2013) 4583–4586
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Bioorganic & Medicinal Chemistry Letters
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