1,3-Bis(aryloxy)propan-2-ols as potential antileishmanial agents

Article abstract of DOI:10.1111/cbdd.13024

We describe herein the synthesis and antileishmanial activity of 1,3-bis(aryloxy)propan-2-ols. Five compounds (2, 3, 13, 17, and 18) exhibited an effective antileishmanial activity against stationary promastigote forms of Leishmania amazonensis (IC₅₀?

Full text of DOI:10.1111/cbdd.13024

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Antileishmanial Bisaryloxypropanols
1,3-Bis(aryloxy)propan-2-ols as potential antileishmanial agents
Stefânia N. Lavorato1, Mariana C. Duarte2,3, Daniela P. Lage3, Carlos A. P. Tavares4,
Eduardo A. F. Coelho2,3, Ricardo J. Alves1,*
1Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade
Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Belo Horizonte, MG, 31.270-
901, Brazil.
2 Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais,
Avenida Antônio Carlos, 6627, Belo Horizonte, MG, 31.270-901, Brazil.
3 Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical,
Faculdade de Medicina, Universidade Federal de Minas Gerais, Avenida Professor
Alfredo Balena, 190, Belo Horizonte, MG, 30130-100, Brazil.
4
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas,
Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Belo Horizonte,
MG, 31.270-901, Brazil.
* Corresponding author; Tel: + 55 31 3409 6955; Fax: + 55 31 3409 6935;
E-mail address: ricardodylan@farmacia.ufmg.br (R. J. Alves)
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Abstract
We describe herein the synthesis and antileishmanial activity of 1,3-bis(aryloxy)propan-
2-ols. Five compounds (2, 3, 13, 17 and 18) exhibited an effective antileishmanial
activity against stationary promastigote forms of Leishmania amazonensis (IC50< 15.0
µM) and an influence of compound lipophilicity on activity was suggested. Most of the
compounds were poorly selective, as they showed toxicity towards murine
macrophages, except 17 and 18, which presented good selective indexes (SI ≥ 10.0).
The five more active compounds (2, 3, 13, 17 and 18) were selected for the treatment of
infected macrophages and all of them were able to reduce the number of internalized
parasites by more than 80%, as well as the number of infected macrophages by more
than 70% in at least one of the tested concentrations. Altogether, these results
demonstrate the potential of these compounds as new hits of antileishmanial agents and
open future possibilities for them to be tested in in vivo studies.
Keywords: Leishmania amazonensis, Leishmaniasis, Cytotoxicity, Bisaryloxyalcohols,
Antileishmanial activity
Leishmaniasis is a neglected tropical disease caused by more than twenty species of
Leishmania protozoa and is transmitted to mammals by the bite of the infected
phlebotomine sandflies. This disease is responsible for 20,000 to 30,000 deaths annually
andit is estimated that 310 million people live in areas at risk of infection, spread
through 98 countries in the world(1).
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The treatment of leishmaniasis is restricted to a few drugs, such as pentavalent
antimonials, amphotericin B, pentamidine, paromomycin and miltefosine, used alone or
in association. All these drugs are not ideal for the treatment of the disease due to their
high toxicity and costs, long treatments and the emergence of parasites resistance cases
(2,3). Therefore, the search for new potent and safe therapeutic alternatives is urgently
needed.
1,3-Bis(aryloxy)propan-2-ols are compounds easily obtained by synthesis, hence our
interest in exploring their pharmacological potential. A survey of the literature on their
biological uses revealed that some compounds with this structural pattern have been
exploited as anti-mycobacterial (4) and antiasthmatic agents (5) and as trimethoprim-
resistant dihydropholate reductase inhibitor (6). However, for the best of our
knowledge, their antileishmanial activity has not been evaluated so far.
In this context, in the present work, a series of 1,3-bis(aryloxy)propan-2-ols was
prepared and submitted to the evaluation of their antileishmanial potential. The in vitro
antileishmanial activity was assessed against stationary-phase promastigotes of
Leishmania amazonensis and the cytotoxicity was evaluated in murine macrophages. In
addition, the compounds displaying better antileishmanial activity were selected to the
investigation of their antileishmanial effect on intra-macrophage amastigotes of the
parasites.
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Experimental
General
Reactants were obtained from commercial suppliers and used without further
purification. Melting points were determined on Microquímica MQAPF 301 apparatus.
The 1H and 13C NMR spectra were obtained on a Bruker Avance DPX-200
spectrometer. The proton and carbon chemical shifts (δ) are given with respect to TMS.
IR spectra were recorded on a Spectrum One, Perkin-Elmer ATR system. Column
chromatography was performed on silica gel 60 0.063-0.200 mm/70-230 mesh Merck.
Anhydrous DMSO was dried over 3Å molecular sieves.
Synthesis
Procedures for synthesis of compounds 1-21 and characterization data are shown in
Supporting information.
ClogP determination
The calculated partition coefficient (ClogP) of each compound was determined using
ACD/ChemSketch software (acdlabs.com).
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