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Bioorg Med Chem Lett. 2017 Jun 1;27(11):2459-2464. doi: 10.1016/j.bmcl.2017.04.010. Epub 2017 Apr 4.

Computer-aided discovery of two novel chalcone-like compounds active and selective against Leishmania infantum.

Author information

1
LabMol - Laboratory for Molecular Modeling and Drug Design, Faculdade de Farmacia, Universidade Federal de Goias, Rua 240, Qd.87, Setor Leste Universitário, Goiania, Goias 74605-510, Brazil.
2
Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), 13083-970, Campinas, Sao Paulo, Brazil. d Instituto Butantan - Sao Paulo, Sao Paulo 05503-900, Brazil.
3
LabMol - Laboratory for Molecular Modeling and Drug Design, Faculdade de Farmacia, Universidade Federal de Goias, Rua 240, Qd.87, Setor Leste Universitário, Goiania, Goias 74605-510, Brazil; Postgraduate Program on Society, Technology and Enviroment, University Center of Anápolis/UniEVANGELICA, Anápolis, Goiás 75083-515, Brazil.
4
Institute Butantan -Sao Paulo, Sao Paulo 05503-900, Brazil.
5
Institute for Tuberculosis Research, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, United States.
6
Laboratory for Molecular Modeling, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States; Department of Chemical Technology, Odessa National Polytechnic University, Odessa 65000, Ukraine; Currently Visiting Professor at Universidade Federal de Goias, Goiania, Brazil.
7
LabMol - Laboratory for Molecular Modeling and Drug Design, Faculdade de Farmacia, Universidade Federal de Goias, Rua 240, Qd.87, Setor Leste Universitário, Goiania, Goias 74605-510, Brazil. Electronic address: carolhandrade@gmail.com.

Abstract

Leishmaniasis are infectious diseases caused by parasites of genus Leishmania that affect affects 12 million people in 98 countries mainly in Africa, Asia, and Latin America. Effective treatments for this disease are urgently needed. In this study, we present a computer-aided approach to investigate a set of 32 recently synthesized chalcone and chalcone-like compounds to act as antileishmanial agents. As a result, nine most promising compounds and three potentially inactive compounds were experimentally evaluated against Leishmania infantum amastigotes and mammalian cells. Four compounds exhibited EC50 in the range of 6.2-10.98μM. In addition, two compounds, LabMol-65 and LabMol-73, exhibited cytotoxicity in macrophages >50μM that resulted in better selectivity compared to standard drug amphotericin B. These two compounds also demonstrated low cytotoxicity and high selectivity towards Vero cells. The results of target fishing followed by homology modeling and docking studies suggest that these chalcone compounds could act in Leishmania because of their interaction with cysteine proteases, such as procathepsin L. Finally, we have provided structural recommendations for designing new antileishmanial chalcones.

KEYWORDS:

Antileishmanial agents; Molecular modeling; Nitroheterocycle chalcones; Selectivity; Target fishing

PMID:
28434763
PMCID:
PMC6020026
DOI:
10.1016/j.bmcl.2017.04.010
[Indexed for MEDLINE]
Free PMC Article

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