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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Gomes, Marcelo N.¹  Alcantara, Laura M.²  Neves, Bruno J.^1,4  Melo-Filho, Cleber C.¹  Freitas-Junior, Lucio H.³  Moraes, Carolina B.²  Ma, Rui⁵  Franzblau, Scott G.⁵  Muratov, Eugene^6,7,8  Andrade, Carolina Horta¹ 

[1] Univ Fed Goias, Fac Farm, LabMol Lab Mol Modeling & Drug Design, Rua 240,Qd 87,Setor Leste Univ, BR-74605510 Goiania, Go, Brazil

[2] Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Biosci Natl Lab LNBio, BR-13083970 Campinas, SP, Brazil

[3] Inst Butantan Sao Paulo, BR-05503900 Sao Paulo, Brazil

[4] Univ Ctr Anapolis UniEVANGELICA, Postgrad Program Soc Technol & Enviroment, BR-75083515 Anapolis, Go, Brazil

[5] Univ Illinois, Inst TB Res, 833 South Wood St, Chicago, IL 60612 USA

[6] Univ N Carolina, Eshelman Sch Pharm, Lab Mol Modeling, Chapel Hill, NC 27599 USA

[7] Odessa Natl Polytech Univ, Dept Chem Technol, UA-65000 Odessa, Ukraine

[8] Univ Fed Goias, Goiania, Go, Brazil

关键词: Antileishmanial agents;    Nitroheterocycle chalcones;    Selectivity;    Molecular modeling;    Target fishing;   

DOI  :  10.1016/j.bmcl.2017.04.010

来源: Elsevier

【 摘 要 】

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 6.2-10.98 mu M. In addition, two compounds, LabMol-65 and LabMol-73, exhibited cytotoxicity in macrophages > 50 mu M 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. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

Free