Synthesis and anticancer evaluation of new lipophilic 1,2,4 and 1,3,4-oxadiazoles

Wiliam Caneschi; Karine Braga Enes; Camille Carvalho de Mendonça; Fábio de Souza Fernandes; Fabio Balbino Miguel; Jefferson da Silva Martins; Mireille Le Hyaric; Roberto Rosas Pinho; Lucas Mattos Duarte; Marcone Augusto Leal de Oliveira; Hélio F Dos Santos; Miriam Teresa Paz Lopes; Dalton Dittz; Heveline Silva; Mara Rubia Costa Couri

doi:10.1016/j.ejmech.2019.01.001

Synthesis and anticancer evaluation of new lipophilic 1,2,4 and 1,3,4-oxadiazoles

Eur J Med Chem. 2019 Mar 1:165:18-30. doi: 10.1016/j.ejmech.2019.01.001. Epub 2019 Jan 2.

Authors

Wiliam Caneschi¹, Karine Braga Enes¹, Camille Carvalho de Mendonça¹, Fábio de Souza Fernandes¹, Fabio Balbino Miguel¹, Jefferson da Silva Martins², Mireille Le Hyaric¹, Roberto Rosas Pinho², Lucas Mattos Duarte¹, Marcone Augusto Leal de Oliveira¹, Hélio F Dos Santos¹, Miriam Teresa Paz Lopes³, Dalton Dittz³, Heveline Silva⁴, Mara Rubia Costa Couri⁵

Affiliations

¹ Departamento de Química, ICE, Universidade Federal de Juiz de Fora, Campus Martelo, CEP 36036-330, Juiz de Fora, MG, Brazil.
² Departamento de Física, ICE, Universidade Federal de Juiz de Fora, Campus Martelo, CEP 36036-330, Juiz de Fora, MG, Brazil.
³ Departamento de Farmacologia, ICB, Universidade Federal de Minas Gerais, Pampulha, CEP 31270-901, Belo Horizonte, MG, Brazil.
⁴ Departamento de Química, Universidade Federal de Minas Gerais, Pampulha, CEP 31270-901, Belo Horizonte, MG, Brazil.
⁵ Departamento de Química, ICE, Universidade Federal de Juiz de Fora, Campus Martelo, CEP 36036-330, Juiz de Fora, MG, Brazil. Electronic address: mara.rubia@ufjf.edu.br.

PMID: 30654237
DOI: 10.1016/j.ejmech.2019.01.001

Abstract

A series of1,2,4- and 1,3,4-oxadiazole derivatives were synthesized and evaluated for their anticancer activity. Halogenated 1,2,4-oxadiazoles were obtained from benzonitrile and coupled either lipophilic amines or with aminoalcohols. Lipophilic 1,3,4-oxadiazole derivatives were obtained through the Mannich reactions between 5-(aryl)-1,3,4-oxadiazole-2-thiol and alkylated or acylated amines. The in vitro cytotoxic effects were evaluated against 4T1- mammary carcinoma and CT26 - colon cancer cells. The best results were obtained for the 1,3,4-oxadiazole coupled to alkylated piperazine with 10-14 carbon chain moiety, with IC₅₀ values ranging from 1.6 to 3.55μΜ for the 4T1 cell line, and from 1.6 to 3.9 μM for the CT26.WT cell line, and selectivity index up to 19. The most potent compounds were investigated with AnnexinV and PI staining as indicative of apoptosis induction.

Keywords: Anticancer activity; Lipophilicity; Mannich bases; Oxadiazoles.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Cell Line, Tumor
Humans
Hydrophobic and Hydrophilic Interactions
Oxadiazoles / chemical synthesis
Oxadiazoles / chemistry
Oxadiazoles / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Oxadiazoles
1,3,4-oxadiazole