Synthesis of alkynylated 1,2,4-oxadiazole/1,2,3-1H-triazole glycoconjugates: Discovering new compounds for use in chemotherapy against lung carcinoma and Mycobacterium tuberculosis

Federal University of Pernambuco. Department of Fundamental Chemistry. Recife, PE, Brazil.
Federal University of Pernambuco. Department of Chemistry. Recife, PE, Brazil.
Oswaldo Cruz Foundation. Aggeu Magalhães Institute. Department of Immunology. Recife, PE, Brazil.
Universidade Federal do Ceará. Núcleo de Pesquisa em Desenvolvimento de Medicamentos. Laboratório de Oncologia Experimental. Fortaleza, CE, Brazil / Fundação Oswaldo Cruz. Fiocruz Ceará. Fortaleza, CE, Brasil.
Universidade Federal do Ceará. Núcleo de Pesquisa em Desenvolvimento de Medicamentos. Laboratório de Oncologia Experimental. Fortaleza, CE, Brazil / Fundação Oswaldo Cruz. Fiocruz Ceará. Fortaleza, CE, Brasil.
Oswaldo Cruz Foundation. Aggeu Magalhães Institute. Department of Immunology. Recife, PE, Brazil.
Universidade Federal do Ceará. Núcleo de Pesquisa em Desenvolvimento de Medicamentos. Laboratório de Oncologia Experimental. Fortaleza, CE, Brasil.
Universidade Federal do Ceará. Núcleo de Pesquisa em Desenvolvimento de Medicamentos. Laboratório de Oncologia Experimental. Fortaleza, CE, Brasil / Fundação Oswaldo Cruz. Fiocruz Ceará. Fortaleza, CE, Brasil.
Federal University of Pernambuco. Department of Fundamental Chemistry. Recife, PE, Brazil.
University of Delhi. Hansraj College University Enclave. Department of Chemistry. Laboratory for Translational Chemistry and Drug Discovery. Delhi, India.
University of Delhi. Hansraj College University Enclave. Department of Chemistry. Laboratory for Translational Chemistry and Drug Discovery. Delhi, India.
Oswaldo Cruz Foundation. Aggeu Magalhães Institute. Department of Virology. Recife, PE, Brazil.
Universite D’Orleans et CNRS. ICOA. Orleans, France.
Universite D’Orleans et CNRS. ICOA. Orleans, France.
Federal Rural University of Pernambuco. Department of Chemistry. Recife, PE, Brazil.

Abstract

A total of forty-three compounds were synthesized, including thirty-two new ones. Among those compounds, seventeen were selected and tested on human tumor cell lines: PC-3 (prostate adenocarcinoma), HCT-116 (colorectal tumor), NCIH-460 (lung carcinoma), SKMEL-103 (melanoma) and AGP-01 (gastric tumor). Alkynylated 1,2,4-oxadiazoles 2m, 3g and 3k exhibited antiproliferative activities against NCIH-460 in culture. Alkynylated N-cyclohexyl-1,2,4-oxadiazoles 3a-m and bis-heterocycle glucoglycero-1,2,3-triazole-N-cyclohexyl-1,2,4-oxadiazole derivatives 5a-k and 6-11 were evaluated for their in vitro efficacy towards Mycobacterium tuberculosis (Mtb) H37Ra and H37Rv strains. In general, glycerosugars conjugated to 1,2,4-oxadiazole via a 1,2,3-triazole linkage (5a, 5e, 5j, 5k, and 7) showed in vitro inhibitory activity against Mtb (H37Rv). The largest molecules bis-triazoles 10 and 11, proved inactive against TB. Probably, the absence of the N-cyclohexyl group in compound 8 and 1,2,4-oxadiazole nucleus in compound 9 were responsible for its low activity. Glucoglycero-triazole-oxadiazole derivatives 5e (10 μM) and 7 (23.9 μM) were the most promising antitubercular compounds, showing a better selective index than when tested against RAW 264.7 and HepG2 cells. Vero cell were used to investigate cytotoxicity of compounds 5a, 5h, 5j, 5k, and these compounds showed good cell viability. Further, in silico studies were performed for most active compounds (5e and 7) with potential drug targets, DprE1 and InhA of Mtb to understand possible interactions aided with molecular dynamic simulation (100ns).

Keywords

1,2,3-Triazole
1,2,4-Oxadiazole
Antiproliferative activity
Antitubercular activity
Glycerosugar
MD simulations

Publisher

Elsevier

Citation

OLIVEIRA, Valentina Nascimento Melo de et al. Synthesis of alkynylated 1,2,4-oxadiazole/1,2,3-1H-triazole glycoconjugates: Discovering new compounds for use in chemotherapy against lung carcinoma and Mycobacterium tuberculosis. European Journal of Medicinal Chemistry, v. 220, p. 1-20, Aug. 2021.

DOI

10.1016/j.ejmech.2021.113472

ISSN

0223-5234

Notes

Highlights: Forty-one compounds were synthesized and tested for human tumor cell lines and/or tuberculosis (H37Ra and H37Rv strains). Alkynylated 1,2,4-oxadiazoles were effective as antiproliferative agents (lung carcinoma, NCIH-460) with IC50 = 3–17 μM. Glucoglycero-triazole-oxadiazoles, mainly the compounds 5a,j,k, 5e and 7 (10-47 µM), were the most active against TB. In silico studies supported the anti-TB compounds complexed with proteins DprE1 and InhA have stable association.

Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/70678

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Restricted access

Embargo date

2030-12-31

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