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

Eur J Med Chem. 2021 Aug 5:220:113472. doi: 10.1016/j.ejmech.2021.113472.

Valentina Nascimento Melo de Oliveira ¹, Cybele Flávia do Amaral Moura ², Aline Dos Santos Peixoto ³, Vanessa Pinheiro Gonçalves Ferreira ⁴, Héverton Mendes Araújo ⁴, Lilian Maria Lapa Montenegro Pimentel ³, Claudia do Ó Pessoa ⁵, Roberto Nicolete ⁴, Janaína Versiani Dos Anjos ¹, Prem Prakash Sharma ⁶, Brijesh Rathi ⁶, Lindomar José Pena ⁷, Patrick Rollin ⁸, Arnaud Tatibouët ⁸, Ronaldo Nascimento de Oliveira ⁹

Affiliations

1 Department of Fundamental Chemistry, Federal University of Pernambuco, 50.740-540, Recife, Brazil.
2 Department of Chemistry, Federal Rural University of Pernambuco, Dois Irmãos, 52171-900, Recife, Brazil.
3 Department of Immunology, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Brazil.
4 Laboratorio de Oncologia Experimental, Nucleo de Pesquisa Em Desenvolvimento de Medicamentos (NPDM), Universidade Federal Do Ceara, Fortaleza, Brazil; Oswaldo Cruz Foundation (Fiocruz), Eusebio, Brazil.
5 Laboratorio de Oncologia Experimental, Nucleo de Pesquisa Em Desenvolvimento de Medicamentos (NPDM), Universidade Federal Do Ceara, Fortaleza, Brazil.
6 Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College University Enclave, University of Delhi, Delhi, India.
7 Department of Virology, Oswaldo Cruz Foundation, Fiocruz, 50740-465, Recife, PE, Brazil.
8 Universite D'Orleans et CNRS, ICOA, UMR 7311, BP 6759, F-45067, Orleans, France.
9 Department of Chemistry, Federal Rural University of Pernambuco, Dois Irmãos, 52171-900, Recife, Brazil. Electronic address: ronaldo.noliveira@ufrpe.br.

PMID: 33940463 DOI: 10.1016/j.ejmech.2021.113472

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.

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