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

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...

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Published in:	European journal of medicinal chemistry Vol. 220; p. 113472
Main Authors:	Melo de Oliveira, Valentina Nascimento, Flávia do Amaral Moura, Cybele, Peixoto, Aline dos Santos, Gonçalves Ferreira, Vanessa Pinheiro, Araújo, Héverton Mendes, Lapa Montenegro Pimentel, Lilian Maria, Pessoa, Claudia do Ó, Nicolete, Roberto, Versiani dos Anjos, Janaína, Sharma, Prem Prakash, Rathi, Brijesh, Pena, Lindomar José, Rollin, Patrick, Tatibouët, Arnaud, Nascimento de Oliveira, Ronaldo
Format:	Journal Article
Language:	English
Published:	France Elsevier Masson SAS 05-08-2021
Subjects:	1,2,3-Triazole 1,2,4-Oxadiazole Antiproliferative activity Antitubercular activity Glycerosugar MD simulations MD simulations 1,2,3-Triazole Antiproliferative activity Glycerosugar 1,2,4-Oxadiazole Antitubercular activity
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Summary:	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). [Display omitted] •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.•Insilico studies supported the anti-TB compounds complexed with proteins DprE1 and InhA have stable association.
ISSN:	0223-5234 1768-3254
DOI:	10.1016/j.ejmech.2021.113472