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. 2021 Sep 6;11(47):29741-29751.
doi: 10.1039/d1ra05602f. eCollection 2021 Sep 1.

Design, synthesis and cytotoxic evaluation of a library of oxadiazole-containing hybrids

Cristián M Camacho  1 , Marianela G Pizzio  1 , David L Roces  1 , Dora B Boggián  1 , Ernesto G Mata  1 , Yanina Bellizzi  2 , Elizabeth Barrionuevo  2 , Viviana C Blank  2 , Leonor P Roguin  2
Affiliations

Design, synthesis and cytotoxic evaluation of a library of oxadiazole-containing hybrids

Cristián M Camacho et al. RSC Adv. .

Abstract

The development of hybrid compounds led to the discovery of new pharmacologically active agents for some of the most critical diseases, including cancer. Herein, we describe a new series of oxadiazole-containing structures designed by a molecular hybridization approach. Penicillin derivatives and amino acids were linked to amino acid and aromatic moieties through the formation of a 1,2,4-oxadiazole ring. Alternatively, condensation between amino acid-derived hydrazides and an activated penicillanic acid led to a series of 1,3,4-oxadiazole penicillin-containing hybrids and non-cyclized diacylhydrazides. From the cytotoxicity assays it is highlighted that two 1,2,4-oxadiazoles and one 1,3,4-oxadiazole connecting a penicillin and aliphatic amino acids displayed a high degree of cytotoxic selectivity, ranging between being three and four times more potent against tumor cells than normal cells. The results give a very interesting perspective suggesting that these hybrid compounds can offer a novel antitumor scaffold with promising cytotoxicity profiles.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. Bioactive compounds containing 1,2,4 and 1,3,4-oxadiazole moiety: 1: ataluren; 2: CAY10734, agonist of sphingosine-1-phosphate receptor 1; 3: L 670548, muscarinic receptor agonist; 4: MX-74420, anticancer agent; 5: antibacterial agent; 6: anticonvulsant agent.
Scheme 1
Scheme 1. Synthesis of 1,2,4-oxadiazoles from N-Boc amino acids 10a–e and amidoximes 11a–b.
Fig. 2
Fig. 2. 3,5-Disubstituted 1,2,4-oxadiazoles 13 obtained from N-Boc amino acids and aryl amidoximes.
Scheme 2
Scheme 2. Synthesis of 1,2,4-oxadiazoles 16 prepared from 6,6-dibromopenicillanic acid 14a and amidoximes 11a–m.
Fig. 3
Fig. 3. 1,2,4-Oxadiazolylaryl penicillins.
Scheme 3
Scheme 3. 1,2,4-Oxadiazoles from the acetyl (16ah) and the oxime (16ai) derivatives and a dimer O-acyl oxime (17ai) from 16ai and carboxylic acid 14a.
Scheme 4
Scheme 4. Synthesis of 1,2,4-oxadiazoles from 6,6-dibromopenicilanic 14a and amidoximes 20a–f.
Fig. 4
Fig. 4. 1,2,4-Oxadiazolylaryl penicillins from amino amidoximes.
Scheme 5
Scheme 5. Synthesis of 1,3,4-oxadiazoles 26 from carboxylic acids 1a–b and hydrazides 24a–c.
Fig. 5
Fig. 5. 1,3,4-Oxadiazoles and disubstituted hydrazides intermediates synthesized from acids 14a–b and corresponding hydrazides 24a–b.
Scheme 6
Scheme 6. Proposed reaction mechanism for the cyclodehydration of diacylhydrazines using CBr4 and PPh3.
Fig. 6
Fig. 6. Effect of hybrid compounds on the proliferation of non-neoplastic and tumor cell lines. 2 × 104 cells per well (NMuMG and LM3) (C and B, respectively) or 1 × 104 cells per well (B16-F0) (A) were incubated in the presence or absence of 20 μM of different compounds for 72 h at 37 °C. Cell proliferation was determined by colorimetric determination of hexosaminidase levels. Results are expressed as the percentage of growth obtained in the absence of compounds (control) and represented as mean ± S. E. M. of three different experiments.
Fig. 7
Fig. 7. Active compounds against B16-F0 (melanoma) and LM3 (breast adenocarcinoma) cells, not cytotoxic against NMuMG normal cells.
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