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Synthesis, characterization, drug-likeness properties and determination of the in vitro antioxidant and cytotoxic activities of new 1,3,4-oxadiazole derivatives

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Abstract

A series of new 1,3,4-oxadiazole derivatives were synthesized and evaluated for their antioxidant, cytotoxic, and apoptosis activities. Antioxidant activity was determined in vitro using free radical scavenging (2,2-diphenyl-1-picrylhydrazyl) and ferric reducing antioxidant power assays. Most of the synthesized compounds exhibited significant antioxidant activities. Compound 3 showed the most potent antioxidant activity, comparable to the antioxidants used as positive controls—quercetin, BHT, trolox, rutin, and ascorbic acid. Compound 1 displayed high radical scavenging activity in the 2,2-diphenyl-1-picrylhydrazyl assay, with an half-maximum inhibitory concentration (IC50) = 2.22 ± 0.01 µg/mL. Cytotoxic activities were evaluated in vitro against three human cancer cell lines (BxPC-3, MCF-7, MDA-MB-231) and one normal cell line (hTERT-HPNE) using the MTT assay. Compound 4e showed the most potent cytotoxic activity against MDA-MB-231 (IC50 = 21.40 ± 1.22 µM), and compound 4c showed the most potent activity against BxPC-3 (IC50 = 26.17 ± 1.10 µM). Further investigation on BxPC-3 cells showed compound 4c induces apoptosis and cell cycle arrest at G0/G1 phase. The drug-likeness parameters of these oxadiazole derivatives were evaluated according to the Lipinski rule, the Veber rule, and Egan’s model. All of the derivatives were found to have good predicted absorption characteristics, with the exception of compound 4d due to its high lipophilicity.

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Abbreviations

BDH:

bond-dissociation enthalpies

BxPC-3:

human primary pancreatic adenocarcinoma

CoQ:

coenzyme q10

δ :

chemical shift in parts per million

J :

coupling constant (in nmr spectrometry)

DPPH:

2,2-diphenyl-1-picrylhydrazyl radical

FRAP:

ferric ion reducing antioxidant power

HBA:

number of hydrogen bond acceptor

HBD:

number of hydrogen bond donor

HAT:

hydrogen atom transfer

hTERT-HPNE:

normal pancreas cell line

IC50 :

half-maximum inhibitory concentration

log p:

logarithm of partition coefficient

MCF-7:

human breast adenocarcinoma cells

MDA-MB-231:

human breast adenocarcinoma

MTT assay:

cell proliferation colorimetric assay

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Acknowledgments

The authors would like to thank the University of Malaya for UMRG grants (RP021B-14AFR), PPP grant (PG033-2012B), PRPUM grant (CG021-2013) and the Ministry of Higher Education of Malaysia grant (FP024-2014A) for supporting this study. The authors acknowledge CRYSTAL for providing the computational resources for computational intensive calculation and model building.

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Authors and Affiliations

  1. Department of Chemistry, Faculty of Science, University of Malaya, 50603 , Kuala Lumpur, Malaysia

    Nafal Nazarbahjat, Azhar Ariffin & Zanariah Abdullah

  2. Department of Medical Analysis, College of Health and Medical Technologies, P.O. 10047, Baghdad, Iraq

    Nafal Nazarbahjat

  3. Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 , Kuala Lumpur, Malaysia

    Mahmood Ameen Abdulla

  4. Integrative Pharmacogenomics Institute (iPROMISE) Level 7, FF3 Building, Universiti Teknologi MARA, 42300 Bandar Puncak Alam, Selangor, Malaysia

    John Kwong Siew Shia

  5. Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 , Kuala Lumpur, Malaysia

    Kok Hoong Leong

  6. Center for Natural Product and Drug Discovery (CENAR), Department of Chemistry, Faculty of Science, University of Malaya, 50603 , Kuala Lumpur, Malaysia

    Kok Hoong Leong

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  1. Nafal Nazarbahjat
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  2. Azhar Ariffin
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Correspondence to Azhar Ariffin or Kok Hoong Leong.

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Nazarbahjat, N., Ariffin, A., Abdullah, Z. et al. Synthesis, characterization, drug-likeness properties and determination of the in vitro antioxidant and cytotoxic activities of new 1,3,4-oxadiazole derivatives. Med Chem Res 25, 2015–2029 (2016). https://doi.org/10.1007/s00044-016-1660-5

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