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
References
Alam MS, Choi J-H, Lee D-U (2012) Synthesis of novel Schiff base analogues of 4-amino-1, 5-dimethyl-2-phenylpyrazol-3-one and their evaluation for antioxidant and anti-inflammatory activity. Bioorg Med Chem 20:4103–4108
Benzie IF, Strain J (1996) The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal Biochem 239:70–76
Bergström CA, Holm R, Jørgensen SA, Andersson SB, Artursson P, Beato S, Borde A, Mullertz A (2013) Early pharmaceutical profiling to predict oral drug absorption: Current status and unmet needs. Eur J Pharm Sci 57:173–199
Brand-Williams W, Cuvelier ME, Berset C (1995) Use of a free radical method to evaluate antioxidant activity. Lebensm Wiss Technol 28:25–30
Derochette S, Franck T, Mouithys-Mickalad A, Ceusters J, Deby-Dupont G, Lejeune J-P, Neven P, Serteyn D (2013) Curcumin and resveratrol act by different ways on NADPH oxidase activity and reactive oxygen species produced by equine neutrophils. Chem Biol Interact 206:186–193
Desai N, Bhatt N, Somani H, Trivedi A (2013) Synthesis, antimicrobial and cytotoxic activities of some novel thiazole clubbed 1, 3, 4-oxadiazoles. Eur J Med Chem 67:54–59
Egan WJ, Lauri G (2002) Prediction of intestinal permeability. Adv Drug Deliver Rev 54:273–289
Egan WJ, Merz KM, Baldwin JJ (2000) Prediction of drug absorption using multivariate statistics. J Med Chem 43:3867–3877
Ferrari E, Lucca C, Foiani MA (2010) Lethal combination for cancer cells: synthetic lethality screenings for drug discovery. Eur J Cancer 46:2889–2895
Fuchs-Tarlovsky V (2013) Role of antioxidants in cancer therapy. Nutrition 29:15–21
Gerhäuser C, Klimo K, Heiss E, Neumann I, Gamal-Eldeen A, Knauft J, Liu G-Y, Sitthimonchai S, Frank N (2003) Mechanism-based in vitro screening of potential cancer chemopreventive agents. Mutat Res 523:163–172
Gozzo A, Lesieur D, Duriez P, Fruchart J-C, Teissier E (1999) Structure-activity relationships in a series of melatonin analogues with the low-density lipoprotein oxidation model. Free Radic Biol Med 26:1538–1543
Hegazy GH, Ali HI (2012) Design, synthesis, biological evaluation, and comparative Cox1 and Cox2 docking of p-substituted benzylidenamino phenyl esters of ibuprofenic and mefenamic acids. Bioorg Med Chem 20:1259–1270
Hoelder S, Clarke PA, Workman P (2012) Discovery of small molecule cancer drugs: successes, challenges and opportunities. Mole Oncol 6:155–176
Husain A, Ahmad A, Alam MM, Ajmal M, Ahuja P (2009) Fenbufen based 3-[5-(substituted aryl)-1, 3, 4-oxadiazol-2-yl]-1-(biphenyl-4-yl) propan-1-ones as safer antiinflammatory and analgesic agents. Eur J Med Chem 44:3798–3804
Karadag A, Ozcelik B, Saner S (2009) Review of methods to determine antioxidant capacities. Food Anal Method 2:41–60
Kotaiah Y, Harikrishna N, Nagaraju K, Venkato RC (2012) Synthesis and antioxidant activity of 1, 3, 4-oxadiazole tagged thieno [2, 3-d] pyrimidine derivatives. Eur J Med Chem 58:340–345
Kundu JK, Surh Y-J (2012) Emerging avenues linking inflammation and cancer. Free Radic Biol Med 52:2013–2037
Lipinski C, Lombardo F, Dominy B, Feeney P (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliver Rev 23:3–25
Lipinski C, Lombardo F, Dominy B, Feeney P (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliver Rev 46:3–26
Looi CY, Moharram B, Paydar M, Wong YL, Leong KH, Mohamad K, Arya A, Wong WF, Mustafa MR (2013) Induction of apoptosis in melanoma A375 cells by a chloroform fraction of Centratherum anthelminticum (L.) seeds involves NF-kappaB, p53 and Bcl-2-controlled mitochondrial signaling pathways. BMC Complement Altern Med 13:166
Malich G, Markovic B, Winder C (1997) The sensitivity and specificity of the MTS tetrazolium assay for detecting the in vitro cytotoxicity of 20 chemicals using human cell lines. Toxicology 124:179–192
Nordberg J, Arnér ES (2001) Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic Biol Med 31:1287–1312
Omar F, Mahfouz N, Rahman M (1996) Design, synthesis and antiinflammatory activity of some 1, 3, 4-oxadiazole derivatives. Eur J Med Chem 31:819–825
Petit J, Meurice N, Kaiser C, Maggiora G (2012) Softening the Rule of Five - where to draw the line? Bioorg Med Chem 20:5343–5351
Pospíšil J (1993) Chemical and photochemical behaviour of phenolic antioxidants in polymer stabilization: a state of the art report, part II. Polym Degrad Stabil 39:103–115
Prasad S, Gupta SC, Tyagi AK, Aggarwal BB (2014) Curcumin, a component of golden spice: From bedside to bench and back. Biotechnol Adv 32:1053–1064
Prior RL, Wu X, Schaich K (2005) Standardized methods for the determination of antioxidant capacity and phenolics in foods and dietary supplements. J Agr Food Chem 53:4290–4302
Priyadarsini KI, Maity DK, Naik GH, Sudheer KM, Unnikrishnan MK, Satav JG, Mohan H (2003) Role of phenolic OH and methylene hydrogen on the free radical reactions and antioxidant activity of curcumin. Free Radic Biol Med 35:475–484
Rapolu S, Alla M, Bommena VR, Ramalinga M, Nishant J, Venkata RB, Madhava RB (2013) Synthesis and biological screening of 5-(alkyl (1H-indol-3-yl))-2-(substituted)-1, 3, 4-oxadiazoles as antiproliferative and anti-inflammatory agents. Eur J Med Chem 66:91–100
Ren S, Wang R, Komatsu K, Patricia B-K, Yegor Z, Charles E, Csaba C, Zoltan A, Eric JL (2002) Synthesis, biological evaluation, and quantitative structure-activity relationship analysis of new Schiff bases of hydroxysemicarbazide as potential antitumor agents. J Med Chem 45:410–419
Revanasiddappa B, Subrahmanyam E (2009) Chloramine-T mediated synthesis of 1, 3, 4-oxadiazoles. Orient J Chem 25:707–710
Soobrattee MA, Neergheen VS, Luximon-Ramma A, Aruoma OI, Bahorun T (2005) Phenolics as potential antioxidant therapeutic agents: mechanism and actions. Mutat Res Fund Mol Mech Mut 579:200–213
Suan J, Li M-H, Qian S-S, Guo F-J, Dang X-F, Wang X-M, Xue Y-R, Zhu H-L (2013) Synthesis and antitumor activity of 1, 3, 4-oxadiazole possessing 1, 4-benzodioxan moiety as a novel class of potent methionine aminopeptidase type II inhibitors. Bioorg Med Chem Lett 23:2876–2879
Tang JJ, Fan GJ, Dai F, Ding DJ, Wang Q, Lu DL, Ran RL, Zhou B (2011) Finding more active antioxidants and cancer chemoprevention agents by elongating the conjugated links of resveratrol. Free Radic Biol Med 50:1447–1457
Tang A, Lien EJ, Lai MM (1985) Optimization of the Schiff bases of N-hydroxy-N’-aminoguanidine as anticancer and antiviral agents. J Med Chem 28:1103–1106
Tung Y-T, Wu JH, Kuo YH, Chang ST (2007) Antioxidant activities of natural phenolic compounds from Acacia confusa bark. Bioresource Technol 98:1120–1123
Veber DF, Johnson SR, Cheng H-Y, Smith BR, Ward KW, Kopple KD (2002) Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 45:2615–2623
Vineis P, Wild CP (2014) Global cancer patterns: causes and prevention. Lancet 383:549–557
Wils P, Warnery A, Phung-Ba V, Legrain S, Scherman D (1994) High lipophilicity decreases drug transport across intestinal epithelial cells. J Pharmacol Exp Ther 269:654–658
Wu Y, Antony S, Meitzler JL, Doroshow JH (2014) Molecular mechanisms underlying chronic inflammation-associated cancers. Cancer Lett 345:164–173
Yehye WA, Abdul RN, Alhadi A, Khaledi H, Ng SW, Ariffin A (2012) Butylated hydroxytoluene analogs: synthesis and evaluation of their multipotent antioxidant activities. Molecules 17:7645–7665
Zhang M-Z, Mulholland N, Beattie D, Irwin D, Gu Y-C, Chen Q, Yang G-F, Clough J (2013) Synthesis and antifungal activity of 3-(1, 3, 4-oxadiazol-5-yl)-indoles and 3-(1, 3, 4-oxadiazol-5-yl) methyl-indoles. Eur J Med Chem 63:22–32
Zhang M-Q, Wilkinson B (2007) Drug discovery beyond the ‘Rule-Of-Five’. Curr Opin Biotechnol 18:478–488
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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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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DOI: https://doi.org/10.1007/s00044-016-1660-5