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Open AccessArticle

Design, Synthesis and Evaluation of New Bioactive Oxadiazole Derivatives as Anticancer Agents Targeting Bcl-2

1
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3NB, Wales, UK
2
Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
3
Research Institute for Medical and Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, UAE
4
Green Chemistry Department, Chemical Industries Research Division, National Research Center, Cairo, Egypt
5
School of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, UK
6
Department of Mathematical and Physical Sciences, University of Chester, Chester CH2 4NU, UK
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(23), 8980; https://doi.org/10.3390/ijms21238980
Received: 23 October 2020 / Revised: 20 November 2020 / Accepted: 21 November 2020 / Published: 26 November 2020
(This article belongs to the Special Issue Bioactive Oxadiazoles)
A series of 2-(1H-indol-3-yl)-5-substituted-1,3,4-oxadiazoles, 4a–m, were designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2 inhibitory anticancer agents based on our previously reported hit compounds. Synthesis of the target 1,3,4-oxadiazoles was readily accomplished through a cyclization reaction of indole carboxylic acid hydrazide 2 with substituted carboxylic acid derivatives 3a–m in the presence of phosphorus oxychloride. New compounds 4a–m showed a range of IC50 values concentrated in the low micromolar range selectively in Bcl-2 positive human cancer cell lines. The most potent candidate 4-trifluoromethyl substituted analogue 4j showed selective IC50 values of 0.52–0.88 μM against Bcl-2 expressing cell lines with no inhibitory effects in the Bcl-2 negative cell line. Moreover, 4j showed binding that was two-fold more potent than the positive control gossypol in the Bcl-2 ELISA binding affinity assay. Molecular modeling studies helped to further rationalize anti-apoptotic Bcl-2 binding and identified compound 4j as a candidate with drug-like properties for further investigation as a selective Bcl-2 inhibitory anticancer agent. View Full-Text
Keywords: oxadiazole; indole; aromatic heterocycle; anticancer; Bcl-2 inhibitor; chemical synthesis; molecular modeling; apoptosis oxadiazole; indole; aromatic heterocycle; anticancer; Bcl-2 inhibitor; chemical synthesis; molecular modeling; apoptosis
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MDPI and ACS Style

Hamdy, R.; Elseginy, S.A.; Ziedan, N.I.; El-Sadek, M.; Lashin, E.; Jones, A.T.; Westwell, A.D. Design, Synthesis and Evaluation of New Bioactive Oxadiazole Derivatives as Anticancer Agents Targeting Bcl-2. Int. J. Mol. Sci. 2020, 21, 8980. https://doi.org/10.3390/ijms21238980

AMA Style

Hamdy R, Elseginy SA, Ziedan NI, El-Sadek M, Lashin E, Jones AT, Westwell AD. Design, Synthesis and Evaluation of New Bioactive Oxadiazole Derivatives as Anticancer Agents Targeting Bcl-2. International Journal of Molecular Sciences. 2020; 21(23):8980. https://doi.org/10.3390/ijms21238980

Chicago/Turabian Style

Hamdy, Rania; Elseginy, Samia A.; Ziedan, Noha I.; El-Sadek, Mohamed; Lashin, Elsaid; Jones, Arwyn T.; Westwell, Andrew D. 2020. "Design, Synthesis and Evaluation of New Bioactive Oxadiazole Derivatives as Anticancer Agents Targeting Bcl-2" Int. J. Mol. Sci. 21, no. 23: 8980. https://doi.org/10.3390/ijms21238980

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