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Article

Design, Synthesis, Biological Evaluation and In Silico Study of Benzyloxybenzaldehyde Derivatives as Selective ALDH1A3 Inhibitors

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Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman 11733, Jordan
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Faculty of Life Sciences, Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, University of Bradford, Bradford BD7 1DP, UK
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Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma de Barcelona, E-08193 Barcelona, Spain
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Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
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College of Engineering and Technology, American University of the Middle East, Kuwait City 54200, Kuwait
*
Authors to whom correspondence should be addressed.
Academic Editor: Patricia Dias Fernandes
Molecules 2021, 26(19), 5770; https://doi.org/10.3390/molecules26195770
Received: 6 August 2021 / Revised: 10 September 2021 / Accepted: 13 September 2021 / Published: 23 September 2021
(This article belongs to the Special Issue Drug Discovery and Development: New Options for Old Diseases)
Aldehyde dehydrogenase 1A3 (ALDH1A3) has recently gained attention from researchers in the cancer field. Several studies have reported ALDH1A3 overexpression in different cancer types, which has been found to correlate with poor treatment recovery. Therefore, finding selective inhibitors against ALDH1A3 could result in new treatment options for cancer treatment. In this study, ALDH1A3-selective candidates were designed based on the physiological substrate resemblance, synthesized and investigated for ALDH1A1, ALDH1A3 and ALDH3A1 selectivity and cytotoxicity using ALDH-positive A549 and ALDH-negative H1299 cells. Two compounds (ABMM-15 and ABMM-16), with a benzyloxybenzaldehyde scaffold, were found to be the most potent and selective inhibitors for ALDH1A3, with IC50 values of 0.23 and 1.29 µM, respectively. The results also show no significant cytotoxicity for ABMM-15 and ABMM-16 on either cell line. However, a few other candidates (ABMM-6, ABMM-24, ABMM-32) showed considerable cytotoxicity on H1299 cells, when compared to A549 cells, with IC50 values of 14.0, 13.7 and 13.0 µM, respectively. The computational study supported the experimental results and suggested a good binding for ABMM-15 and ABMM-16 to the ALDH1A3 isoform. From the obtained results, it can be concluded that benzyloxybenzaldehyde might be considered a promising scaffold for further drug discovery aimed at exploiting ALDH1A3 for therapeutic intervention. View Full-Text
Keywords: aldehyde dehydrogenase; ALDH1A1; ALDH1A3; ALDH3A1; A549 cells; H1299 cells; non-small cell lung cancer; cytotoxicity; in silico aldehyde dehydrogenase; ALDH1A1; ALDH1A3; ALDH3A1; A549 cells; H1299 cells; non-small cell lung cancer; cytotoxicity; in silico
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MDPI and ACS Style

Ibrahim, A.I.M.; Ikhmais, B.; Batlle, E.; AbuHarb, W.K.; Jha, V.; Jaradat, K.T.; Jiménez, R.; Pequerul, R.; Parés, X.; Farrés, J.; Pors, K. Design, Synthesis, Biological Evaluation and In Silico Study of Benzyloxybenzaldehyde Derivatives as Selective ALDH1A3 Inhibitors. Molecules 2021, 26, 5770. https://doi.org/10.3390/molecules26195770

AMA Style

Ibrahim AIM, Ikhmais B, Batlle E, AbuHarb WK, Jha V, Jaradat KT, Jiménez R, Pequerul R, Parés X, Farrés J, Pors K. Design, Synthesis, Biological Evaluation and In Silico Study of Benzyloxybenzaldehyde Derivatives as Selective ALDH1A3 Inhibitors. Molecules. 2021; 26(19):5770. https://doi.org/10.3390/molecules26195770

Chicago/Turabian Style

Ibrahim, Ali I.M., Balqis Ikhmais, Elisabet Batlle, Waed K. AbuHarb, Vibhu Jha, Khaled T. Jaradat, Rafael Jiménez, Raquel Pequerul, Xavier Parés, Jaume Farrés, and Klaus Pors. 2021. "Design, Synthesis, Biological Evaluation and In Silico Study of Benzyloxybenzaldehyde Derivatives as Selective ALDH1A3 Inhibitors" Molecules 26, no. 19: 5770. https://doi.org/10.3390/molecules26195770

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