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Pyrimido[4,5-B]Indole Derivatives Bearing 1,2,4-Oxadiazole Moiety As Mdm2 Inhibitor Candidates in Cancer Treatment Publisher Pubmed



Mehri A1 ; Mardanshahi M1 ; Sirous H2 ; Khanahmad H3 ; Rostami M1
Authors
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Authors Affiliations
  1. 1. Isfahan Pharmaceutical Sciences Research Center, Department of Medicinal Chemistry, School of Pharmacy & Pharmaceutical Science, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran
  2. 2. Bioinformatics Research Center, School of Pharmacy & Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran
  3. 3. Department of Genetics & Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran

Source: Future Medicinal Chemistry Published:2023


Abstract

Aim: In this study, novel hybrid structures of pyrimido-indole-oxadiazole were developed as MDM2 inhibitors for restoring the regular function of the p53. Materials & methods: A multistep chemical pathway was used to synthesize the derivatives. Nutlin-3a was used as a standard lead in molecular docking and molecular dynamics simulations. Finally, cytotoxicity was evaluated against MCF-7 cancer cells versus Doxorubicin. Results: The most promising candidate was 12c, which had an NO2 group in the para position of the oxadiazole ring (IC50: 1.1 μM). A satisfactory result was obtained with the combined application of 12c and Doxorubicin (IC50 decreased to 0.63 μM), which could be potentially attributed to MDM2 inhibition. Conclusion: These hybrid structures can be further investigated as potential MDM2 inhibitors. © 2023 Newlands Press.
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