Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis
Human dihydroorotate dehydrogenase (DHODH) is a viable target for the development of therapeutics to treat cancer and immunological diseases, such as rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS). Herein, a series of acrylamide-based novel DHODH inhibitors as potential RA treatmen...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-03-01
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| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383520307590 |
| _version_ | 1818427125206614016 |
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| author | Fanxun Zeng Shiliang Li Guantian Yang Yating Luo Tiantian Qi Yingfan Liang Tingyuan Yang Letian Zhang Rui Wang Lili Zhu Honglin Li Xiaoyong Xu |
| author_facet | Fanxun Zeng Shiliang Li Guantian Yang Yating Luo Tiantian Qi Yingfan Liang Tingyuan Yang Letian Zhang Rui Wang Lili Zhu Honglin Li Xiaoyong Xu |
| author_sort | Fanxun Zeng |
| collection | DOAJ |
| description | Human dihydroorotate dehydrogenase (DHODH) is a viable target for the development of therapeutics to treat cancer and immunological diseases, such as rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS). Herein, a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents were designed and synthesized. 2-Acrylamidobenzoic acid analog 11 was identified as the lead compound for structure–activity relationship (SAR) studies. The replacement of the phenyl group with naphthyl moieties improved inhibitory activity significantly to double-digit nanomolar range. Further structure optimization revealed that an acrylamide with small hydrophobic groups (Me, Cl or Br) at the 2-position was preferred. Moreover, adding a fluoro atom at the 5-position of the benzoic acid enhanced the potency. The optimization efforts led to potent compounds 42 and 53‒55 with IC50 values of 41, 44, 32, and 42 nmol/L, respectively. The most potent compound 54 also displayed favorable pharmacokinetic (PK) profiles and encouraging in vivo anti-arthritic effects in a dose-dependent manner. |
| first_indexed | 2024-12-14T14:40:45Z |
| format | Article |
| id | doaj.art-a6e128545ee649bda5a9f6d25bd6f15f |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-12-14T14:40:45Z |
| publishDate | 2021-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-a6e128545ee649bda5a9f6d25bd6f15f2022-12-21T22:57:25ZengElsevierActa Pharmaceutica Sinica B2211-38352021-03-01113795809Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritisFanxun Zeng0Shiliang Li1Guantian Yang2Yating Luo3Tiantian Qi4Yingfan Liang5Tingyuan Yang6Letian Zhang7Rui Wang8Lili Zhu9Honglin Li10Xiaoyong Xu11Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, ChinaShanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, ChinaShanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, ChinaShanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, ChinaShanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, ChinaShanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, ChinaShanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, ChinaShanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, ChinaShanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China; Corresponding authors. Tel.: +86 21 64250823 (Rui Wang), +86 21 64253379 (Lili Zhu), +86 21 64250213 (Honglin Li), +86 21 64252945 (Xiaoyong Xu).Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China; Corresponding authors. Tel.: +86 21 64250823 (Rui Wang), +86 21 64253379 (Lili Zhu), +86 21 64250213 (Honglin Li), +86 21 64252945 (Xiaoyong Xu).Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China; Corresponding authors. Tel.: +86 21 64250823 (Rui Wang), +86 21 64253379 (Lili Zhu), +86 21 64250213 (Honglin Li), +86 21 64252945 (Xiaoyong Xu).Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China; Corresponding authors. Tel.: +86 21 64250823 (Rui Wang), +86 21 64253379 (Lili Zhu), +86 21 64250213 (Honglin Li), +86 21 64252945 (Xiaoyong Xu).Human dihydroorotate dehydrogenase (DHODH) is a viable target for the development of therapeutics to treat cancer and immunological diseases, such as rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS). Herein, a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents were designed and synthesized. 2-Acrylamidobenzoic acid analog 11 was identified as the lead compound for structure–activity relationship (SAR) studies. The replacement of the phenyl group with naphthyl moieties improved inhibitory activity significantly to double-digit nanomolar range. Further structure optimization revealed that an acrylamide with small hydrophobic groups (Me, Cl or Br) at the 2-position was preferred. Moreover, adding a fluoro atom at the 5-position of the benzoic acid enhanced the potency. The optimization efforts led to potent compounds 42 and 53‒55 with IC50 values of 41, 44, 32, and 42 nmol/L, respectively. The most potent compound 54 also displayed favorable pharmacokinetic (PK) profiles and encouraging in vivo anti-arthritic effects in a dose-dependent manner.http://www.sciencedirect.com/science/article/pii/S2211383520307590DHODHDe novo pyrimidine biosynthesisDHODH inhibitorsAcrylamide derivativesRheumatoid arthritis |
| spellingShingle | Fanxun Zeng Shiliang Li Guantian Yang Yating Luo Tiantian Qi Yingfan Liang Tingyuan Yang Letian Zhang Rui Wang Lili Zhu Honglin Li Xiaoyong Xu Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis Acta Pharmaceutica Sinica B DHODH De novo pyrimidine biosynthesis DHODH inhibitors Acrylamide derivatives Rheumatoid arthritis |
| title | Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis |
| title_full | Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis |
| title_fullStr | Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis |
| title_full_unstemmed | Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis |
| title_short | Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis |
| title_sort | design synthesis molecular modeling and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis |
| topic | DHODH De novo pyrimidine biosynthesis DHODH inhibitors Acrylamide derivatives Rheumatoid arthritis |
| url | http://www.sciencedirect.com/science/article/pii/S2211383520307590 |
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