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Design, synthesis of novel 4,5-dihydroisoxazole-containing benzamide derivatives as highly potent FtsZ inhibitors capable of killing a variety of MDR Staphylococcus aureus.
Bioorg Med Chem. 2020 11 01; 28(21):115729.BM

Abstract

Antibiotic resistance among clinically significant bacterial pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) is becoming a prevalent threat to public health, and new antibacterial agents with novel mechanisms of action hence are in an urgent need. As a part of continuing effort to develop antibacterial agents, we rationally designed and synthesized two series of 4,5-dihydroisoxazol-5-yl and 4,5-dihydroisoxazol-3-yl-containing benzamide derivatives that targeted the bacterial cell division protein FtsZ. Evaluation of their activity against a panel of Gram-positive and -negative pathogens revealed that compound A16 possessing the 4,5-dihydroisoxazol-5-yl group showed outstanding antibacterial activity (MIC, ≤0.125-0.5 μg/mL) against various testing strains, including methicillin-resistant, penicillin-resistant and clinical isolated S. aureus strains. Besides, further mouse infection model revealed that A16 could be effective in vivo and non-toxic to Hela cells. Finally, a detailed discussion of structure-activity relationships was conducted, referring to the docking results. It is worth noting that substituting a 4,5-dihydroisoxazole ring for the isoxazole ring not only broadened the antibacterial spectrum but also resulted in a significant increase in antibacterial activity against S. aureus strains. Taken together, these results suggest a promising chemotype for the development of new FtsZ-targeting bactericidal agents.

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Authors+Show Affiliations

Song D
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan 250012, China.
Bi F
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan 250012, China.
Zhang N
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan 250012, China.
Qin Y
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan 250012, China.
Liu X
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan 250012, China.
Teng Y
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan 250012, China.
Ma S
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan 250012, China. Electronic address: mashutao@sdu.edu.cn.

MeSH

AnimalsAnti-Bacterial AgentsBacterial ProteinsBenzamidesBinding SitesCell SurvivalCytoskeletal ProteinsDrug DesignDrug Resistance, BacterialDrug StabilityGram-Negative BacteriaGram-Positive BacteriaHeLa CellsHumansIsoxazolesMethicillin-Resistant Staphylococcus aureusMiceMicrobial Sensitivity TestsMolecular Docking SimulationStructure-Activity Relationship

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33065440

Citation

Song, Di, et al. "Design, Synthesis of Novel 4,5-dihydroisoxazole-containing Benzamide Derivatives as Highly Potent FtsZ Inhibitors Capable of Killing a Variety of MDR Staphylococcus Aureus." Bioorganic & Medicinal Chemistry, vol. 28, no. 21, 2020, p. 115729.
Song D, Bi F, Zhang N, et al. Design, synthesis of novel 4,5-dihydroisoxazole-containing benzamide derivatives as highly potent FtsZ inhibitors capable of killing a variety of MDR Staphylococcus aureus. Bioorg Med Chem. 2020;28(21):115729.
Song, D., Bi, F., Zhang, N., Qin, Y., Liu, X., Teng, Y., & Ma, S. (2020). Design, synthesis of novel 4,5-dihydroisoxazole-containing benzamide derivatives as highly potent FtsZ inhibitors capable of killing a variety of MDR Staphylococcus aureus. Bioorganic & Medicinal Chemistry, 28(21), 115729. https://doi.org/10.1016/j.bmc.2020.115729
Song D, et al. Design, Synthesis of Novel 4,5-dihydroisoxazole-containing Benzamide Derivatives as Highly Potent FtsZ Inhibitors Capable of Killing a Variety of MDR Staphylococcus Aureus. Bioorg Med Chem. 2020 11 1;28(21):115729. PubMed PMID: 33065440.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis of novel 4,5-dihydroisoxazole-containing benzamide derivatives as highly potent FtsZ inhibitors capable of killing a variety of MDR Staphylococcus aureus. AU - Song,Di, AU - Bi,Fangchao, AU - Zhang,Nan, AU - Qin,Yinhui, AU - Liu,Xingbang, AU - Teng,Yuetai, AU - Ma,Shutao, Y1 - 2020/08/27/ PY - 2020/06/03/received PY - 2020/07/30/revised PY - 2020/08/19/accepted PY - 2020/10/17/pubmed PY - 2021/6/22/medline PY - 2020/10/16/entrez KW - 4,5-Dihydroisoxazole-containing benzamide KW - Antibacterial activity KW - Design and synthesis KW - FtsZ inhibitor KW - Structure-activity relationships SP - 115729 EP - 115729 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 28 IS - 21 N2 - Antibiotic resistance among clinically significant bacterial pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) is becoming a prevalent threat to public health, and new antibacterial agents with novel mechanisms of action hence are in an urgent need. As a part of continuing effort to develop antibacterial agents, we rationally designed and synthesized two series of 4,5-dihydroisoxazol-5-yl and 4,5-dihydroisoxazol-3-yl-containing benzamide derivatives that targeted the bacterial cell division protein FtsZ. Evaluation of their activity against a panel of Gram-positive and -negative pathogens revealed that compound A16 possessing the 4,5-dihydroisoxazol-5-yl group showed outstanding antibacterial activity (MIC, ≤0.125-0.5 μg/mL) against various testing strains, including methicillin-resistant, penicillin-resistant and clinical isolated S. aureus strains. Besides, further mouse infection model revealed that A16 could be effective in vivo and non-toxic to Hela cells. Finally, a detailed discussion of structure-activity relationships was conducted, referring to the docking results. It is worth noting that substituting a 4,5-dihydroisoxazole ring for the isoxazole ring not only broadened the antibacterial spectrum but also resulted in a significant increase in antibacterial activity against S. aureus strains. Taken together, these results suggest a promising chemotype for the development of new FtsZ-targeting bactericidal agents. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/33065440/Design_synthesis_of_novel_45_dihydroisoxazole_containing_benzamide_derivatives_as_highly_potent_FtsZ_inhibitors_capable_of_killing_a_variety_of_MDR_Staphylococcus_aureus_ DB - PRIME DP - Unbound Medicine ER -