Tags

Type your tag names separated by a space and hit enter

Design, synthesis and structure-based optimization of novel isoxazole-containing benzamide derivatives as FtsZ modulators.
Eur J Med Chem. 2018 Nov 05; 159:90-103.EJ

Abstract

Antibiotic resistance among clinically significant bacterial pathogens is becoming a prevalent threat to public health, and new antibacterial agents with novel mechanisms of action hence are in an urgent need. Utilizing computational docking method and structure-based optimization strategy, we rationally designed and synthesized two series of isoxazol-3-yl- and isoxazol-5-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 compounds B14 and B16 that possessed the isoxazol-5-yl group showed strong antibacterial activity against various testing strains, including methicillin-resistant Staphylococcus aureus and penicillin-resistant S. aureus. Further molecular biological studies and docking analyses proved that the compound functioned as an effective inhibitor to alter the dynamics of FtsZ self-polymerization via a stimulatory mechanism, which finally terminated the cell division and caused cell death. Taken together, these results could suggest a promising chemotype for development of new FtsZ-targeting bactericidal agent.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Bi F
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, 250012, China.
Song D
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, 250012, China.
Zhang N
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, 250012, China.
Liu Z
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, 250012, China.
Gu X
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, 250012, China.
Hu C
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, 250012, China.
Cai X
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, 250012, China.
Venter H
School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, SA, 5000, Australia.
Ma S
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, 250012, China. Electronic address: mashutao@sdu.edu.cn.

MeSH

Anti-Bacterial AgentsBacillus pumilusBacillus subtilisBacterial ProteinsBenzamidesCell SurvivalCytoskeletal ProteinsDose-Response Relationship, DrugDrug DesignHeLa CellsHumansIsoxazolesMicrobial Sensitivity TestsMolecular StructureStaphylococcus aureusStructure-Activity Relationship

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30268826

Citation

Bi, Fangchao, et al. "Design, Synthesis and Structure-based Optimization of Novel Isoxazole-containing Benzamide Derivatives as FtsZ Modulators." European Journal of Medicinal Chemistry, vol. 159, 2018, pp. 90-103.
Bi F, Song D, Zhang N, et al. Design, synthesis and structure-based optimization of novel isoxazole-containing benzamide derivatives as FtsZ modulators. Eur J Med Chem. 2018;159:90-103.
Bi, F., Song, D., Zhang, N., Liu, Z., Gu, X., Hu, C., Cai, X., Venter, H., & Ma, S. (2018). Design, synthesis and structure-based optimization of novel isoxazole-containing benzamide derivatives as FtsZ modulators. European Journal of Medicinal Chemistry, 159, 90-103. https://doi.org/10.1016/j.ejmech.2018.09.053
Bi F, et al. Design, Synthesis and Structure-based Optimization of Novel Isoxazole-containing Benzamide Derivatives as FtsZ Modulators. Eur J Med Chem. 2018 Nov 5;159:90-103. PubMed PMID: 30268826.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis and structure-based optimization of novel isoxazole-containing benzamide derivatives as FtsZ modulators. AU - Bi,Fangchao, AU - Song,Di, AU - Zhang,Nan, AU - Liu,Zhiyang, AU - Gu,Xinjie, AU - Hu,Chaoyu, AU - Cai,Xiaokang, AU - Venter,Henrietta, AU - Ma,Shutao, Y1 - 2018/09/22/ PY - 2018/07/15/received PY - 2018/09/19/revised PY - 2018/09/19/accepted PY - 2018/10/1/pubmed PY - 2018/11/14/medline PY - 2018/10/1/entrez KW - Antibacterial activity KW - FtsZ inhibitor KW - Isoxazole-containing benzamide KW - Molecular docking analysis KW - Structure-based optimization SP - 90 EP - 103 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 159 N2 - Antibiotic resistance among clinically significant bacterial pathogens is becoming a prevalent threat to public health, and new antibacterial agents with novel mechanisms of action hence are in an urgent need. Utilizing computational docking method and structure-based optimization strategy, we rationally designed and synthesized two series of isoxazol-3-yl- and isoxazol-5-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 compounds B14 and B16 that possessed the isoxazol-5-yl group showed strong antibacterial activity against various testing strains, including methicillin-resistant Staphylococcus aureus and penicillin-resistant S. aureus. Further molecular biological studies and docking analyses proved that the compound functioned as an effective inhibitor to alter the dynamics of FtsZ self-polymerization via a stimulatory mechanism, which finally terminated the cell division and caused cell death. Taken together, these results could suggest a promising chemotype for development of new FtsZ-targeting bactericidal agent. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/30268826/Design_synthesis_and_structure_based_optimization_of_novel_isoxazole_containing_benzamide_derivatives_as_FtsZ_modulators_ DB - PRIME DP - Unbound Medicine ER -