Discovery of 1,3,4-oxadiazol-2-one-containing benzamide derivatives targeting FtsZ as highly potent agents of killing a variety of MDR bacteria strains |
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| Institution: | 1. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China;2. Department of Environmental Science & Engineering, Fudan University, Shanghai 200433, PR China;1. 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;2. The Affiliated Hospital of Qingdao University, Qingdao, 266003, China;1. Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo 11884, Egypt;2. Department of Pharmaceutical Analytical Chemistry, College of Pharmacy, Al-Azhar University, Cairo 11884, Egypt;3. Department of Pharmaceutical Chemistry, College of Pharmacy, Horus University – Egypt, New Damietta, Egypt;1. Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, PR China;2. School of Chemical Engineering, Chongqing University of Technology, Chongqing, 400054, PR China;1. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China;2. Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China;3. Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China |
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| Abstract: | The spread of infections caused by multidrug-resistant (MDR) pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA), has created a need for new antibiotics with novel mechanisms of action. The bacterial division protein FtsZ has been identified as a novel drug target that can be exploited clinically. As part of an ongoing effort to develop FtsZ-targeting antibacterial agents, we describe herein the design, synthesis and bioactivity of six series of novel 1,3,4-oxadiazol-2-one-containing, 1,2,4-triazol-3-one-containing and pyrazolin-5-one-containing benzamide derivatives. Among them, compound A14 was found to be the most potent antibacterial agent, much better than clinical drugs such as ciprofloxacin, linezolid and erythromycin against all the tested gram-positive strains, particularly methicillin-resistant, penicillin-resistant and clinical isolated S. aureus. Subsequent studies on biological activities and docking analyses proved that A14 functioned as an effective compound targeting FtsZ. Preliminary SAR indicated a general direction for further optimization of these novel analogues. Taken together, this research provides a promising chemotype for developing newer FtsZ-targeting bactericidal agents. |
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| Keywords: | 1 3 4-Oxadiazol-2-one-containing benzamides FtsZ-targeting Multidrug-resistant bacteria Antibacterial activity |
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