Synthesis and molecular docking studies of novel pyrimidine derivatives as potential antibacterial agents
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ORIGINAL ARTICLE
Synthesis and molecular docking studies of novel pyrimidine derivatives as potential antibacterial agents Xue‑Qian Bai1 · Chun‑Shi Li2 · Ming‑Yue Cui2 · Ze‑Wen Song1,3 · Xing‑Yu Zhou1 · Chao Zhang1 · Yang Zhao1 · Tian‑Yi Zhang1 · Tie‑Yan Jiang4 Received: 9 September 2019 / Accepted: 21 November 2019 © Springer Nature Switzerland AG 2019
Abstract The present work describes the in vitro antibacterial evaluation of some new pyrimidine derivatives. Twenty-two target compounds were designed, synthesized and preliminarily explored for their antimicrobial activities. The antimicrobial assay revealed that some target compounds exhibited significantly inhibitory efficiencies toward bacteria and fungal including drug-resistant pathogens. Compound 7c presented the most potent inhibitory activities against Gram-positive bacteria (e.g., Staphylococcus aureus 4220), Gram-negative bacteria (e.g., Escherichia coli 1924) and the fungus Candida albicans 7535, with an MIC of 2.4 μmol/L. Compound 7c was also the most potent, with MICs of 2.4 or 4.8 μmol/L against four multidrugresistant, Gram-positive bacterial strains. The toxicity evaluation of the compounds 7c, 10a, 19d and 26b was assessed in human normal liver cells (L02 cells). Molecular docking simulation and analysis suggested that compound 7c has a good interaction with the active cavities of dihydrofolate reductase (DHFR). In vitro enzyme study implied that compound 7c also displayed DHFR inhibition.
Xue-Qian Bai and Chun-Shi Li have contributed equally to this work. * Tian‑Yi Zhang [email protected] * Tie‑Yan Jiang [email protected] 1
Jilin Medical University, Jilin 132013, People’s Republic of China
2
The Third People’s Hospital of Dalian, Dalian 116000, People’s Republic of China
3
Department of Pharmary, Yanbian University, Yanji 133002, People’s Republic of China
4
Changning Branch of Shanghai Municipal Public Security Bureau, Shanghai 200336, People’s Republic of China
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Vol.:(0123456789)
Molecular Diversity
Graphic abstract
Keywords Pyrimidine · Antibacterial activity · Toxicity · Molecular docking · DHFR inhibition
Introduction Infections caused by bacterial resistance to the major classes of therapeutic drugs have become one of the greatest threats to public health problems [1]. Drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Escherichia coli, cause great difficulties in the treatment of nosocomial infections [2–5], which severely threaten global public health [6]. Drug-resistant bacteria and the simultaneous decline in efforts by academic laboratories or pharmaceutical companies directed toward the discovery of new antibacterial agents to combat resistant strains now pose a serious threat to the treatment of life-threatening infections
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[7]. “The cost in terms of lost global production between now and 2050 would be an enormous 100 trillion USD if we do not take action,” as a UK Government report states [8]. Furthermore, fungal infections pose a serious
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