Design, synthesis and biological evaluation of novel hybrids of N-aryl pyrrothine-base α-pyrone as bacterial RNA polymerase inhibitors

Bioorg Med Chem Lett. 2020 Jun 1;30(11):127146. doi: 10.1016/j.bmcl.2020.127146.

Xiangduan Tan ¹, Mohan Huang ², Siyun Nian ³, Yanfen Peng ¹, Jianli Qin ¹, Bo Kong ⁴, Xiaoqun Duan ⁵

Affiliations

1 College of Pharmacy, Guilin Medical University, Guilin 541004, China.
2 College of Pharmacy, Guilin Medical University, Guilin 541004, China; Department of Pharmacy, Liuzhou People's Hospital, Liuzhou 545006, China.
3 Zhejiang Hisun Pharmaceutical Co., Ltd, Taizhou 318000, China.
4 School of Life Sciences, Guangzhou University, Guangzhou 510006, China. Electronic address: kongbo@gzhu.edu.cn.
5 College of Pharmacy, Guilin Medical University, Guilin 541004, China. Electronic address: robortduan@163.com.

PMID: 32249118 DOI: 10.1016/j.bmcl.2020.127146

Abstract

Antibiotic resistance in bacteria has been an emerging public health problem, thus discovery of novel and effective Antibiotics is urgent. A series of novel hybrids of N-aryl pyrrothine-base α-pyrone hybrids was designed, synthesized and evaluated as Bacterial RNA polymerase (RNAP) inhibitors. Among them, compound 13c exhibited potent Antibacterial activity against antibiotic-resistant S. aureus with the minimum inhibitory concentration (MIC) in the range of 1-4 μg/mL. Moreover, compound 13c exhibited strong inhibitory activity against E.coli RNAP with IC₅₀ value of 16.06 μM, and cytotoxicity in HepG2 cells with IC₅₀ value of 7.04 μM. The molecular docking study further suggested that compound 13c binds to the switch region of Bacterial RNAP. In summary, compound 13c is a novel Bacterial RNAP inhibitor, and a promising lead compound for further optimization.

Keywords

Bacterial RNA polymerase; Hybrid; N-aryl pyrrothine; Switch region; α-pyrone.

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