Synthesis, evaluation and mechanism exploration of 2-(N-(3-nitrophenyl)-N-phenylsulfonyl)aminoacetohydroxamic acids as novel urease inhibitors

Wan-Qing Song; Mei-Ling Liu; Liang-Chao Yuan; Su-Ya Li; Yi-Ning Wang; Zhu-Ping Xiao; Hai-Liang Zhu

doi:10.1016/j.bmcl.2022.129043

Synthesis, evaluation and mechanism exploration of 2-(N-(3-nitrophenyl)-N-phenylsulfonyl)aminoacetohydroxamic acids as novel urease inhibitors

Bioorg Med Chem Lett. 2022 Dec 15:78:129043. doi: 10.1016/j.bmcl.2022.129043. Epub 2022 Nov 1.

Authors

Wan-Qing Song¹, Mei-Ling Liu¹, Liang-Chao Yuan², Su-Ya Li¹, Yi-Ning Wang¹, Zhu-Ping Xiao³, Hai-Liang Zhu⁴

Affiliations

¹ Hunan Provincial Key Laboratory of Research, Resource Mining and High-valued Utilization on Edible & Medicinal Plant, National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, PR China.
² State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
³ Hunan Provincial Key Laboratory of Research, Resource Mining and High-valued Utilization on Edible & Medicinal Plant, National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, PR China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China. Electronic address: xiaozhuping2005@163.comzhu.
⁴ Hunan Provincial Key Laboratory of Research, Resource Mining and High-valued Utilization on Edible & Medicinal Plant, National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, PR China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China. Electronic address: hl@nju.edu.cn.

PMID: 36332883
DOI: 10.1016/j.bmcl.2022.129043

Abstract

Thirteen 2-(N-(3-nitrophenyl)-N-phenylsulfonyl)aminoacetohydroxamic acids which were reported for the first time were designed and synthesized as novel urease inhibitors. Most of them showed higher potency than the positive control acetohydroxamic acid, with 2-(N-(3-nitrophenyl)-N-(4-bromophenylsulfonyl)aminoacetohydroxamic acid (d7) being the most active (IC₅₀ = 0.13 ± 0.01 μM). Compound d7 reversibly inhibits urease with mixed mechanism showing excellent binding affinity to urease active site (K_D = 0.34 nM, K_i=0.065 ± 0.003 µM andK_i^' = 1.20 ± 0.09 µM) and very low cytotoxicity against mammalian cells (cell viability of 91.4 % against HepG2 at 250 μg/mL). These positive results indicated that d7 may be used as the lead for further research to develop urease inhibitors with promising properties.

Keywords: Hydroxamic acid; Inhibition with mixed mechanism; Phenylsulfonamide; Reversible urease inhibitor.

Publication types

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

MeSH terms

Animals
Cell Survival
Mammals*
Urease*

Substances

Urease