Synthesis and Biological Evaluation of Dithiobisacetamides as Novel Urease Inhibitors

• Published in: ChemMedChem 2022-01, Vol.17 (2), p.e202100618-n/a
• Main Authors: Liu, Mei‐Ling, Li, Wei‐Yi, Fang, Hai‐Lian, Ye, Ya‐Xi, Li, Su‐Ya, Song, Wan‐Qing, Xiao, Zhu‐Ping, Ouyang, Hui, Zhu, Hai‐Liang
• Format: Article
• Language: English
• Subjects: Acetamides - chemical synthesis; Acetamides - chemistry; Acetamides - pharmacology; Amoxicillin; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Chemical compounds; Cytotoxicity; Disulfides; Dithiobisacetamide; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Helicobacter pylori; Helicobacter pylori - drug effects; Helicobacter pylori - enzymology; Humans; Inhibitors; Mammalian cells; Microbial Sensitivity Tests; Molecular Structure; Pharmacology; reversible urease inhibitor; Structure-Activity Relationship; Sulfhydryl Compounds - chemical synthesis; Sulfhydryl Compounds - chemistry; Sulfhydryl Compounds - pharmacology; Toxicity; Urease; Urease - antagonists & inhibitors; Urease - metabolism
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202100618

Thirty‐eight disulfides containing N‐arylacetamide were designed and synthesized in an effort to develop novel urease inhibitors. Biological evaluation revealed that some of the synthetic compounds exhibited strong inhibitory potency against both cell‐free urease and urease in intact cell with low cytotoxicity to mammalian cells even at concentration up to 250 μM. Of note, 2,2′‐dithiobis(N‐(2‐fluorophenyl)acetamide) (d7), 2,2′‐dithiobis(N‐(3,5‐difluorophenyl)acetamide) (d24), and 2,2′‐dithiobis(N‐(3‐fluorophenyl)acetamide) (d8) were here identified as the most active inhibitors with IC50 of 0.074, 0.44, and 0.81 μM, showing 32‐ to 355‐fold higher potency than the positive control acetohydroxamic acid. These disulfides were confirmed to bind urease without covalent modification of the cysteine residue and to inhibit urease reversibly with a mixed inhibition mechanism. They also showed very good anti‐Helicobacter pylori activities with d8 showing a comparable potency to the clinical used drug amoxicillin. The impressive in vitro biological profile indicated their immense potential as therapeutic agents to tackle H. pylori caused infections. Potent and reversible: Dithiobisacetamides were determined to be urease inhibitors that function through a mechanism of mixed inhibition. They showed excellent potency against Helicobacter pylori urease and good antibacterial activity with nearly no cytotoxicity. The impressive biological profile of d8 (shown) underscores its suitability for further development as a therapeutic agent to tackle infections caused by H. pylori.