Acetohydroxamic Acid

Acetohydroxamic acid（AHA，CAS号546-88-3）是不可逆尿素酶（urease）抑制剂，为羟基脲类衍生物，可针对细菌和植物尿素酶，主要用于慢性尿路感染、尿素酶相关结石（鸟粪石、磷酸镁铵结石）和 Helicobacter pylori 感染等研究。AHA 还能抑制花生四烯酸 5‑脂氧合酶、减少晚期糖基化终末产物（AGEs）形成、清除自由基，并显示对 HIV 的抗病毒活性和抗氧化、抗炎作用。

AHA 在体外可抑制 Proteus mirabilis 在人工尿中的鸟粪石晶体生成，并抑制 H. pylori 生长（不同菌株 MIC 约为 200–400 mg/L）。在细胞实验中，AHA（约 7 mM，孵育 24 h）能进入细菌细胞、抑制 H. pylori 尿素酶活性并降低其对胃组织的黏附，从而发挥抗菌作用。AHA 还可在 2.5–5 mM，10–14 天 的条件下显著减少 AGEs 形成，在 6 μM–50 mM，30 min 范围内清除 DPPH 和羟基自由基，并在 0–50 μM，1 min 条件下非竞争性抑制半卡巴肼敏感型胺氧化酶（SSAO）。

在犬模型中，长期给予 AHA 能剂量依赖性降低尿液尿素酶活性、pH 和结晶发生，显著抑制膀胱结石生成；在 P. mirabilis 相关的尿路结石模型中，可促进结石溶解并减少复发。在蒙古沙鼠 H. pylori 胃炎模型中，AHA 给药（报道剂量约2500 ppm/只 饲喂）可明显降低胃炎程度和胃内菌负荷。含 AHA 的制剂已用于慢性尿路感染伴尿素酶阳性菌和磷酸镁铵结石的治疗研究，是探索尿素酶靶向治疗、抗氧化/抗炎及抗HIV机制的重要工具化合物。

参考文献：

[1] FISHBEIN WN, CARBONE PP. UREASE CATALYSIS. II. INHIBITION OF THE ENZYME BY HYDROXYUREA, HYDROXYLAMINE, AND ACETOHYDROXAMIC ACID. J Biol Chem. 1965 Jun;240:2407-14. PMID: 14304845.

[2] Krawiec DR, Osborne CA, Leininger JR, Griffith DP. Effect of acetohydroxamic acid on dissolution of canine struvite uroliths. Am J Vet Res. 1984 Jul;45(7):1266-75. PMID: 24049882.

[3] Downey JA, Nickel JC, Clapham L, McLean RJ. In vitro inhibition of struvite crystal growth by acetohydroxamic acid. Br J Urol. 1992 Oct;70(4):355-9. doi: 10.1111/j.1464-410x.1992.tb15787.x. PMID: 1450840.

[4] Phillips K, Munster DJ, Allardyce RA, Bagshaw PF. Antibacterial action of the urease inhibitor acetohydroxamic acid on Helicobacter pylori. J Clin Pathol. 1993 Apr;46(4):372-3. doi: 10.1136/jcp.46.4.372. PMID: 8496397; PMCID: PMC501224.

[5] Ohta T, Shibata H, Kawamori T, Iimuro M, Sugimura T, Wakabayashi K. Marked reduction of Helicobacter pylori-induced gastritis by urease inhibitors, acetohydroxamic acid and flurofamide, in Mongolian gerbils. Biochem Biophys Res Commun. 2001 Jul 20;285(3):728-33. doi: 10.1006/bbrc.2001.5229. PMID: 11453654.

[6] Umamaheshwari RB, Jain NK. Receptor-mediated targeting of lipobeads bearing acetohydroxamic acid for eradication of Helicobacter pylori. J Control Release. 2004 Sep 14;99(1):27-40. doi: 10.1016/j.jconrel.2004.06.006. PMID: 15342178.

[7] Sharma M, Sharma NN, Bhalla TC. Biotransformation of Acetamide to Acetohydroxamic Acid at Bench Scale Using Acyl Transferase Activity of Amidase of Geobacillus pallidus BTP-5x MTCC 9225. Indian J Microbiol. 2012 Mar;52(1):76-82. doi: 10.1007/s12088-011-0211-5. Epub 2011 Aug 11. PMID: 23449317; PMCID: PMC3298591.

[8] Liu YH, Lu YL, Liu DZ, Hou WC. Antiglycation, radical scavenging, and semicarbazide-sensitive amine oxidase inhibitory activities of acetohydroxamic acid in vitro. Drug Des Devel Ther. 2017 Jul 13;11:2139-2147. doi: 10.2147/DDDT.S141740. PMID: 28761331; PMCID: PMC5516777.