Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran.
Daru. 2013 Aug 8;21(1):66. doi: 10.1186/2008-2231-21-66.
Helicobacter pylori is recognized as the main cause of gastritis and gastroduodenal ulcers and classified as class 1 carcinogen pathogen. Different 1,3,4-thiadiazole derivatives bearing 5-nitroaryl moiety have been shown considerable anti- H. pylori activity. In attempt to find new and potent derivatives of described scaffold, a new series of 1-(substituted benzyl)-4-(5-(5-nitroaryl-2-yl)-1,3,4-thiadiazol-2-yl)piperazine derivatives were synthesized and evaluated against three metronidazole-resistant isolates of H. pylori using paper disk diffusion bioassay test.
The title compounds were prepared through the reaction of 1-(5-(5-nitroaryl-2-yl)-1,3,4-thiadiazol-2-yl) piperazine 5a-b and substituted benzyl chloride in DMF. The inhibitory activity of the new derivatives 6a-q against three metronidazole-resistant isolates of H. pylori was evaluated by the disc diffusion method and compared with the commercially available standard drug metronidazole.
The results of SAR study indicated that the potency and anti-H. pylori activity profile of synthesized derivatives is mainly attributed to the substituted nitroaryl moiety at the C-5 position of 1,3,4-thiadiazole ring. Most of 1,3,4-thiadiazole derivatives bearing 5-nitrofuran moiety at C-5 position of central thiadiazole ring, demonstrated more promising anti-H. pylori than the 5-nitrothiophen counterpart.
The most potent nitrofuran derivative containing 3-methoxybenzyl piperazine pendant at the C-2 position of 1,3,4-thiadiazole ring (compound 6i), demonstrated strong anti-H. pylori potential at studied concentrations 100-25 μg/disk (IZD > 20 mm) against all studied metronidazole- resistant isolates of H. pylori.
幽门螺杆菌被认为是胃炎和消化性溃疡的主要病因，被归类为 1 类致癌病原体。带有 5-硝基芳基部分的不同 1,3,4-噻二唑衍生物已显示出相当的抗 H. pylori 活性。为了寻找描述支架的新的有效衍生物，我们合成了一系列新的 1-(取代苄基)-4-(5-(5-硝基芳基-2-基)-1,3,4-噻二唑-2-基)哌嗪衍生物，并使用纸片扩散生物测定试验评估它们对三种甲硝唑耐药的 H. pylori 分离株的活性。
标题化合物是通过 1-(5-(5-硝基芳基-2-基)-1,3,4-噻二唑-2-基)哌嗪 5a-b 与取代苄基氯在 DMF 中的反应制备的。通过纸片扩散法评估新衍生物 6a-q 对三种甲硝唑耐药的 H. pylori 分离株的抑制活性，并与市售标准药物甲硝唑进行比较。
SAR 研究结果表明，合成衍生物的效力和抗 H. pylori 活性主要归因于噻二唑环 C-5 位置的取代硝基芳基部分。噻二唑环 C-5 位置带有 5-硝基呋喃部分的大多数 1,3,4-噻二唑衍生物比 5-硝基噻吩部分具有更有前途的抗 H. pylori 活性。
噻二唑环 C-2 位置带有 3-甲氧基苄基哌嗪侧链的最有效硝基呋喃衍生物（化合物 6i）在研究浓度下（100-25μg/disk）对所有研究的甲硝唑耐药的 H. pylori 分离株均表现出较强的抗 H. pylori 潜力（IZD>20mm）。
