Department of Medicinal Chemistry, School of Pharmacy and Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Eur J Med Chem. 2011 Jun;46(6):2602-8. doi: 10.1016/j.ejmech.2011.03.053. Epub 2011 Mar 31.
In order to optimize the antileishmanial activity of piperazinyl-linked 5-(5-nitrofuran-2-yl)-1,3,4-thiadiazoles, we synthesized a series of 5-(5-nitrofuran-2-y1)-1,3,4-thiadiazoles with piperazinyl-linked benzamidine substituent as scaffold found in pentamidine related antiprotozoals. The structure of target compounds was confirmed by IR, 1H NMR, 13C NMR and Mass spectral data. All compounds were tested for in vitro activity against the promastigote and amastigote forms of Leishmania major. From the results, we found that the substitution on amidine nitrogen has profound role in the biological activity of these compounds. The 5-nitrofuran-2-yl-1,3,4-thiadiazoles having n-propyl, n-butyl and benzyl side chain on benzamidine (as in compounds 2d, 2e and 2g, respectively) showed very good activity in both forms of promastigote and amastigote. The most active compound was N-propyl-4-(4-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl)piperazin-1-yl) benzamidine hydrochloride (2d) with IC50 value of 0.08 μM in promastigote model. This compound showed a very low level of toxicity against macrophages (CC50=785 μM), with the highest selectivity index (SI=78.5) among the tested compounds.
为了优化哌嗪基连接的 5-(5-硝基呋喃-2-基)-1,3,4-噻二唑的抗利什曼原虫活性，我们合成了一系列以哌嗪基连接的苯甲脒取代基为支架的 5-(5-硝基呋喃-2-基)-1,3,4-噻二唑，该支架存在于戊烷脒相关抗原生动物药物中。目标化合物的结构通过 IR、1H NMR、13C NMR 和质谱数据得到确认。所有化合物均在体外对利什曼原虫前鞭毛体和无鞭毛体形式进行了活性测试。结果表明，脒氮上的取代基对这些化合物的生物活性有深远的影响。在苯甲脒上具有正丙基、正丁基和苄基侧链的 5-硝基呋喃-2-基-1,3,4-噻二唑（如化合物 2d、2e 和 2g）在两种前鞭毛体和无鞭毛体形式中均表现出非常好的活性。最活跃的化合物是 N-丙基-4-(4-(5-(5-硝基呋喃-2-基)-1,3,4-噻二唑-2-基)哌嗪-1-基)苯甲脒盐酸盐（2d），在前鞭毛体模型中的 IC50 值为 0.08 μM。该化合物对巨噬细胞的毒性非常低（CC50=785 μM），在所测试的化合物中具有最高的选择性指数（SI=78.5）。
