Medicinal Chemistry Department, Faculty of Pharmacy, Deraya University, Minia, 61768, Egypt.
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt.
Chem Biodivers. 2020 Jun;17(6):e2000100. doi: 10.1002/cbdv.202000100. Epub 2020 May 8.
A facile and convenient synthesis of new pyridazines suitable for use as antimicrobial agents was reported. The hydrazide intermediate was coupled with various benzaldehydes and/or acetophenones and cyclized instantaneously to afford target pyridazine derivatives. The structures of new pyridazines were confirmed by IR, H- and C-NMR, elemental analysis in addition to representative LC/MS. Antimicrobial activity was screened against 10 bacterial and fungal strains. The new pyridazines showed strong to very strong antibacterial activity against Gram-negative (GNB) bacteria, while none of them showed significant antifungal activity at the same concentration range. Chloro derivatives exhibited the highest antibacterial activity with MICs (0.892-3.744 μg/mL) lower than that of chloramphenicol (2.019-8.078 μg/mL) against E. coli, P. aeruginosa, and S. marcescens. Prediction of ADME parameters, pharmacokinetics, and substrate promiscuity revealed that these new pyridazines could be promising drug candidates. Cytotoxic studies on rat hepatocytes showed how much safe these new pyridazines on living organisms (IC >64 μg/mL). MOE docking studies showed a good overlay of these new pyridazines with co-crystallized ligand within an E. coli DNA gyrase subunit B active sites (4KFG).
报道了一种简便合成新型哒嗪类化合物的方法，可作为抗菌剂。将酰腙中间体与各种苯甲醛和/或苯乙酮偶联，瞬时环化得到目标哒嗪衍生物。新哒嗪的结构通过红外、氢谱和碳谱、元素分析以及代表性的 LC/MS 得到确认。对 10 株细菌和真菌菌株进行了抗菌活性筛选。新哒嗪类化合物对革兰氏阴性（GNB）细菌具有很强到极强的抗菌活性，而在相同浓度范围内对真菌均无明显的抗菌活性。氯代衍生物表现出最高的抗菌活性，其 MIC 值（0.892-3.744μg/mL）低于氯霉素（2.019-8.078μg/mL），对大肠杆菌、铜绿假单胞菌和粘质沙雷氏菌均有作用。ADME 参数、药代动力学和底物混杂性预测表明，这些新哒嗪类化合物可能是有前途的药物候选物。大鼠肝细胞的细胞毒性研究表明，这些新哒嗪类化合物对生物体的安全性较高（IC>64μg/mL）。MOE 对接研究表明，这些新哒嗪类化合物与大肠杆菌 DNA 回旋酶亚基 B 活性部位的共晶配体（4KFG）有很好的重叠。
