Department of Chemistry, Hazara University, Mansehra 21120, Pakistan.
Department of Chemistry, School of Natural Sciences (SNS), National University of Sciences and Technology (NUST), H-12, Islamabad 44000, Pakistan.
Eur J Med Chem. 2018 Feb 10;145:140-153. doi: 10.1016/j.ejmech.2017.12.089. Epub 2017 Dec 29.
Present work describes the in vitro antibacterial evaluation of some new amino acid conjugated antimicrobial drugs. Structural modification was attempted on the three existing antimicrobial pharmaceuticals namely trimethoprim, metronidazole, isoniazid. Twenty one compounds from seven series of conjugates of these drugs were synthesized by coupling with some selected Boc-protected amino acids. The effect of structural features and lipophilicity on the antibacterial activity was investigated. The synthesized compounds were evaluated against five standard American type culture collection (ATCC) i.e. Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi strains of bacteria. Our results identified a close relationship between the lipophilicity and the activity. Triazine skeleton proved beneficial for the increase in hydrophobicity and potency. Compounds with greater hydrophobicity have shown excellent activities against Gram-negative strains of bacteria than Gram-positive. 4-amino unsubstituted trimethoprim-triazine derivative 7b have shown superior activity with MIC = 3.4 μM (2 μg/mL) for S. aureus and 1.1 μM (0.66 μg/mL) for E. coli. The synthesized compounds were also evaluated for their urease inhibition study. Microbial urease from Bacillus pasteurii was chosen for this study. Triazine derivative 7a showed excellent inhibition with IC = 6.23 ± 0.09 μM. Docking studies on the crystal structure of B. pasteurii urease (PDB ID 4UBP) were carried out.
本工作描述了一些新的氨基酸偶联抗菌药物的体外抗菌评价。尝试对三种现有的抗菌药物——甲氧苄啶、甲硝唑和异烟肼进行结构修饰。通过与一些选定的 Boc 保护氨基酸偶联，合成了来自这三种药物的七个系列偶联物的 21 种化合物。研究了结构特征和疏水性对抗菌活性的影响。合成的化合物对五种标准美国典型培养物保藏（ATCC）即金黄色葡萄球菌、枯草芽孢杆菌、大肠杆菌、铜绿假单胞菌和伤寒沙门氏菌进行了评估。我们的结果表明，疏水性和活性之间存在密切关系。三嗪骨架有利于增加疏水性和效力。疏水性更强的化合物对革兰氏阴性菌的活性比革兰氏阳性菌更好。4-氨基未取代的三甲氧嘧啶-三嗪衍生物 7b 对金黄色葡萄球菌的 MIC=3.4 μM（2 μg/mL）和大肠杆菌的 MIC=1.1 μM（0.66 μg/mL）表现出优异的活性。还对合成的化合物进行了脲酶抑制研究。选择巴氏芽孢杆菌的脲酶进行这项研究。三嗪衍生物 7a 对脲酶的抑制活性优异，IC=6.23±0.09 μM。对巴氏芽孢杆菌脲酶（PDB ID 4UBP）的晶体结构进行了对接研究。
