Rashid Umer, Ahmad Waqas, Hassan Syed Fahad, Qureshi Naveeda Akhtar, Niaz Basit, Muhammad Bakhtiar, Imdad Sameera, Sajid Muhammad
Department of Chemistry, Hazara University, Mansehra 21120, Pakistan; Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan.
Department of Chemistry, Hazara University, Mansehra 21120, Pakistan.
Bioorg Med Chem Lett. 2016 Dec 1;26(23):5749-5753. doi: 10.1016/j.bmcl.2016.10.051. Epub 2016 Oct 18.
In present study, nineteen novel trimethoprim (TMP) derivatives were designed, synthesized and evaluated for their antibacterial potential. Hydroxy trimethoprim 2 (HTMP) was synthesized by following the demethylation of 4-methoxy group at trimethoxy benzyl ring of TMP. Structure-activity relationship (SAR) studies were explored on HTMP by incorporating various substituents leading to the identification of some new compounds with improved antibacterial activities. The results revealed that the introduction of benzyloxy (4a-e) and phenyl ethanone (5a-e) group at 4-position of dimethoxy benzyl ring leads to overall increase in the antibacterial activity. The most potent antibacterial compound discovered is benzyloxy derivative 4b with MIC value of 5.0μM against Staphylococcus aureus and 4.0μM against Escherichia coli strains higher than the standard TMP (22.7μM against S. aureus and 55.1μM against E. coli). Substitution at 4-NH group was not tolerated and the resulting Schiff base derivatives 3a-h demonstrated very little or no antibacterial activity in the tested concentration domain. We further performed exploratory docking studies on dihydrofolate reductase (DHFR) to rationalize the in vitro biological data and to demonstrate the mechanism of antibacterial activity. For the ability to cross lipophilic outer membrane, logP was computed. It was found that the compounds possessing high hydrophobicity have high activity against E. coli.
在本研究中，设计、合成了19种新型甲氧苄啶（TMP）衍生物，并对其抗菌潜力进行了评估。通过对TMP三甲氧基苄基环上的4-甲氧基进行脱甲基反应合成了羟基甲氧苄啶2（HTMP）。通过引入各种取代基对HTMP进行构效关系（SAR）研究，从而鉴定出一些具有改善抗菌活性的新化合物。结果表明，在二甲氧基苄基环的4-位引入苄氧基（4a-e）和苯乙酮（5a-e）基团会导致抗菌活性总体增加。发现的最有效的抗菌化合物是苄氧基衍生物4b，其对金黄色葡萄球菌的MIC值为5.0μM，对大肠杆菌菌株的MIC值为4.0μM，高于标准TMP（对金黄色葡萄球菌为22.7μM，对大肠杆菌为55.1μM）。4-NH基团处的取代不被耐受，所得席夫碱衍生物3a-h在测试浓度范围内显示出极少或没有抗菌活性。我们进一步对二氢叶酸还原酶（DHFR）进行了探索性对接研究，以合理化体外生物学数据并证明抗菌活性机制。为了评估穿越亲脂性外膜的能力，计算了logP。发现具有高疏水性的化合物对大肠杆菌具有高活性。
