Gündüz Miyase Gözde, Uğur Sümeyye Buran, Güney Funda, Özkul Ceren, Krishna Vagolu Siva, Kaya Serdal, Sriram Dharmarajan, Doğan Şengül Dilem
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Sıhhiye, 06100 Ankara, Turkey.
Department of Basic Sciences, Faculty of Pharmacy, Erciyes University, Kayseri, Turkey.
Bioorg Chem. 2020 Sep;102:104104. doi: 10.1016/j.bioorg.2020.104104. Epub 2020 Jul 17.
The development of new antimicrobial compounds is in high demand to overcome the emerging drug resistance against infectious microbial pathogens. In the present study, we carried out the extensive antimicrobial screening of disubstituted urea derivatives. In addition to the classical synthesis of urea compounds by the reaction of amines and isocyanates, we also applied a new route including bromination, oxidation and azidination reactions, respectively, to convert 2-amino-3-methylpyridine to 1,3-disubstituted urea derivatives using various amines. The evaluation of antimicrobial activities against various bacterial strains, Candida albicans as well as Mycobacterium tuberculosis resulted in the discovery of new active molecules. Among them, two compounds, which have the lowest MIC values on Pseudomonas aeruginosa, were further evaluated for their inhibition capacities of biofilm formation. In order to evaluate their potential mechanism of biofilm inhibition, these two compounds were docked into the active site of LasR, which is the transcriptional regulator of bacterial signaling mechanism known as quorum sensing. Finally, the theoretical parameters of the bioactive molecules were calculated to establish their drug-likeness properties.
为克服针对传染性微生物病原体新出现的耐药性，对新型抗菌化合物的需求十分迫切。在本研究中，我们对二取代脲衍生物进行了广泛的抗菌筛选。除了通过胺与异氰酸酯反应经典合成脲化合物外，我们还应用了一条分别包括溴化、氧化和叠氮化反应的新路线，使用各种胺将2-氨基-3-甲基吡啶转化为1,3-二取代脲衍生物。对各种细菌菌株、白色念珠菌以及结核分枝杆菌的抗菌活性评估导致发现了新的活性分子。其中，对铜绿假单胞菌具有最低MIC值的两种化合物进一步评估了它们对生物膜形成的抑制能力。为了评估它们生物膜抑制的潜在机制，将这两种化合物对接至LasR的活性位点，LasR是称为群体感应的细菌信号传导机制的转录调节因子。最后，计算了生物活性分子的理论参数以确定它们的类药性质。
