Mohi El-Deen Eman M, Abd El-Meguid Eman A, Karam Eman A, Nossier Eman S, Ahmed Marwa F
Department of Therapeutic Chemistry, National Research Centre, Dokki, Cairo 12622, Egypt.
Department of Chemistry of Natural and Microbial Products, National Research Centre, Dokki, Cairo 12622, Egypt.
Antibiotics (Basel). 2020 Oct 14;9(10):695. doi: 10.3390/antibiotics9100695.
The growing resistance of bacteria to many antibiotics that have been in use for several decades has generated the need to discover new antibacterial agents with structural features qualifying them to overcome the resistance mechanisms. Thus, novel pyridothienopyrimidine derivatives (,-,) were synthesized by a series of various reactions, starting with 3-aminothieno[2,3-]pyridine-2-carboxamides (,). Condensation of compounds , with cyclohexanone gave 1'-spiro[cyclohexane-1,2'-pyrido[3',2':4,5]thieno[3,2-]pyrimidin]-4'(3)-ones (,), which in turn were utilized to afford the target 4-substituted derivatives (,-,). In vitro antibacterial activity evaluations of all the new compounds (,-,) were performed against six strains of Gram-negative and Gram-positive bacteria. The target compounds showed significant antibacterial activity, especially against Gram-negative strains. Moreover, the compounds (,; ,; ,; and ,) that exhibited potent activity against were selected to screen their inhibitory activity against topoisomerase II (DNA gyrase and topoisomerase IV) enzymes. Compounds and showed potent dual inhibition of the two enzymes with IC values of 3.44 µΜ and 5.77 µΜ against DNA gyrase and 14.46 µΜ and 14.89 µΜ against topoisomerase IV, respectively. In addition, docking studies were carried out to give insight into the binding mode of the tested compounds within the DNA gyrase B active site compared with novobiocin.
细菌对已使用数十年的多种抗生素的耐药性不断增强，这就需要发现具有能够克服耐药机制结构特征的新型抗菌剂。因此，从3-氨基噻吩并[2,3-b]吡啶-2-甲酰胺（化合物1）开始，通过一系列不同反应合成了新型吡啶并噻吩并嘧啶衍生物（化合物2-7）。化合物1与环己酮缩合得到1'-螺[环己烷-1,2'-吡啶并[3',2':4,5]噻吩并[3,2-b]嘧啶]-4'(3)-酮（化合物2），进而利用这些化合物得到目标4-取代衍生物（化合物3-7）。对所有新化合物（化合物2-7）进行了针对六种革兰氏阴性和革兰氏阳性细菌菌株的体外抗菌活性评估。目标化合物显示出显著的抗菌活性，尤其是对革兰氏阴性菌株。此外，选择了对大肠杆菌表现出强效活性的化合物（化合物3；化合物4；化合物5；和化合物7）来筛选它们对大肠杆菌拓扑异构酶II（DNA促旋酶和拓扑异构酶IV）的抑制活性。化合物3和化合物7对这两种酶表现出强效双重抑制作用，对DNA促旋酶的IC值分别为3.44 μΜ和5.77 μΜ，对拓扑异构酶IV的IC值分别为14.46 μΜ和14.89 μΜ。此外，进行了对接研究，以深入了解与新生霉素相比，测试化合物在大肠杆菌DNA促旋酶B活性位点内的结合模式。
