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 (2a,b–a,b) were synthesized by a series of various reactions, starting with 3-aminothieno[2,3-b]pyridine-2-carboxamides (1a,b). Condensation of compounds 1a,b with cyclohexanone gave 1’H-spiro[cyclohexane-1,2’-pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidin]-4’(3’H)-ones (2a,b), which in turn were utilized to afford the target 4-substituted derivatives (3a,b–8a,b). In vitro antibacterial activity evaluations of all the new compounds (2a,b–8a,b) 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 (2a,b; 3a,b; 4a,b; and 5a,b) that exhibited potent activity against Escherichia coli were selected to screen their inhibitory activity against Escherichia coli topoisomerase II (DNA gyrase and topoisomerase IV) enzymes. Compounds 4a and 4b showed potent dual inhibition of the two enzymes with IC₅₀ 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 E. coli DNA gyrase B active site compared with novobiocin.

中文翻译：

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新型吡啶并嘧啶嘧啶衍生物作为抗菌剂和大肠杆菌拓扑异构酶II抑制剂的合成及生物学评价

细菌对已经使用了几十年的许多抗生素的抗药性不断增长，因此有必要发现具有结构特征的新型抗菌剂，以使其具有克服抗药性的资格。因此，新颖pyridothienopyrimidine衍生物（图2a，b -一个，b）通过一系列的各种反应的，从3-氨基噻吩并[2,3-合成b ]吡啶-2-甲酰胺（1A，b）。化合物的缩合1a中，b与环己酮，得到1' ħ -螺[环己烷-1,2'-吡啶并[3' ，2 '：4,5]噻吩并[3,2- d ]嘧啶] -4'（3 ' H）一（2a，b），依次用来提供目标4取代的衍生物（3a，b – 8a，b）。所有新化合物（2a，b - 8a，b）的体外抗菌活性评估均针对6株革兰氏阴性和革兰氏阳性细菌。目标化合物显示出显着的抗菌活性，尤其是针对革兰氏阴性菌株。此外，化合物（2a，b ; 3a，b ; 4a，b ;和选择对大肠杆菌表现出有效活性的图5a，b）以筛选其对大肠杆菌拓扑异构酶II（DNA促旋酶和拓扑异构酶IV）酶的抑制活性。化合物4a和4b显示出对两种酶的有效双重抑制，分别针对DNA促旋酶的IC ₅₀值为3.44 µM和5.77 µM，针对拓扑异构酶IV的IC ₅₀值为14.46 µM和14.89 µM。此外，进行了对接研究，以深入了解与新霉素相比，被测化合物在大肠杆菌DNA促旋酶B活性位点内的结合模式。