Fluoroquinolones are a class of antibacterial agents used clinically to treat a wide array of bacterial infections and target bacterial type-II topoisomerases (DNA gyrase and topoisomerase IV). Fluoroquinolones, however potent, are susceptible to bacterial resistance with prolonged use, which limits their use in the clinic. Quinazoline-2,4-diones also target bacterial type-II topoisomerases and are not susceptible to bacterial resistance similar to fluoroquinolones, however, their potency pales in comparison to fluoroquinolones. To meet the increasing demand for antibacterial development, nine modified quinazoline-2,4-diones were developed to probe quinazoline-2,4-dione structure modification for possible new binding contacts with the bacterial type-II topoisomerase, DNA gyrase. Evaluation of compounds for inhibition of the supercoiling activity of DNA gyrase revealed a novel ethyl 5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate derivative as a modest inhibitor of DNA gyrase, having an IC50 of 3.5 μM. However, this ethyl 5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate does not trap the catalytic intermediate like fluoroquinolones or typical quinazoline-2,4-diones do. Thus, the ethyl 5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate derivative discovered in this work acts as a catalytic inhibitor of DNA gyrase and therefore represents a new structural type of catalytic inhibitor of DNA gyrase.

中文翻译：

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5，6-二氢吡唑并[1,5-c]喹唑啉-1-羧酸乙酯作为DNA促旋酶的催化抑制剂的鉴定。

氟喹诺酮类是临床上用于治疗多种细菌感染和靶向细菌II型拓扑异构酶（DNA促旋酶和拓扑异构酶IV）的一类抗菌剂。然而，氟喹诺酮类药物很强效，长时间使用对细菌具有抵抗力，这限制了它们在临床上的使用。喹唑啉-2,4-二酮也靶向细菌II型拓扑异构酶，与氟喹诺酮类相似，对细菌的耐药性不敏感，但是，与氟喹诺酮类相比，它们的药效低下。为了满足对抗菌素开发的不断增长的需求，开发了九种修饰的喹唑啉-2,4-二酮，以探测喹唑啉-2,4-二酮的结构修饰，以寻找与细菌II型拓扑异构酶，DNA促旋酶的新结合接触。化合物对DNA促旋酶超螺旋活性的抑制作用评估显示，新型的5,6-二氢吡唑并[1,5-c]喹唑啉-1-羧酸乙酯衍生物是DNA促旋酶的适度抑制剂，IC50为3.5μM。但是，这种5,6-二氢吡唑并[1,5-c]喹唑啉-1-羧酸乙酯不能像氟喹诺酮或典型的喹唑啉-2,4-二酮那样捕获催化中间体。因此，在这项工作中发现的5,6-二氢吡唑并[1,5-c]喹唑啉-1-羧酸乙酯衍生物可作为DNA促旋酶的催化抑制剂，因此代表了一种新型的DNA促旋酶催化抑制剂。5-c]喹唑啉-1-羧酸酯不像氟喹诺酮类或典型的喹唑啉-2,4-二酮类那样捕获催化中间体。因此，在这项工作中发现的5,6-二氢吡唑并[1,5-c]喹唑啉-1-羧酸乙酯衍生物可作为DNA促旋酶的催化抑制剂，因此代表了一种新型的DNA促旋酶催化抑制剂。5-c]喹唑啉-1-羧酸酯不像氟喹诺酮类或典型的喹唑啉-2,4-二酮类那样捕获催化中间体。因此，在这项工作中发现的5,6-二氢吡唑并[1,5-c]喹唑啉-1-羧酸乙酯衍生物可作为DNA促旋酶的催化抑制剂，因此代表了一种新型的DNA促旋酶催化抑制剂。