The drug-resistance problem is widely spread and becoming more common in community-acquired and nosocomial strains of bacteria. Therefore, finding new antimicrobial agents remains an important drug target. From this perspective, new derivatives of benzothiazole were synthesized and evaluated for their antimicrobial activity and ability to inhibit the DHPS enzyme. The synthesis was carried out by the reaction of benzothiazole N-arylsulphonylhydrazone with N-aryl-2-cyano-3-(dimethylamino)acrylamide, N-aryl-3-(dimethylamino)prop-2-en-1-one, arylaldehydes or diazonium salt of arylamine derivatives, which led to the formation of N-arylsulfonylpyridones 6a-d (yield 60-70%) and 12a-c (yield 50-60%),N-(2-(benzo[d]thiazole-2-yl)-3-arylacryloyl-4-methylsulfonohydrazide 14a-c (yield 60-65%), 4-(benzo[d]thiazole-2-yl)-5-aryl-1H-pyrazol-3(2H)-one 16a-c (yield 65-75%), and N'-(2-(benzo[d]thiazol-2-yl)-2-(2-arylhydrazono)acetyl)-4-arylsulfonohydrazide 19a-e (yield 85-70%). The antimicrobial evaluations resulted into a variety of microbial activities against the tested strains. Most compounds showed antimicrobial activity against S. aureus with an MIC range of 0.025 to 2.609 mM. The most active compound, 16c, exhibited superior activity against the S. aureus strain with an of MIC 0.025 mM among all tested compounds, outperforming both standard drugs ampicillin and sulfadiazine. The physicochemical-pharmacokinetic properties of the synthesized compounds were studied, and it was discovered that some compounds do not violate rule of five and have good bioavailability and drug-likeness scores. The five antimicrobial potent compounds with good physicochemical-pharmacokinetic properties were then examined for their inhibition of DHPS enzyme. According to the finding, three compounds, 16a-c, had IC50 values comparable to the standard drug and revealed that compound 16b was the most active compound with an IC50 value of 7.85 μg/mL, which is comparable to that of sulfadiazine (standard drug) with an IC50 value of 7.13 μg/mL. A docking study was performed to better understand the interaction of potent compounds with the binding sites of the DHPS enzyme, which revealed that compounds 16a-c are linked by two arene-H interactions with Lys220 within the PABA pocket.

中文翻译：

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新型苯并噻唑衍生物作为靶向 DHPS 酶的抗菌剂的合成、理化性质和分子对接。

耐药性问题广泛传播，并且在社区获得性和医院获得性细菌菌株中变得越来越普遍。因此，寻找新的抗菌药物仍然是重要的药物靶点。从这个角度出发，合成了新的苯并噻唑衍生物，并评估了它们的抗菌活性和抑制 DHPS 酶的能力。合成通过苯并噻唑N-芳基磺酰腙与N-芳基-2-氰基-3-(二甲基氨基)丙烯酰胺、N-芳基-3-(二甲基氨基)丙-2-en-1-酮、芳基醛或芳基胺衍生物的重氮盐，导致形成 N-芳基磺酰基吡啶酮 6a-d（产率 60-70%）和 12a-c（产率 50-60%），N-(2-(benzo[d]thiazole-2 -基)-3-芳基丙烯酰基-4-甲基磺酰肼14a-c(产率60-65%)，4-(benzo[d]thiazole-2-yl)-5-aryl-1H-pyrazol-3(2H)-one 16a-c (yield 65-75%), and N'-(2-(benzo[d ]噻唑-2-基)-2-(2-芳基亚肼基)乙酰基)-4-芳基磺酰肼 19a-e (产率 85-70%)。抗微生物评估导致针对测试菌株的多种微生物活性。大多数化合物显示出对金黄色葡萄球菌的抗菌活性，MIC 范围为 0.025 至 2.609 mM。活性最强的化合物 16c 在所有测试化合物中表现出优异的抗金黄色葡萄球菌菌株活性，MIC 为 0.025 mM，优于标准药物氨苄青霉素和磺胺嘧啶。对合成化合物的理化药代动力学特性进行了研究，发现部分化合物不违反五法则，具有良好的生物利用度和类药性。然后检查了具有良好物理化学-药代动力学特性的五种有效抗菌化合物对 DHPS 酶的抑制作用。根据该发现，三种化合物 16a-c 的 IC50 值与标准药物相当，化合物 16b 是活性最强的化合物，其 IC50 值为 7.85 μg/mL，与磺胺嘧啶（标准药物）相当) 的 IC50 值为 7.13 μg/mL。进行了对接研究以更好地了解强效化合物与 DHPS 酶结合位点的相互作用，结果表明化合物 16a-c 通过两个芳烃-H 相互作用与 PABA 口袋内的 Lys220 连接。具有与标准药物相当的 IC50 值，表明化合物 16b 是最具活性的化合物，其 IC50 值为 7.85 μg/mL，与磺胺嘧啶（标准药物）的 IC50 值为 7.13 μg/mL 相当。进行了对接研究以更好地了解强效化合物与 DHPS 酶结合位点的相互作用，结果表明化合物 16a-c 通过两个芳烃-H 相互作用与 PABA 口袋内的 Lys220 连接。具有与标准药物相当的 IC50 值，表明化合物 16b 是最具活性的化合物，其 IC50 值为 7.85 μg/mL，与磺胺嘧啶（标准药物）的 IC50 值为 7.13 μg/mL 相当。进行了对接研究以更好地了解强效化合物与 DHPS 酶结合位点的相互作用，结果表明化合物 16a-c 通过两个芳烃-H 相互作用与 PABA 口袋内的 Lys220 连接。