| Summary: | 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 <i>N</i>-arylsulphonylhydrazone with <i>N</i>-aryl-2-cyano-3-(dimethylamino)acrylamide, <i>N</i>-aryl-3-(dimethylamino)prop-2-en-1-one, arylaldehydes or diazonium salt of arylamine derivatives, which led to the formation of <i>N</i>-arylsulfonylpyridones <b>6a–d</b> (yield 60–70%) and <b>12a</b>–<b>c</b> (yield 50–60%)<b>,</b><i>N</i>-(2-(benzo[<i>d</i>]thiazole-2-yl)-3-arylacryloyl-4-methylsulfonohydrazide <b>14a</b>–<b>c</b> (yield 60–65%)<b>,</b> 4-(benzo[<i>d</i>]thiazole-2-yl)-5-aryl-1<i>H</i>-pyrazol-3(2<i>H</i>)-one <b>16a</b>–<b>c</b> (yield 65–75%), and <i>N′</i>-(2-(benzo[<i>d</i>]thiazol-2-yl)-2-(2-arylhydrazono)acetyl)-4-arylsulfonohydrazide <b>19a</b>–<b>e</b> (yield 85–70%). The antimicrobial evaluations resulted into a variety of microbial activities against the tested strains. Most compounds showed antimicrobial activity against <i>S. aureus</i> with an MIC range of 0.025 to 2.609 mM. The most active compound, <b>16c</b>, exhibited superior activity against the <i>S. aureus</i> 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, <b>16a</b>–<b>c</b>, had IC<sub>50</sub> values comparable to the standard drug and revealed that compound <b>16b</b> was the most active compound with an IC<sub>50</sub> value of 7.85 μg/mL, which is comparable to that of sulfadiazine (standard drug) with an IC<sub>50</sub> 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 <b>16a</b>–<b>c</b> are linked by two arene-H interactions with Lys220 within the PABA pocket.
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