Sulfonamides and trimethoprim (TMP) drugs are normally used to inhibit the action of dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) enzymes, respectively. In this work, a new series of N-sulfonamide 2-pyridone derivatives that combine the inhibitory activities of DHPS and DHFR into one molecule were synthesized and evaluated for its in vitro antimicrobial activity and the ability to inhibit the action of both enzymes simultaneously. The synthesis was carried out via the reaction of novel benzothiazol sulfonylhydrazide with ketene dithioacetal derivatives, and the structures of the resultant compounds were confirmed using spectral and elemental techniques. Among the synthesized compounds, five compounds 3b, 5a, 5b, 11a, and 11b were found to possess significant antimicrobial activities against tested bacterial and fungi strains. The compounds were also examined for their cytotoxicity on HFB4 human dermal fibroblast cell line using MTT assay. The in vitro enzyme assay study of these compounds against DHPS and DHFR enzymes showed that compound 11a was the most potent inhibitor against both enzymes with IC 50 values of 2.76 and 0.20 μg/mL, respectively. Docking studies showed that this compound has occupied both the p-aminobenzoic acid and pterin binding pockets of DHPS as well as the pterin binding pocket of DHFR. The results of these investigations confirmed that compound 11a is the most potent dual DHPS/DHFR inhibitor.

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A new strategy for designing and assembling a novel class of functionalized pyridine-based benzothiazole and benzimidazole incorporating sulfonamide moieties was developed. The synthesis was carried out by reacting N -cyanoacetoarylsulfonylhydrazide with various electrophiles such as 2-(benzo[ d ]thiazol-2-yl)-3,3-bis(alkylthio)acrylonitriles and 2-(benzo[ d ]imidazol-2-yl)-3,3-bis(methylthio)-acrylonitriles, as well as 2-ethoxyl acrylonitrile derivatives. The synthesized compounds were tested for their antiviral and antimicrobial potency. Two of the synthesized compounds, 15c and 15d , showed more than 50% viral reduction against HSV-1 and CBV4, with significant IC 50 and CC 50 values. The two potent compounds 15c and 15d have also shown inhibitory activity against Hsp90α protein with IC 50 values of 10.24 and 4.48 μg/mL, respectively. A combination of 15c and 15d with acyclovir has led to IC 50 values that are lower than that of acyclovir alone. Molecular modeling studies were used to identify the interactions between the 15c and 15d compounds and the active site of Hsp90α enzyme. The antimicrobial investigation of the new compounds has also shown that 8b and 15d exhibited a higher inhibition zone (IZ) than sulfadiazine and gentamicin against Klebsiella pneumonia, whereas 9a showed higher IZ than ampicillin against Staphylococcus aureus . According to the enzyme assay study on dihydrofolate reductase, 9a was shown to be the most potent compound among all examined compounds.