Design, Synthesis, and Antimicrobial Evaluation of a New Series of N-Sulfonamide 2-Pyridones as Dual Inhibitors of DHPS and DHFR Enzymes

Abstract

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.

Chromene-Containing Aromatic Sulfonamides with Carbonic Anhydrase Inhibitory Properties

“…The classical CA inhibitors (CAIs) are the primary sulfonamides, which coordinate the zinc ion with their terminal deprotonated nitrogen atom and have been in clinical use for more than 70 years as diuretics and systemically acting antiglaucoma drugs [ 10 ]. Chromenes have attracted the interest of the scientific community due to their wide range of biological activities, such as antimicrobial [ 11 , 12 ], anticancer [ 13 , 14 ], anti-inflammatory [ 15 , 16 ], and CA inhibitors [ 17 , 18 , 19 , 20 , 21 ], nematicidal [ 22 ], antiallergic [ 23 ] Some sulfonamides also show antimicrobial [ 24 , 25 ], anticancer [ 26 , 27 ], antidiabetic [ 28 ], anti-inflammatory [ 15 , 29 ], and antitubercular [ 30 ] activities. Taking into account all of the above-mentioned, here we report the synthesis of (4-sulfamoylphenyl)-4 H -chromene-2-carboxamide derivatives for its incorporation into one scaffold chromene and sulfonamide moieties.…”

Antibacterial Activities and Molecular Docking of Novel Sulfone Biscompound Containing Bioactive 1,2,3-Triazole Moiety

“…Compounds that compete with pABA and bind to the active site of DHPS inhibit it from preventing bacterial growth. Sulfonamide antibiotics work with a similar mechanism [ 33 ]. In the current study, compound 2 was docked against DHPS (PDB ID: 3TYE).…”

Synthesis of new pyridines with sulfonamide moietyviaa cooperative vinylogous anomeric-based oxidation mechanism in the presence of a novel quinoline-based dendrimer-like ionic liquid

“…The biological importance of sulfonamide containing drugs are well demonstrated in the literatures. [16][17][18][19][20][21][22][23][24][25] Some sulfonamide drugs are portrayed in Scheme 1.…”