Design, synthesis, antimicrobial evaluation and molecular docking studies of some new thiophene, pyrazole and pyridone derivatives bearing sulfisoxazole moiety

• Twenty eight N-substituted sulfisoxazole derivatives were synthesized.
• N-substituted sulfisoxazoles were evaluated for their antimicrobial activities.
• These compounds could inhibit DHPS as revealed by molecular docking studies.
• Synergistic effect and high lipophilicity improved their antimicrobial activities.
• Compounds 4d, 5e, 6 and 17 exhibited the best antimicrobial activities.

Development of new antimicrobial agents is a good solution to overcome drug-resistance problems. In this context, new functionalized thiophene, acrylamide, arylhydrazone, pyrazole and pyridone derivatives bearing sulfisoxazole moiety were designed, synthesized and evaluated for their in vitro antibacterial and antifungal activities. Among the synthesized compounds, thiophene 4d and 6-thioglucosylpyridone 17 displayed significant antibacterial activities against Escherichia coli (MIC, 0.007 μg/mL vs gentamycin 1.95 μg/mL) and Bacillis subtilis (MIC, 0.007 μg/mL vs ampicillin 0.24 μg/mL), respectively. Whereas, the pyrazole 6 showed the highest antifungal activity against Aspergillus fumigates (MIC, 0.03 μg/mL vs amphotericin B 0.12 μg/mL). In general, most of the synthesized compounds exhibited better antimicrobial activities than sulfisoxazole; this might be attributed to the synergistic effect of the sulfonamide and attached heterocyclic moieties as well as the increased lipophilic characters of the synthesized compounds. Molecular docking studies indicated that the synthesized compounds could occupy both p-amino benzoic acid (PABA) and pterin binding pockets of the dihydropteroate synthase (DHPS), suggesting that the target compounds could act by the inhibition of microbial DHPS enzyme. The results provide important information for the future design of more potent antimicrobial agents.

New series of N-substituted sulfisoxazole derivatives were synthesized and evaluated in vitro for their antimicrobial activities. Molecular docking studies showed that these compounds were able to inhibit the microbial dihydropteroate synthase (DHPS).Figure optionsDownload as PowerPoint slide