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<p>Motivated by the structure of II (potent anti <i>Staphylococcus aureus</i> pyrazole derivative) four pyrazole derivatives 5, 6, 7 and 8 (7 and 8 are novel compounds) bearing the biologically active sulfonamide group were synthesized. Compound 5 was obtained using Vilsmeier-Haack strategy, while compound 6 was derived from compound 5 through treatment with potassium hydroxide in methanol. Compounds 7 (acetal derivative) and 8 (hydrazone derivative) were synthesized for the first time from compound 5 by nucleophilic attack on the aldehyde moiety using potassium hydroxide in ethanol (followed by neutralization with diluted acetic acid) and hydrazine hydrate, respectively. Under these basic reaction conditions, similar deprotection of the sulfonamide moiety was also observed. The four compounds were screened for the first time against three cultures of methicillin resistant <i>Staphylococcus aureus</i> (MRSA) (ATCC 43300, ATCC 12600 and ATCC BAA-1708). All the four compounds showed good activity against ATCC 43,300 (IC<sub>50</sub> ranged from 7.35 to 13.39&#xa0;µg/ml) and ATCC 12,600 (IC<sub>50</sub> ranged from 11.70 to 26.32&#xa0;µg/ml), while two compounds only (6 and 7) showed activity against ATCC BAA-1708 (IC<sub>50</sub> 28.42 and 13.81, respectively). Compound 6 and 7 showed constant activity against the three strains, indicating the advantages of the free sulfonamide group at position-1 and aldehyde or acetal moieties at position-4 for the activity. ADME-Tox study showed that our structure modification increases the drug likeness (better pharmacokinetic and less toxicity) in comparison to compound II, while our docking study showed for the first time that 1,3-Diaryl-4-Functionalized Pyrazoles can exert its reported activity on bacterial cell wall synthesis through undecaprenyl pyrophosphate Synthase (UPPS) enzyme.</p>

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Synthesis of 1,3-Diaryl-4-Functionalized Pyrazoles Bearing Benzenesulfonamide as Promising Anti-MRSA Scaffold: Design, Synthesis, In Vitro and In Silico Studies

  • 期刊论文

  • 发表日期：

    2026年7月30日

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  • Ahmed A.M.A. Selim,
  • Kashif Shamim

摘要

Motivated by the structure of II (potent anti Staphylococcus aureus pyrazole derivative) four pyrazole derivatives 5, 6, 7 and 8 (7 and 8 are novel compounds) bearing the biologically active sulfonamide group were synthesized. Compound 5 was obtained using Vilsmeier-Haack strategy, while compound 6 was derived from compound 5 through treatment with potassium hydroxide in methanol. Compounds 7 (acetal derivative) and 8 (hydrazone derivative) were synthesized for the first time from compound 5 by nucleophilic attack on the aldehyde moiety using potassium hydroxide in ethanol (followed by neutralization with diluted acetic acid) and hydrazine hydrate, respectively. Under these basic reaction conditions, similar deprotection of the sulfonamide moiety was also observed. The four compounds were screened for the first time against three cultures of methicillin resistant Staphylococcus aureus (MRSA) (ATCC 43300, ATCC 12600 and ATCC BAA-1708). All the four compounds showed good activity against ATCC 43,300 (IC50 ranged from 7.35 to 13.39 µg/ml) and ATCC 12,600 (IC50 ranged from 11.70 to 26.32 µg/ml), while two compounds only (6 and 7) showed activity against ATCC BAA-1708 (IC50 28.42 and 13.81, respectively). Compound 6 and 7 showed constant activity against the three strains, indicating the advantages of the free sulfonamide group at position-1 and aldehyde or acetal moieties at position-4 for the activity. ADME-Tox study showed that our structure modification increases the drug likeness (better pharmacokinetic and less toxicity) in comparison to compound II, while our docking study showed for the first time that 1,3-Diaryl-4-Functionalized Pyrazoles can exert its reported activity on bacterial cell wall synthesis through undecaprenyl pyrophosphate Synthase (UPPS) enzyme.