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Background <p>Discovery of multi-target therapeutic agents remains a popular approach towards identifying chemical scaffolds with biological relevance and for overcoming complex biological disorders. Fluorinated aromatic amines that contain nitrogen heterocycles are interesting targets for discovery as they can alter physicochemical properties that affect enzyme recognition and protein reactivity.In the present study, series of recently synthesized 4-fluoro-2-nitroaniline <b>4a-j</b> and 4-fluorobenzene-1,2-diamine <b>5a-j</b> derivatives were evaluated against the urease enzyme, acetylcholinesterase (AChE) enzyme, dipeptidyl peptidase-4 (DPP-4) enzyme and protein glycation to manage stomach ulcer, Alzheimer’s disease, diabetes mellitus, and diabetic complication, respectively. Moreover, structure–activity relationship (SAR) information was combined with molecular docking experiments to ascertain target selective structural requirements.</p> Results <p>Among the twenty compounds tested against the urease enzyme, compounds <b>4a</b> and <b>5c</b> showed promising inhibition with IC<sub>50</sub> values of 40.42 ± 1.2 µM and 83.24 ± 1.5 µM, respectively. Against acetylcholinesterase enzyme compounds <b>5b</b> and <b>5j</b> exhibited significant inhibition with IC<sub>50</sub> values of 102.35 ± 1.0 µM and 123.52 ± 1.5 µM, respectively. Similarly, compounds <b>5g</b>, <b>5h</b> and <b>5i</b> depicted novel antiglycation activity with IC<sub>50</sub> values of &lt; 32.0 µM as compared to the rutin used as a standard inhibitor with an IC<sub>50</sub> of 98.01 ± 1.5 µM. However, these derivatives showed no inhibition activity against the DPP-4 enzyme. SAR analysis of promising inhibitors was established. SAR studies indicated that the fluorinated aromatic scaffold forms a common structural platform for recognition whilst target selectivity is conferred by the terminal cyclic amine together with either the nitro or diamine group. Additionally, in silico molecular docking studies validated the SAR information by revealing stable interactions of these derivatives within the active sites of urease and acetylcholinesterase enzyme through H-bonds, π interactions and hydrophobic contacts. The docking results revealed that these compounds bind to the active site residues specifically, preventing the enzymes from performing their regular functions.</p> Conclusions <p>Fluorinated nitroaniline and benzene-1,2-diamine derivatives exhibited selective urease, acetylcholinesterase and anti-glycation activities. Compounds <b>4a</b>, <b>5b</b>, <b>5c</b>, <b>5g</b>, <b>5h</b> and <b>5i</b> were singled out as lead-worthy structures worth further development demonstrating the power of combining SAR and biological screening data with molecular docking simulations.</p>

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Identification of 4-fluoro-2-nitroaniline and 4-fluorobenzene-1,2-diamine derivatives as new diverse antiglycation agents and enzyme inhibitors: in vitro, SAR, and in silico molecular docking studies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月19日

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  • Said Al Ghawi,
  • Ayoub Al Uwaisi,
  • Abdul Wadood,
  • Quazi M. I. Haq,
  • Issa Al-Amri,
  • Thuraya Al-Harthy,
  • Ghulam Abbas,
  • Raid J. Abdel-Jalil

摘要

Background

Discovery of multi-target therapeutic agents remains a popular approach towards identifying chemical scaffolds with biological relevance and for overcoming complex biological disorders. Fluorinated aromatic amines that contain nitrogen heterocycles are interesting targets for discovery as they can alter physicochemical properties that affect enzyme recognition and protein reactivity.In the present study, series of recently synthesized 4-fluoro-2-nitroaniline 4a-j and 4-fluorobenzene-1,2-diamine 5a-j derivatives were evaluated against the urease enzyme, acetylcholinesterase (AChE) enzyme, dipeptidyl peptidase-4 (DPP-4) enzyme and protein glycation to manage stomach ulcer, Alzheimer’s disease, diabetes mellitus, and diabetic complication, respectively. Moreover, structure–activity relationship (SAR) information was combined with molecular docking experiments to ascertain target selective structural requirements.

Results

Among the twenty compounds tested against the urease enzyme, compounds 4a and 5c showed promising inhibition with IC50 values of 40.42 ± 1.2 µM and 83.24 ± 1.5 µM, respectively. Against acetylcholinesterase enzyme compounds 5b and 5j exhibited significant inhibition with IC50 values of 102.35 ± 1.0 µM and 123.52 ± 1.5 µM, respectively. Similarly, compounds 5g, 5h and 5i depicted novel antiglycation activity with IC50 values of < 32.0 µM as compared to the rutin used as a standard inhibitor with an IC50 of 98.01 ± 1.5 µM. However, these derivatives showed no inhibition activity against the DPP-4 enzyme. SAR analysis of promising inhibitors was established. SAR studies indicated that the fluorinated aromatic scaffold forms a common structural platform for recognition whilst target selectivity is conferred by the terminal cyclic amine together with either the nitro or diamine group. Additionally, in silico molecular docking studies validated the SAR information by revealing stable interactions of these derivatives within the active sites of urease and acetylcholinesterase enzyme through H-bonds, π interactions and hydrophobic contacts. The docking results revealed that these compounds bind to the active site residues specifically, preventing the enzymes from performing their regular functions.

Conclusions

Fluorinated nitroaniline and benzene-1,2-diamine derivatives exhibited selective urease, acetylcholinesterase and anti-glycation activities. Compounds 4a, 5b, 5c, 5g, 5h and 5i were singled out as lead-worthy structures worth further development demonstrating the power of combining SAR and biological screening data with molecular docking simulations.