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<p>Carbonic anhydrases (CAs) are zinc-dependent metalloenzymes that regulate pH homeostasis and are overexpressed in several hypoxic tumors. This study integrates experimental cytotoxicity screening with molecular docking and ADME profiling to evaluate 2-mercaptobenzimidazole Mannich derivatives (AK1 and AK12). Cytotoxicity was evaluated using brine shrimp lethality (LC<sub>50</sub>) and MTT cell viability assays (IC<sub>50</sub>). Molecular docking was performed against carbonic anhydrase and compared with acetazolamide. SwissADME was employed to predict pharmacokinetic and drug-likeness properties. Structure–activity relationship (SAR) analysis was conducted to correlate substitution patterns with biological outcomes. Cytotoxicity of synthesized compounds was evaluated by Brine Shrimp lethality assay; doxorubicin was taken as a reference standard, % mortality was checked, and different compounds show different cytotoxic activity. Cell viability was evaluated by MTT assay; doxorubicin was taken as a reference standard, different compounds show different compatibility. LC<sub>50</sub> values were 3.27&#xa0;µg/mL (AK1) and 3.55&#xa0;µg/mL (AK12). IC<sub>50</sub> values were 6.12&#xa0;µg/mL and 7.18&#xa0;µg/mL respectively. Molecular docking was performed against Carbonic Anhydrase II as a structural model enzyme, and binding energies ranged from − 5.9 to − 9.8&#xa0;kcal/mol, with AK7 and AK9 exhibiting the most favorable docking scores. However, no direct enzymatic inhibition assay was performed; therefore, the proposed carbonic anhydrase-mediated mechanism remains preliminary and requires biochemical validation. SAR indicated that optimized lipophilicity and Mannich substitution enhance enzyme binding and cytotoxicity. The combined results from experimentation and calculations point to these compounds as lead structures based on benzimidazoles. Nevertheless, the hypothesis that involves carbonic anhydrase is only theoretical and needs experimental confirmation through the inhibition tests of the enzyme.</p>

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Cytotoxic and computational profiling of 2-mercaptobenzimidazole Mannich derivatives: structure activity relationship and carbonic anhydrase binding assessment

  • 期刊论文

  • 发表日期：

    2026年7月7日

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  • Muhammad Naeem,
  • Arooj Mohsin Alvi,
  • Muhammad Mehmmod Moin Ul Haq,
  • Najia Shabbir,
  • Shumaila Mehdi,
  • Areen Khalid,
  • Saqib Khan,
  • Hafiz Muhammad Ahmad,
  • Najm Ul Hassan Khan,
  • Muhammad Nouman Arif,
  • Hafiz Aamir Ali Kharl

摘要

Carbonic anhydrases (CAs) are zinc-dependent metalloenzymes that regulate pH homeostasis and are overexpressed in several hypoxic tumors. This study integrates experimental cytotoxicity screening with molecular docking and ADME profiling to evaluate 2-mercaptobenzimidazole Mannich derivatives (AK1 and AK12). Cytotoxicity was evaluated using brine shrimp lethality (LC50) and MTT cell viability assays (IC50). Molecular docking was performed against carbonic anhydrase and compared with acetazolamide. SwissADME was employed to predict pharmacokinetic and drug-likeness properties. Structure–activity relationship (SAR) analysis was conducted to correlate substitution patterns with biological outcomes. Cytotoxicity of synthesized compounds was evaluated by Brine Shrimp lethality assay; doxorubicin was taken as a reference standard, % mortality was checked, and different compounds show different cytotoxic activity. Cell viability was evaluated by MTT assay; doxorubicin was taken as a reference standard, different compounds show different compatibility. LC50 values were 3.27 µg/mL (AK1) and 3.55 µg/mL (AK12). IC50 values were 6.12 µg/mL and 7.18 µg/mL respectively. Molecular docking was performed against Carbonic Anhydrase II as a structural model enzyme, and binding energies ranged from − 5.9 to − 9.8 kcal/mol, with AK7 and AK9 exhibiting the most favorable docking scores. However, no direct enzymatic inhibition assay was performed; therefore, the proposed carbonic anhydrase-mediated mechanism remains preliminary and requires biochemical validation. SAR indicated that optimized lipophilicity and Mannich substitution enhance enzyme binding and cytotoxicity. The combined results from experimentation and calculations point to these compounds as lead structures based on benzimidazoles. Nevertheless, the hypothesis that involves carbonic anhydrase is only theoretical and needs experimental confirmation through the inhibition tests of the enzyme.