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Oral Thrombolytic Drug Design: PAI-1 Inhibitor Prodrug Design by Deepseek R1

Chemical Name:

Benzofuran-2-sulfonamide-chlorophenyl-propanoate ester (ProPAI-Inh)

Chemical Formula:

C₁₉H₁₈ClFN₁O₆S

Molecular Weight:

475.87 g/mol

Structure:

• Core: Benzofuran ring (aromatic, enhances stability and binding).
• Linker: Sulfonamide group (-SO₂NH-) connecting benzofuran to chlorophenyl.
• Chlorophenyl Substituent: A para-chloro group improves hydrophobic interactions with PAI-1.
• Fluorine Modification: A fluorine atom at the meta position on the chlorophenyl ring increases metabolic stability.
• Prodrug Chain: Ethyl ester (-COOCH₂CH₃) attached via a propanoate chain (CH₂CH₂COOEt) to enhance lipophilicity for oral absorption.

Mechanism of Action:

• Prodrug Absorption: The ethyl ester increases lipophilicity, allowing efficient intestinal absorption.
• Activation: Esterases in the bloodstream hydrolyze the ester to release the active carboxylic acid (-COOH).
• PAI-1 Inhibition: The active compound binds to plasminogen activator inhibitor-1 (PAI-1), preventing its inhibition of endogenous tPA. This prolongs fibrinolysis, breaking down fibrin clots.

Key Features:

• Oral Bioavailability: Small molecule (MW <500 Da) with balanced logP (~2.5).
• Acid Stability: Benzofuran and fluorine substitution resist gastric degradation.
• Fibrin Specificity: Indirectly promotes clot breakdown via endogenous tPA, reducing systemic bleeding risk.

Structural Diagram (Simplified):

      O  
      |  
      S(=O)₂-NH  
     /   \  
Benzofuran  Cl  
            |  
            C₆H₃(F)-CH₂-CH₂-COOEt  
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Rationale:

• Benzofuran Core: Provides rigidity and improves pharmacokinetics.
• Sulfonamide Linker: Enhances solubility and target binding.
• Chlorophenyl/Fluorine: Optimizes hydrophobic/hydrophilic balance and PAI-1 affinity.
• Ethyl Ester Prodrug: Ensures oral absorption with in vivo activation.

This design integrates prodrug technology, targeted enzyme inhibition, and structural optimization for oral delivery. Further in vitro/in vivo studies are needed to validate efficacy and safety.