Para-amino salicylic acid (PAS): Chemical Structure, SAR, Mechanism of Action, Uses & Side effects

Chemical formula:

• C7H7NO3

Structure of Para amino salicylic acid

The Structure-Activity Relationship (SAR):

1.Salicylic Acid Core:

• The core structure of salicylic acid is crucial for its biological activity. The hydroxyl group and the carboxyl group in the salicylic acid moiety are essential for its anti-inflammatory and bacteriostatic effects.

2.Para-Amino Group:

• The addition of the amino group at the para position of the salicylic acid ring significantly alters its activity. This modification leads to enhanced antimycobacterial properties, making PAS particularly effective against Mycobacterium tuberculosis.

3.Substitutions on the Amino Group:

• Modifications or substitutions on the amino group can influence the drug's potency and pharmacokinetic properties. However, significant alterations might reduce the compound's effectiveness against tuberculosis.

4.Acidity:

• The acidic nature of PAS (due to the carboxyl group) is important for its solubility and pharmacokinetic properties. The ionization state can affect its absorption and distribution in the body.

5.Lipophilicity/Hydrophilicity Balance:

• The balance between lipophilic (fat-soluble) and hydrophilic (water-soluble) properties in PAS influences its absorption and distribution. The right balance is necessary for optimal therapeutic efficacy.

6.Molecular Size and Shape:

• The overall size and shape of the PAS molecule affect its ability to interact with its biological target (e.g., bacterial enzymes or cells).

Synthesis of Para-Amino Salicylic Acid (PAS)

1.Nitration of Salicylic Acid:

• Salicylic Acid+HNO3→4-Nitrosalicylic Acid+H2OSalicylic Acid+HNO3​→4-Nitrosalicylic Acid+H2​O

• In this step, salicylic acid is nitrated using nitric acid, usually in the presence of a catalyst like sulfuric acid, to form 4-nitrosalicylic acid.

2.Reduction of 4-Nitrosalicylic Acid:

• 4-Nitrosalicylic Acid+Reducing Agent→Para-Amino Salicylic Acid4-Nitrosalicylic Acid+Reducing Agent→Para-Amino Salicylic Acid

• The 4-nitrosalicylic acid is then reduced to form para-amino salicylic acid. The reducing agent is typically tin (Sn) and hydrochloric acid (HCl) or iron (Fe) in the presence of acetic acid. The choice of reducing agent will affect the specific conditions and byproducts of the reaction.

Mechanism of action:

• PAS inhibits the synthesis of folic acid in mycobacteria by acting as a competitive inhibitor of the enzyme dihydropteroate synthetase, thereby inhibiting the growth of Mycobacterium tuberculosis.

Uses:

• PAS is used in combination with other antitubercular drugs for the treatment of multidrug-resistant tuberculosis (MDR-TB).

Side effects:

• Side effects can include gastrointestinal disturbances, hypersensitivity reactions, hepatotoxicity, and hematological disturbances (e.g., anemia, leukopenia, thrombocytopenia).