Local Anesthetics Agents Medicinal Chemistry – PPT

Local Anesthetics: SAR of Local anesthetics Benzoic Acid derivatives; Cocaine, Hexylcaine,
Meprylcaine, Cyclomethycaine, Piperocaine.
Amino Benzoic acid derivatives: Benzocaine*, Butamben, Procaine*, Butacaine, Propoxycaine,
Tetracaine, Benoxinate.
Lidocaine/Anilide derivatives: Lignocaine, Mepivacaine, Prilocaine, Etidocaine.
Miscellaneous: Phenacaine, Diperodon, Dibucaine.*

Local Ansthetics Drugs Medicinal Chemistry

Slide 2: Introduction to Local Anesthetics

Definition: Local anesthetics are drugs that cause reversible inhibition of nerve conduction, leading to a temporary loss of sensation in a specific area.
Mechanism of Action: Block voltage-gated sodium channels, preventing the initiation and propagation of action potentials in neurons.
Classification:
- Benzoic Acid Derivatives
- Amino Benzoic Acid Derivatives
- Lidocaine/Anilide Derivatives
- Miscellaneous

Slide 3: SAR of Local Anesthetics

Core Structural Features:
1. Lipophilic Aromatic Group: Provides affinity for lipid membranes (e.g., benzene ring).
2. Intermediate Chain: Usually an ester (-COO-) or amide (-NHCO-) that links the aromatic group to the amine.
3. Hydrophilic Amine: Interacts with the receptor and determines the ionized form at physiological pH.

Slide 4: Benzoic Acid Derivatives

General Structure:
- Lipophilic benzoic acid-based aromatic ring attached to a hydrophilic amine through an ester linkage.
Examples:
1. Cocaine: The prototype local anesthetic, used medically for its numbing effect but limited due to its addictive potential.
2. Hexylcaine
3. Meprylcaine
4. Cyclomethycaine
5. Piperocaine
SAR Highlights: Modifications to the aromatic ring and alkyl chain can influence potency and duration of action.

Slide 5: Amino Benzoic Acid Derivatives

Structure Overview: Aromatic amino benzoic acid linked to an ester group and a hydrophilic amine.
Examples and Key Compounds:
1. Benzocaine: Lacks amine; used topically (Synthesis required)
2. Butamben
3. Procaine: One of the earliest local anesthetics; short-acting (Synthesis required)
4. Butacaine
5. Propoxycaine
6. Tetracaine: More potent and longer duration than procaine
7. Benoxinate
SAR Highlights: The ester linkage is crucial for hydrolysis by esterases, and the amino group contributes to solubility and receptor binding.

Slide 6: Synthesis of Benzocaine and Procaine

Synthesis Overview:
- Benzocaine:
  1. Start from p-aminobenzoic acid (PABA).
  2. Esterification reaction with ethanol in the presence of an acid catalyst.
- Procaine:
  1. Start with PABA.
  2. React with diethylaminoethanol in the presence of a catalyst to form the ester bond.

Slide 7: Lidocaine/Anilide Derivatives

Structure: Amide-linked derivatives, where the aromatic group is connected to an amine group through an amide bond.
Examples:
1. Lidocaine (Lignocaine): Widely used, rapid onset, intermediate duration
2. Mepivacaine
3. Prilocaine
4. Etidocaine
SAR Highlights: The amide bond provides greater stability compared to ester-linked anesthetics, leading to a longer duration of action. Modification on the amine group alters lipophilicity and potency.

Slide 8: Miscellaneous Local Anesthetics

Examples:
1. Phenacaine
2. Diperodon
3. Dibucaine: Highly potent and long-acting (Synthesis required)
SAR Notes: These compounds often contain complex ring structures that enhance binding affinity and increase the duration of action.

Slide 9: Synthesis of Dibucaine

Synthesis Overview:
1. Start from quinoline derivatives.
2. Formation of the amide bond with alkylamines.
3. Modification of the structure to enhance lipophilicity and activity.

Slide 10: Comparative SAR Overview

Ester vs. Amide Anesthetics:
- Ester-type (e.g., Procaine): Rapidly metabolized by plasma esterases; shorter duration of action.
- Amide-type (e.g., Lidocaine): Metabolized by hepatic enzymes; longer-lasting.
Effect of Substituents:
- Alkyl groups on the amine increase lipophilicity and duration.
- Electron-donating groups on the aromatic ring enhance activity.

Slide 11: Clinical Applications

Benzoic Acid Derivatives: Used mainly for infiltration and regional anesthesia.
Amino Benzoic Acid Derivatives: Topical anesthetics and injections for short procedures.
Lidocaine Derivatives: Versatile for local, epidural, and spinal anesthesia.
Miscellaneous: Specialty uses for long-lasting effects in spinal or epidural anesthesia.

Slide 12: Conclusion

Key Takeaways:
- SAR insights guide the development of anesthetics with optimal properties.
- Ester and amide linkages critically influence pharmacokinetics and metabolism.
- Synthesis of specific local anesthetics like Benzocaine, Procaine, and Dibucaine highlight different approaches to modifying structure for activity.