1. MEDICINAL CHEMISTRY- III Lecture 2 Wed. 16/ 5/ 1432H Prof. Dr. Wafaa Zaghary

2. III-Anthranilates Flufenamic acid 2—{[3-(Trifluoromethyl)phenyl]amino}benzoic acid. Uses anti-inflammatory

3. Synthesis

4. Structure Activity relationships Substitution on the anthranilic acid ring reduce activity. The most active anthranilic acid derivatives have substituents at position 2`,3` and 6`of the ring attached to the anthranilic acid nitrogen. Replacing the –NH- function in fenamic acids produces less active compounds. Thus ether, ketones, and thioether are essentially inactive.

5. The carboxylic function is required at the 2-position for biological activity. Isomeric 3-carboxy or 4-carboxy derivatives are inactive. A tetrazole function can substitute for carboxylic acid function with retention of anti-inflammatory activity. On the basis of structure-activity relationships for indomethacin and other NSAIDs, and anti- inflammatory receptor site consisting of two non coplaner hydrophobic regions and a cationic centre.

6. The anti-inflammatory receptor consists of a largely flat area, a trough to accommodate an out-of-plane group (such as an aryl ring acting possibly by charge–transfer type of interaction) and a cationic site to accommodate an acidic anion.

7. IV-Aryl acetic Acids: Diclofenac Voltaren ® 2-[(2,6-dichlorophenyl)amino]benzene acetic. It is a NSAIDs with balanced cox-1 and cox-2 inhibiting effect.

8. Indomethacin It is still one of the most potent NSAIDs in use, possessing approximately 25 times the activity of phenylbutazone. It is more potent than aspirin and acetaminophen. CN: 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H- indol-3-acetic acid.

9. Structure activity relationships All agents posses a centre of activity can be represented by carboxylic acid function, enolic function hydroxamic acid function a sulfonamide or tetrazole. The activity of ester and amide derivatives of carboxylic acid is attributed to the metabolic hydrolysis product. The center of acidity is located on carbon atom adjacent to a flat surface represented by aromatic or heteroaromatic. Increasing the distance to two to three carbons diminish activity.

10. Derivatives of aryl or heteroaryl acetic or propionic acids are most common. Substitution of methyl group on the carbon atom separating the acid centre from the aromatic ring increase the anti-inflammatory activity. Group larger than methyl decrease activity. A second area of lipophilicity which is generally noncoplaner with aromatic or heteroaromatic ring enhance activity. The lipophilic function may consist of an addition aromatic ring or alkyl group.

11. V-Aryl propionic Acids Ibuprofen Brufen ® 2-(4-isobutylphenyl)propionic acid It is a NSAID used for the treatment of mild to moderate pain.

12. VI-Pyrazolinone derivatives Metamizole Novalgin®, Baralgin® It has strong analgesic spasmolytic and antipyretic but no anti-inflammatory properties.

13. VII-Acidic enolic compounds 1. Pyrazolidine 3,5-diones Oxyphenbutazone Tanderil ® Anti-inflammatory

14. 2. Aryl sulfonamides (oxicames): Piroxicam Anti-inflammatory