SAR of Tetracyclines

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Chapter: Medicinal Chemistry : Antibiotics

The key structural feature is a linearly fused tetracyclic nucleus and each ring needs to be six membered and purely carbocyclic. A tetracyclic backbone skeleton is essential for activity.

SAR of Tetracyclines

The key structural feature is a linearly fused tetracyclic nucleus and each ring needs to be six membered and purely carbocyclic. A tetracyclic backbone skeleton is essential for activity.

·The D-ring needs to be aromatic and the A-ring must be appropriately substituted at each of its carbon atoms for notable activity.

·The B-ring and the C-ring tolerate certain substitutent changes as long as the keto-enol systems (at C-11, 12, 12a) remain intact and conjugated to the phenolic D-ring.

·The D, C, B-ring phenol, keto-enol system is imperative and the A-ring must also contain a conjugated keto enol system.

·Specifically, the A-ring contains a tricarbonyl derived keto-enol array at positions C-1, 2, and -3. Other structural requirements for good antibacterial activity include a basic amine function at C-4 position of the A-ring.

Modification of C-1 and C-3 position: The keto-enol tautomerism of ring A in carbon atom 1 and 3 is a common feature to all biologically active tetracyclines, blocking this system by forming derivatives at C-1 and C-3 results in loss of antibacterial activity A–C = O, a function of C-1 and C-3 is essential for activity. In addition, equilibrium between non-ionized and Zwitterionic structure of tetracycline is essential for activity.

Modification of C-2 position: The antibacterial activity resides on the carboxamide moiety. The amide is best left unsubstituted or monosubstitution is acceptable in the form of activated alkylaminomethyl amide (Mannich bases). An example includes rolitetracycline large alkyl group on the carboxamide that may alter the normal keto-enol equilibrium of the C-1, 2, and 3 conjugated systems and diminishes inherent antibacterial activity. The replacement of carboxamide group or dehydration of carboxamide to the corresponding nitrile results in a loss of activity.

Modification of C-4 position: The keto-enolic character of the A-ring is due to the α-C-4 dimethyl amino substituent. Loss of activity is exerted when dimethyl amino group is replaced with hydrazone oxime or hydroxyl group.

Modification of C-4a position: The α-hydrogen at C-4a position of tetracyclines is necessary for useful antibacterial activity.

Modification of the C-5 and C-5a positions: Alkylation of the C-5 hydroxyl group results in loss of activity. Naturally occurring antibacterial tetracyclines have an unsubstituted methylene moiety at the C-5 position. However, oxytetracycline contains C-5 α-hydroxyl group, was found to be a potent compound, and has been modified chemically to some semisynthetic tetracyclines. Esterification is only acceptable if the free oxytetracycline can be liberated in vivo; only small alkyl esters are useful. Epimerization is detrimental to antibacterial activity.

Modification at the C-6 position: The C-6 methyl group contributes little to the activity of tetracycline. The C-6 position is tolerant to a variety of substituents. The majority of tetracyclines have α-methyl group and α β-hydroxyl group at this position. Demeclocyclin is a naturally occurring C-6 demethylated chlortetracycline with an excellent activity. Removal of C-6 hydroxyl group affords doxycycline, which exerts good antibacterial activity.

C-7 and C-9 substituents: The nature of the aromatic D-ring predisposes the C-7 position to electrophilic substitution. Substitution with electron withdrawing group such as nitro and halogen groups are introduced in some C-7 tetracyclines, which produces the most potent of all the tetracyclines in vitro, but their are compounds are potentially toxic and carcinogenic. The C-7 acetoxy, azido, and hydroxyl tetracyclines are inferior in terms of antibacterial activity.

C-10 substituents: The C-10 phenolic moiety is necessary for antibacterial activity. C-10 substitution with para or ortho hydrogen group activates the C-9 and C-7.

C-11 substituents: The C-11 carbonyl moiety is a part of one of the conjugated keto-enol system required for antibacterial activity.

C-11a substituents: No stable tetracyclines are formed by modifications at the C-11a position.

C-12/12a substituents: Esterification of the hydroxyl group leads to the incorporation of drug with the tissues due to the enhanced lipophilicity and it should undergo hydrolysis to leave the active tetracycline with hydroxyl group at 12a position, which is necessary to produce good antibacterial action. The transport and binding of these drugs depends on keto-enol system.

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