tetracyclines

Presented byT.SHIVAKUMAR

KOTTAM INSTITUTE OF PHARMACY

TETRACYCLINES

CHEMICAL STRUCTURE OF TETRACYCLINE:

NOMENCLATURESystematic (IUPAC) name(4S,6S,12aS)-4-(dimethylamino)-

1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxonaphthacene-2-carboxamide

OR(4S,6S,12aS)-4-(dimethylamino)-3,6,10,12,12a-

pentahydroxy-6-methyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide

CHEMICALNAMEChemical Name: A variably hydrated form

of (4S,4aS,5aS,6S,12aS)-4-Dimethylamino- 1,4,4a,5,5a,6,11,12a-octahydro-

3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxonaphthacene-2-

CarboxamideMolecular Formula: C22H24N2O8

Physical Properties

COLOUR: yellow crystalline powder. SOLUBOLITY: Very slightly soluble in water; soluble in alcohol and in methyl alcohol;

sparingly soluble in acetone.

It dissolves in dilute acid and alkaline solutions. . It loses not more than13% of its weight on drying.

Chemical properties

The reactions that tetracyclines undergo are generally of a sophisticated nature, dictated by the complex functionality and the sensitivity of the molecules to mild reaction conditions (acid, base, heat) .

The conjugated triones system extending from C1 to C3 of ring A is acidic in nature with PKa1=2.8 to 3.4.

When exposed to dilute acid conditions, tetracycline undergoes dehydration to yield anhydrotetracycline. Anhydroterramycin suffers further cleavage and lactonization to apoterramycin:

Diluted acid promotes epimerization at C-4 as well.

Acidic conditions 

Basic conditions C4 atom and its substitute exhibits PKa2 ranging from 9.1 to 9.7 which represents strong alkaline nature

Mild alkali attacks 11a carbon of tetracycline, which is transformed to isotetracycline

The reasons for ammphoteric nature of tetracyclines is their complex structure with three structural units representing three PKa values.

The conjugate phenolic enone system from C10 to C12 is associated with weak basic PKa values ranging from 7.2 to 7.8.

Amphoteric nature:

Because of the amphoteric nature, tetracyclines are capable of forming water-sluble salts with strong acids such as hydrochloric acid and strong bases such as sodium hydroxide and potassium hydroxide.

And water insoluble salts of tetracyclines are formed with divalent and polyvalent metals

INCOMPATIBILITY: Chelation with metals: among the chemical and clinical

properties of tetracyclins, chelation with ions is an important feature.

Tetracyclins are able to form complexes with divalent and trivalent metal ions such as Fe3+, Fe2+, Cu2+, Ni2+, Co2+, Zn2+, Mn2+, Mg2+, Ca2+, Be2+, Al3+ and with salicilates, phosphates,citrates,polyvinylprrolidine,thiourea,lipoproteins,serum albumin,globulin and RNA.

These salts of metal ions are insoluble in water at neutral conditions and cause inconvenience in the prepararion of solutions and also produce unfavourable blood titres of tetracyclines, within the body

EPIMERISATION: One of the important property of tetracycline is their ability to undergo epimerization at C4 position and the isomers are referred to as epitetracyclines.

STBILITY:

CLASSIFICTION OF TETRACYCLINS:

According to source:Naturally occurringTETRACYCLINECHLORTETRACYCLINEOXYTETRACYCLINEDEMOCYCLINE

Semi-syntheticDoxycyclineLymecyclineMeclocyclineMethacyclineMinocycline

Rolitetracycline

Short-acting (Half-life is 6-8 hrs)TetracyclineChlortetracyclineOxytetracycline

According to duration of action:

Intermediate-acting (Half-life is ~12 hrs)1.Demeclocycline2.Methacycline

Long-acting (Half-life is 16 hrs or more) 1.Doxycycline2.Minocycline3.Tigecycline

REFERENCESBurden, V. (1991). Purification and

characterizationof tet(M), a protein that renders ribosomes resistantto tetracycline. Journal of Biological Chemistry 266,2872-7 

.Chaudhary, I., Wirth, M., Rosen, R., Nicolau, G.

& Yacobi, A. (1993). Metabolism of DMGDMDOTa novel antibiotic in laboratory animals, in vitro/in vivo correlations.

Chopra, I., Hawkey, P. M. & Hinton, M. (1992). Tetracyclines, molecular and clinical aspects.

Journal of Antimicrobial Chemotherapy 29,245-77.

Eliopoulos, G. M., Wennersten, C. B., Cole, G.& Moellering, R. C. (1994). In vitro activities of

Thank you….T.SHIVA

SHIVA.PHARMACIST@GMAIL.COM