Methacycline ,Chemistry ,Synthesis ,SAR and Uses .

METHACYCLINE

Methacycline is a tetracycline antibiotic .                          

It is mainly used as  precursor in the industrial synthesis of doxycycline…                                                                              

It has been found to act as an agonist of the human pregnane X receptor ligand-binding domain and to increases CYP3A4 expression in vitro.

CHEMISTRY

           

Molecular formula C22H22N2O8

   Molecular weight 442.41

    Unstable in light and stable at room temperature.                                                                            Boiling point 695.1.

Mechanism of action

Methacycline, a tetracycline antibiotic, is a protein synthesis inhibitor.

stop the binding of aminoacyl-tRNA to the mRNA-ribosome complex.   

   Methacycline prevent cell growth by inhibit translation.                                                                             

It mainly bind  to the 16S part of the 30S ribosomal subunit and prevent  the aminoacyl tRNA from bind  to the A site of the ribosome…                                                                                                                            

The binding is reversible in nature.                                                                                                      

Tetracycline also been found to  prevent matrix metalloproteinasess

 This mechanism do not add to their antibiotic effect but has led to extensive research  chemically modified tetracycline on CMTs (like incyclinide) for the treatment of rosacea, acne, and various types of neoplasm..

Structure of Methacycline

        

Synthesis of methacycline  

Synthesis 1 formation of anhydrotetracyclines can be  remove during semisythesis                         ,where protection of the 11a position as the 11th a chloro derivative is readily afforded by n-chlorosuccinimide chemically introducing 11a cl halogen group stabilizers the oxytetracycline c ring.                                                                                                                    

allowing it to be reacted with acid bases and other chemical reagents under Harsh chemical condition and the treatment with anhydrous halogen fluoride forces in exocyclic 

dehydration to occur to produce 6 methylaminen11 CL oxytetracycline 2 the 11 a CL group is 

readily removed by the reaction with sodium hydrosulfite to produce methicillin 3 a clinically 

significant tetracycline that possess activity against broad spectrum of bacteria.

Synthesis 2:

 

                 

SAR

The amide hydrogen may be changed by methyl group but larger groups have deleterious effect except these which are remove spontaneously in water.

All tetracycline derivatives contains less than four rings are  active.

Changes of amide at carbon 2 with aldehyde or nitrile change the

      activity.

The hydrophobic part of the molecule from C-5 to C-9 may be change in various ways: modifications at C-6 and C-7 in particular afford products having greater chemical stability increased antibiotic activity and more favourable pharmacokinetics.

The dimethyl amino group change by a primary amino group without

 loss of in vitro activity but all other changes so far lead to low bacteriostatic action.

Mono alkylation of amide group  in losee  of activity Presence of electron withdrawing group ( cl - or Na+) and electron donating group ( dimethylamine ) at c7 increases activity.

Uses

Methacycline is mainly use to treat many different bacterial infections, and                                        
1) such as urinary tract
2)skin infection                                                                     3)severe acne                                                                    
4)gonorrhea,                                                                         5)tick fever,                                                                           6)chlamydia, and others.