SAR OF PENICILLIN

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SAR OF PENICILLIN: 

SAR OF PENICILLIN BY- JYOTIRMOY DAS CHOUDHURY, (M.PHARM) DEPT. OF PHARMOCOLOGY R.C.P.H.S 1

INTRODUCTION: 

INTRODUCTION Discovered by Sir Alexander Fleming in 1929. TILL 1944 was assumed that the active principle in penicillin was a single substance and variation in the activity is due to the inert materials in it. Consist of ß- lactam ring fused with thiazolidine ring. Biosynthetic penicillin today depends chiefly on the various strains of Pencillium notatum , Pencillium chrysogenum . 2

REASONS: 

REASONS Naturally occurring Penicillin is acid labile and cannot administered orally. Improvement of stability both against ß- lactamase and gastric acid Increasing the spectrum of antibacterial activity. Improvement of pharmokinetic profile. Improvement of the action and potency against resistance strains. Decrease the side effects. 3

STRUCTURE OF PENICILLIN: 

STRUCTURE OF PENICILLIN Iupac name- 7-oxo-4-thia-1-azabicycloheptane 4

STRUCTURAL ACTIVITY RELATIONSHIP: 

STRUCTURAL ACTIVITY RELATIONSHIP 6-Aminopenicillanic acid (6-APA) Acyl side chain Thiazolidine ring b -Lactam ring 5

CONTINUED…..: 

CONTINUED….. 6

CONTINUED……: 

CONTINUED…… Basic skeleton (6-aminopencillanic acid)- Bactericidal Activity. ß- lactam ring- binding with the pencillinase binding ring in transpeptidase enzyme which is responsible for cross linking of linear peptidoglycan layer. Introduction of alpha – aryloxy alkyl (side chain)- increases the acid stability & oral absorption of penicillin. Ex- Phenoxy methyl penicillin 7

CONTINUED……….: 

CONTINUED………. Substituent on alpha carbon of side chain like-amino guanidine and chloro - resistant against acid. Ex – Ampicillin . Pka of penicillin is 2.5-3.0 Penicillin contain basic group – zwitter ion – pka 7.4 and these free acid are sparingly soluble in water. Active against gram positive organism. Amino group - confers more activity to pass through cell wall barriers 8

Continued………..: 

Continued……….. Aromatic ring attach to the carbonyl group and has some substitution on the aryl ring at the position ortho to the point of attachment- resistant to acid hydrolysis , protect the lactam ring from dregadation Ex- oxacillin , cloxacillin . Cloxacillin better absorbed than oxacillin 9

Continued………: 

Continued……… Ex Methicillin , Naficillin 2 and 6methoxy –more resistant to enzymatic hydrolysis 10

Continued………: 

Continued……… Size and type of the ortho substituent – increases the steric hindrance near the ß- lactam ring produce ß- lactamase enzyme is unable to bind with ß- lactam ring, making this analogue of pencillin more resistant against ß- lactam ring . Introduction of ionisable group at the alpha position of the side chain increase the activity, greatest activity against gram negative bacteria Ex – carbenicillin Antimicrobial activity 11

CONTINUED………: 

CONTINUED……… Sulphar of thizolidine ring replace by other atom like oxygen , methyl increased broad spectrum of antibiotic Ex – clavullinic acid 12

CONTINUED………: 

CONTINUED……… -COOH group at the position 2 nd --- can be esterified – result in the pro drug – longer duration of action Ex - talampicillin Resistant to most b - lactamases Less active vs Gram + ve bacteria (note the hydrophilic group) Acid sensitive and must be injected 13

CONTINUED……..: 

CONTINUED…….. Administered by injection Generally more active than carboxypenicillins vs. streptococci and Haemophilus species Generally have similar activity vs Gram - ve aerobic rods Generally more active vs other Gram - ve bacteria Azlocillin is effective vs P. aeruginosa Piperacillin can be administered alongside tazobactam Ex- Azlocillin Mezlocillin Piperacillin Ure a group at the Alpha-position ( ureidopenicillins ) 14

CONTINUED…………..: 

CONTINUED………….. ß-ring of penicillin ( thiazolidine ) can also be remove and result in the monobactyms which are monocyclic ß- lactam Ab. Ex – Azetreonam So the development of mono bactams indicate that minimum requirement to inhibit enzyme transpeptidase is ß- lactam ring. 15

USES: 

USES Bacteriocidal activity. Syphillis Diptheria Tetanus Gonorrhea Respiratory tract infection- ampicillin 16

LIMITATIONS : 

LIMITATIONS Develops bacterial resistance. Cannot administered orally. Can be degrade in the acidic ph. Local irritancy Hypersensitivity 17

RECENT ADVANCES: 

RECENT ADVANCES As the recent advances in antibiotic are slow , but the focus are solely on the new ways to combat the bacteria resistance and to finding ways to combat antibiotic resistance The industry responded to the challenge of rising resistance and recently developed some novel beta- lactams such as ceftobiprole , ceftaroline etc. and many beta- lactam compounds, including beta- lactamase -inhibitors, such as BMS-247243, S-3578, RWJ-54428, CS-023, SMP-601, NXL 104, BAL 30376, LK 157, and so on are under trials. 18

REFERENCES: 

REFERENCES John H.Block John M. Beale, Wilson and Gisvold’s the text book of organic medicinal and pharmaceutical chemistry eleventh edition, lipincott Williams & Wilkins. Thomas L.Lemke , Foye's Principles of Medicinal Chemistry,sixth edition, lipincott Williams & Wilkins 19

THANK YOU: 

THANK YOU 20