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Epicillin

A semisynthetic penicillin, structurally related to ampicillin [1]. has been assigned the generic name epicillin, 6-[D-2-amino-2-(1 ,4-cyclohexadienyl)acetamido]-penicillanic acid. The antimicrobial spectrum and level of activity of epicillin in vitro are similar to those of ampicillin.

Therapeutic use


 

 

Dosage and Administration

 

Toxicology

Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
mouse LD50 intraperitoneal 3870mg/kg (3870mg/kg)   Medicamentos de Actualidad. Vol. 9, Pg. 100, 1973.

 

Pharmacokinetic

 

Bioavailability  
Protein binding 10-30%
Metabolism  
Half-life  
Cmax (mg/ml)  
tmax (hrs)  
Distribution volume Vd  
Clearance  
Excretion  

Absorption

 

Distribution


Excretion

 

Metabolism

 

Mechanism of Action

 

Antibacterial activity

Epicillin was inactivated by the b-lactamases from certain strains of Staphylococcus and Bacillus known to elaborate these enzymes. The antimicrobial activity of epicillin in comparison to ampicillin is reported in table 1, while table 2 reports the comparison of the susceptibility of various clinical bacterial isolates to epicillin, ampicillin, and carbenicillin.

Table 1. Antimicrobial spectrum of epicillin and ampicillin in vitro

Organism

MIC (mg/ml)

  epicillin ampicillin
S.aureus SC2399 (non penicillinase producer) 0.2 0.1
S.aureus SC2400 (penicillinase producer) >50 >50
S.epidermidis ATCC12228 0.2 0.1
Streptococcus pyogenes SC3862 0.004 0.006
S.viridans SC9026 0.6 0.8
S.faecalis ATCC10541 0.5 0.6
Diplococcus pneumoniae ATCC6303 0.02 0.03
Listeria monocytogenes SC8523 0.2 0.2
Corynebacterium diphtheriae ATCC19409 0.15 0.2
C.xerosis SC3638 0.1 0.1
Clostridium tetanomorphum SC3103 0.2 0.1
C.histolyticum SC8572 0.8 1.6
C.novyi ATCC9690 0.1 0.1
Bacillus anthracis ATCC14578 0.6 1.3
Actinomyces israelii ATCC10048 0.2 0.2
Escherichia coli SC8294 1.4 1.4
Salmonella typhosa SC1195 0.3 0.2
S. schottmuelleri SC3850 0.2 0.1
S. gallinarum SC3030 1.2 1.2
S.typhimurium SC3821 0.5 0.4
S. paratyphi ATCC11511 0.2 0.2
Shigella flexneri SC1462 0.4 0.5
S. sonnei SC8445 1.6 1.6
S. dysenteriae SC1572 0.3 0.3
Proteus vulgaris SC8504 2.0 2.0
P. morganii SC8217 15.6 28.1
P. rettgeri SC9186 50 50
P. mirabilis SC3873 1.2 0.6
Klebsiella spp. SC8495 1.6 1.0
K. pneumoniae SC8411 18.7 18.7
Enterobacter cloacae SC8236 0.6 0.6
Herellea spp. SC1468 6.3 9.4
Serratia marcescens SC1468 14 18.7
Pseudomonas aeruginosa SC8329 9.4 25
Pasteurella multocida SC8826 0.1 0.1
Bordetella pertussis ATCC9797 0.1 0.1
Haemophilus influenzae ATCC9333 0.3 0.2
Neisseria meningitidis SC6238 1.6 1.6
N. gonorrhoeae SC8586 0.1 0.1
Brucella abortus ATCC17384 0.3 0.3
B. suis ATCC4312 0.6 0.5
Bacteroides funduliformis ATCC12990 9.4 4.7

Table 2. Comparison of the susceptibility of various clinical bacterial isolates to epicillin, ampicillin,
and carbenicillin

Organism Drug n.of strains

No. of bacterial isolates susceptible at MIC (mg/ml)

      <0.1 0.2-0.8 0.9-3.2 3.3-12.5 12.6-50 >50
S.aureus epicillin 13 4 9        
  ampicillin 13 4 9        
  carbenicillin 13   5 6 1 1  
S.pyogenes epicillin 34 33   1      
  ampicillin 34 31 2 1      
  carbenicillin 34   6 21 7    
E.coli epicillin 40   2 31 4 1 2
  ampicillin 40     34 3 1 2
  carbenicillin 40     2 18 17 3
Klebsiella-Enterobacter spp. epicillin 17     1 1 6 9
  ampicillin 17     1 1 7 8
  carbenicillin 17       3 3 11
Proteus spp. epicillin 49   40 3 3 1 2
  ampicillin 49   40 3 2 2 2
  carbenicillin 49   18 24 4 3  

Epicillin, like all penicillins, is a bactericidal drug as shown in studies with Staphylococcus, Streptococcus, Escherichia, Proteus, Shigella, Enterobacter, and Pseudomonas (Table 3). The relationship between MBC and MIC was qualitatively and quantitatively similar to that shown by ampicillin.

Table 3. Comparison of the bacteriostatic and bactericidal activities of epicilliin and ampicillin

Organism epicillin ampicillin
  MIC MBC ratio MIC MBC ratio
Staphylococcus aureus 0.01 0.06 6 0.01 0.04 4
Streptococcus faecalis 0.45 1.6 3 0.6 1.6 2
Escherichia coli 1.3 6.3 5 1.3 6.3 5
Proteus mirabilis 0.8 1.6 2 0.5 1.6 3
Shigella flexneri 0.3 0.4 1 0.45 0.4 1
Enterobacter aerogenes 18.7 18.7 1 18.7 31.2 2
Pseudomonas aeruginosa 9.4 18.0 2 25 100 4

In vivo efficacy

Table 4 show the efficacy data in a mouse model of infection using both Gram-positive and negative strains using epicillin either orally or subcutaneously [2].

Table 4. Chemotherapeutic activity of epicillin in experimental bacterial infections in mice

Strain Geometric mean of ED50 (mg/kg)a
Oral Subcutaneous
Streptococcus pyogenes SC3862 1.7 (1.4-2.3) 0.2 (0.15-0.25)
Staphylococcus aureus SC 2399 (non penicillinase producer) 3.2 (2.6-3.9) 0.15 (0.1-0.23)
Staphylococcus aureus SC 2400 (penicillinase producer) 1,250 (740-2,200)  
Diplococcus pneumoniae SC 5479 3.4 (2.6-4.5)  
Escherichia coli SC 8294 55 (37-106) 55 (37-106)
Proteus mirabilis SC 3873 15 (13-20) 13.2 (11-18)
Salmonella schottmuelleri SC 3850 16 (13-42) 14.8 (10-20)
Pseudomonas aeruginosa SC 8327 >800 413 (402-459)

a) Confidence limits (95%) in parentheses.

 

Other pharmacological effects

 

Chemical synthesis

Scheme 1 shows the synthesis of epicillin starting from penicillanic acid and (D)-phenylglycine [3].

Scheme 1. Synthesis of epicillin.

 


Medicinal Chemistry

CAS number: 26774-90-3  EINECS:  248-001-7

Molecular Formula:  C16H21N3O4S

Average mass: 351.420593 Da

Monoisotopic mass:  351.125275 Da

Systematic name: (2S,5R,6R)-6-{[(2R)-2-Amino-2-(1,4-cyclohexadien-1-yl)acetyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

SMILES: CC1([C@@H](N2[C@H](S1)[C@@H](C2=O)NC(=O)[C@@H](C3=CCC=CC3)N)C(=O)O)C

Std. InChI: 1S/C16H21N3O4S/c1-16(2)11(15(22)23)19-13(21)10(14(19)24-16)18-12(20)9(17)8-6-4-3-5-7-8/h3-4,7,9-11,14H,5-6,17H2,1-2H3,(H,18,20)(H,22,23)/t9-,10-,11+,14-/m1/s1

ACD/LogP: 1.900.40 # of Rule of 5 Violations: 0
ACD/LogD (pH 5.5): -0.61 ACD/LogD (pH 7.4): -1.15
ACD/BCF (pH 5.5): 1.00 ACD/BCF (pH 7.4): 1.00
ACD/KOC (pH 5.5): 1.00 ACD/KOC (pH 7.4): 1.00
#H bond acceptors: 7 #H bond donors: 4
#Freely Rotating Bonds: 5 Polar Surface Area: 138.03 2
Index of Refraction: 1.66 Molar Refractivity: 90.60.4 cm3
Molar Volume: 245.25.0 cm3 Polarizability: 35.90.5 10-24cm3
Surface Tension: 70.85.0 dyne/cm Density: 1.40.1 g/cm3
Flash Point: 348.731.5 C Enthalpy of Vaporization: 104.96.0 kJ/mol
Boiling Point: 653.055.0 C at 760 mmHg Vapour Pressure: 0.04.2 mmHg at 25C

 

Major Impurities:

Appearance: white crystalline powder

Melting point: decompose at 202C (hemihydrate)

Optical rotation:

Solubility:

logP:

pKa: 7.62
 

Stability: epicillin is stable at 37C for 24 hrs at pH ranging between 2 and 8.

 


1. Basch H.,Erickson R., Gadebusch H. "Epicillin: In Vitro Laboratory Studies". INFECTION AND IMMUNITY 4, (1) 44-49, (1971).

2. Gadebusch H., Miraglia G., Pansy F., Renz K. "Epicillin: Experimental Chemotherapy, Pharmacodynamics, and Susceptibility Testing". INFECTION AND IMMUNITY, 4, (1), 50-53, (1971).

3. Schwartz J.,  and Weisenborn F. L. "A new class of semisynthetic penicillins and cephalosporins derived from D-2-(1 ,4-cyclohexadienyl)glycine". J. Med. Chem. 14:117-
119, (1971).

 

 

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