Amides

Amide bonds are commonly found in drug molecules. Amide bonds are less susceptible to hydrolysis than ester bonds because the carbonyl carbon of the amide bond is less electrophilic (the carbon-to-nitrogen bond has considerable double bond character) and the leaving group, an amine, is a poorer leaving group (Scheme 10). Figure 3 shows the structure

CH20PO3Na2

CH2OH

CH20PO3Na2

CH2OH

hydrocortisone disodium phosphate hydrocortisone disodium phosphate

<CH3)3N*CH2CH2Sr^

,Loc2h5

(CH^NXHjCHJSH

OOjHg

'oh echothiophate iodide

CHjONOJ CHjOH CH20N02

CH2ONOj CHJOH , CHjOH

nitroglycerin

CHjONOJ CHjOH CH20N02

CH2ONOj CHJOH , CHjOH

nitroglycerin nlcoramdil

Scheme 9. Other esters of pharmaceutical relevance susceptible to hydrolysis.

nlcoramdil

Scheme 9. Other esters of pharmaceutical relevance susceptible to hydrolysis.

Scheme 10. Hydrolysis of amides.

Scheme 10. Hydrolysis of amides.

of acetaminophen,54 chloramphenicol,13-15 lincomycin,55 indomethacin,56-59 and sulfacetamide,60 all of which are known to produce an amine and an acid through hydrolysis of their amide bonds; moricizine, a derivative of phenothiazine, which undergoes hydrolysis of its amide bonds followed by oxidation61; and HI-6, a bis(pyridimium)aldoxime having an amide bond, which exhibits fast hydrolysis in concentrated aqueous solutions owing to the acidifying effect of a strongly acidic oxime group.62

P-Lactam antibiotics such as penicillins and cephalosporins, which are cyclic amides or lactams, undergo rapid ring opening due to hydrolysis. Ring opening of the P-lactam group has been reported for penams, such as, benzylpenicillin,63-64 ampicillin,65 amoxicillin,66 carbenicillin,67 phenethicillin,68 and methicillin69 (Scheme 11), and for cephems, such as cephalothin70 cefadroxil,71-72 cephradine,70 and cefotaxime73-75 (Scheme 12). These drug substances have both a lactam and an amide bond in their molecular structure, the former being considerably more susceptible to hydrolysis. Cephalothin and cefotaxime are also acetoxy esters, and opening of their lactam ring competes with hydrolysis of the ester bond. Decomposition products produced by hydrolysis of penam and cephem P-lactams are still reactive and undergo various side reactions. For example, condensation products were formed upon hydrolysis of cefaclor,76 and dimeric products were detected upon hydrolysis of loracarbef,77 as shown in Scheme 13, as well as of ampicillin.78 Cycloserine, which can be considered a cyclic amide, undergoes opening of its isoxazolidone ring due to hydrolysis in acidic media,79 as shown in Scheme 14. Like loracarbef and ampicilllin, it also undergoes self-condensation.

The reactivity of these amides toward hydrolysis depends on the substituents R1, R2, and R3 (Scheme 10), as shown in Table 3. The P-lactam antibiotics, including penicillins and cephalosporins, undergo surprisingly facile hydrolysis compared to other amides. The

Hydrolysis Ampicillin

HI-6

Figure 3. Representative amides of pharmaceutical significance that are susceptible to hydrolysis.

Indomethacin

CH=NOH.

moricizine

HI-6

Figure 3. Representative amides of pharmaceutical significance that are susceptible to hydrolysis.

Like All Pathway
Scheme 11. Hydrolysis of B-lactam penicillins. This pathway is mostly seen in the neutral to alkaline pH range.

most likely contributors to this facile hydrolysis are electronic factors, the relief of ring strain (a four-membered ring coupled to a five- or six-membered ring), and the lower double bond character between the carbonyl carbon and the amide nitrogen.

2.1.1.3. Barbiturates, Hydantoins, and Imides

Barbiturates, hydantoins, and imides contain functional groups related to amides but tend to be more reactive. Barbituric acids such as barbital, phenobarbital, amobarbital, and metharbital undergo ring-opening hydrolysis, as shown in Scheme 15.8081 Decomposition products formed from these drug substances are susceptible to further decomposition reactions such as decarboxylation. The hydrolysis rates of these substances depend on the substituents Ri, R2, and R3. For some allylbarbituric acids, the effects of these substituents on hydrolysis rates can be explained in terms of Hammett's o value.82

Scheme 12. Hydrolysis of ß-lactam cephalosporins.
Barbital Hydrolysis
Scheme 13. Other degradation products of cefaclor and loracarbef.

Scheme 14. Hydrolysis of cycloserine.

Scheme 14. Hydrolysis of cycloserine.

Table 3. Apparent Rate Constants of Hydrolysis of Various Amides under a Variety of pH and

Temperature Conditions

Table 3. Apparent Rate Constants of Hydrolysis of Various Amides under a Variety of pH and

Temperature Conditions

k (s-1) (temperature)

pH

Reference

Benzylpenicillin

1.5 x 10-4 (25°C)

2.70

64

3.9 x 10-6 (60°C)

6.75

63

Acetaminophen

1.0 x 10-9(25°C)'

6

54

Indomethacin

2.2 x 10-4 (25.8°C)

11

58

3.9 x 10-6 (60°C)

7

59

Cephalothin

5.6 x 10-5 (35°C)

9.84

70

Cefotaxime

2.4 x 10-5 (35°C)

8.94

73

Cephradine

2 x 10-5 (35°C)

10.00

70

Phenethicillin

3.3 x 10-6 (35°C)

1.4

68

Cefadroxil

2.1 x 10-6(35°C)

7.20

71

carbenicillin

2.0 x 10-6 (35°C)

7.00

67

Amoxicillin

~1.1 x 10-6(35°C)»

8.2

66

Ampicillin

2.5 x 10-7 (35°C)

7.11

65

Moricizine

8.2 x 10-6 (60°C)

6.0

61

Lincomycin

4.9 x 10-6 (70°C)

1

55

Chloramphenicol

6.0 x 10-6 (85,36°C)

6.00

15

Sulfacetamide

9.3 x 10-6(120°C)

6.91

60

a Value of k estimated from plots in Ref. 54.

b Value of k estimated using the reported value of the activation energy (Eg).

a Value of k estimated from plots in Ref. 54.

b Value of k estimated using the reported value of the activation energy (Eg).

Stability Amides
Scheme 15. Hydrolysis of barbituric acids.

As shown in Scheme 16, the hydantoin allantoin83 is susceptible to hydrolysis, and the imide bonds in NSC-28435684 and (+)-1,2-bis(3,5-dioxopiperazinyl-l-yl)propane (ICRF-187)8586 are hydrolyzed by parallel and successive reactions. In the case of ICRF-187, the reactivity of the imide groups is intramolecularly affected by the tertiary amine groups in its structure.85 86 This conclusion was drawn from the observation that model compound A

Bioisosters Drug Discovery
Scheme 16. Imides of pharmaceutical significance susceptible to hydrolysis.
Stability Amides
Scheme 17. Hydrolysis of benodiazepines.
Scheme 18. Hydrolysis of chlordiazepoxide.

(Scheme 16) hydrolyzed, as expected, at approximately half the rate of ICRF-187, whereas the glutarimide, compound B, was significantly more stable.

2.1.1.4. Schiff Base and Other Reactions Involving Carbon-Nitrogen Bond Cleavage

Benzodiazepines such as diazepam,87 oxazepam,87 and nitrazepam88 89 undergo ring opening due to reversible hydrolysis of the amide and azomethine bonds, as shown in Scheme 17. Chlordiazepoxide is converted to a lactam form, which is then similarly hydrolyzed (Scheme 18).9091 Triazolam, a triazole-condensed benzodiazepine, also undergoes ring opening due to hydrolysis, as shown in Scheme 19.92 Benzodiazepinooxazoles (oxazole-condensed benzodiazepines) such as oxazolam,93 flutazolam,94 haloxazolam,94 and cloxazolam94 are not Schiff bases per se but undergo ring opening due to hydrolysis as shown

Stability Drug Time Points
Scheme 19. Hydrolysis of triazolam.

Scheme 21. Representative drug substances having a reactive nitrogen in their structure that are susceptible to hydrolysis.

CH3CHCOOH CHjCHCOOH CHjCHCOOH CHaCHCOOH

CH3CHCOOH CHjCHCOOH CHjCHCOOH CHaCHCOOH

3,4-dihydro-1,3-benzoxazine derivative 3,4-dihydro-1,3-pyridooxazine derivative

3,4-dihydro-1,3-benzoxazine derivative 3,4-dihydro-1,3-pyridooxazine derivative

Scheme 22. Hydrolysis of dihydrooxazines.

in Scheme 20. The oxazolidine ring of these drugs is known to exhibit an acid-base equilibrium reaction between ring opening and closing.95-97

Drug substances such as sulpyrine,98 99 furosemide,100101 thiamine hydrochloride,102 diethylpropion,103 mitomycin C,104 105 zileuton,106 and cifenline107 have reactive nitrogens in their molecular structure and undergo hydrolysis, as shown in Scheme 21. The derivatives of 3,4-dihydro-1,3-benzoxazine and 3,4-dihydro-1,3-pyridooxazine undergo ring opening due to hydrolysis accompanied by elimination of formaldehyde (Scheme 22).108

Nitrofurantoin109-110 and rifampicin111 undergo hydrolysis of the iminelike structure as shown in Scheme 23. Similarly, chlorothiazide112 and hydrochlorothiazide113,114 undergo ring opening due to hydrolysis by acid-base catalysis (Scheme 24). Nucleosides115 such as 5-azacytidine116117 and cytarabine118119 form various hydrolysis products through different reactions (such as ring opening) depending on the conditions, as shown in Scheme 25.

2.1.1.5. Other Hydrolysis Reactions

Other drug substances susceptible to hydrolysis include chloramphenicol,13 chloram-bucil,120121 spirohydantoin mustard,122 alkyl halides such as clindamycin,123 azathio-prine,124 sulfides such as thimerosal,125-126 and platinum compounds such as carboplatin,127 as shown in Scheme 26.

Drug substances with carbohydrate moieties, such as digoxin,128,129 eliminate the carbohydrate group(s) due to acid-catalyzed hydrolysis. Nucleosides such as 5-azacytidine

rifampicin

Scheme 23. Hydrolysis of other drug substances having a reactive nitrogen in their structure.

rifampicin

Scheme 23. Hydrolysis of other drug substances having a reactive nitrogen in their structure.

HjNOJS

chlorothiazide

CIn^s^NH, hydrochlorothiazide

HjNOJS^^SOJNHJ

Scheme 24. Hydrolysis of chlorothiazide and hydrochlorothiazide.

and cytarabine (Scheme 25) exhibit sugar-elimination reaction130 in addition to the ring-opening reactions described earlier. Idoxuridine131 and 2',3'-dideoxyguanosine132 undergo rapid hydrolysis in alkaline and acidic pH ranges, respectively (Scheme 27). 4'-Azi-dothymidine undergoes similar hydrolysis.133 06-Benzylguanine hydrolyzes to benzyl alcohol and guanine in an acid-catalyzed reaction.134

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Responses

  • iago
    Which functional group is hydrolysis likely to occur in indomethacin?
    2 years ago
  • amy watt
    Which drugs are amides?
    7 months ago
  • ferdinanda
    What pharmaceutical products are amides in?
    30 days ago

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